Chronic venous disease, platelet and haemostatic abnormalities contribute to the pathogenesis of pigmented purpuric dermatoses.

BACKGROUND: To investigate the aetiology of pigmented purpuric dermatoses (PPD). METHODS: 63 patients with a provisional diagnosis of PPD were assessed. Skin biopsies were performed to confirm the clinical diagnosis. Haemostasis was assessed using platelet function analyser-100 (PFA-100), light transmission aggregometry (LTA), impedance aggregometry (Multiplate) and measurement of clotting times and clotting factors. Chronic venous disease (CVD) was assessed by duplex ultrasound. When not contraindicated, patients were advised to discontinue haemostatic-modifying drugs or supplements for 4 weeks after which the laboratory measurements were repeated and the clinical resolution of PPD was assessed. Subsequently, a cohort of patients identified with CVD underwent endovenous interventions and further resolution of PPD was assessed. RESULTS: CVD was found in 48 patients (76.2%) while haemostatic abnormalities were found in 36 (57.1%). 30 patients (47.6%) had concurrent CVD and haemostatic abnormalities. Modifiable risk factors such as the intake of platelet inhibitors or other drugs and supplements such as fish oil were identified in 53 patients (84.1%). These could be ceased in 35 patients of whom 28 (80.0%) achieved either complete or partial resolution of PPD. Treatment of the underlying CVD was performed in 18 patients resulting in complete or partial resolution in 17 (94.4%). In seven patients (11.1%), no CVD or haemostatic abnormalities were identified, and the risk factors included dietary factors such as excessive caffeine or soft drink consumption. CONCLUSION: Haemostatic abnormalities and CVD contribute to the pathogenesis of PPD. Resolution of PPD in the vast majority of patients may be achieved by cessation of modifiable risk factors and in particular platelet-modifying drugs or supplements and treatment of the underlying venous disease.

Design, fabrication, and characterization of graft co-polymer assisted ocular insert: a state of art in reducing post-operative pain.

PURPOSE: Targeted delivery of drugs at appropriate concentrations to ocular tissues is required to avoid wastage. Hence, advanced systems that maximize the release of poorly soluble drugs and deliver them at ocular sites must be designed. METHODS: In this study, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol-graft copolymer) was selected as a solubilizer as well as film former for preparing ocular inserts and polyethylene glycol 400 (PEG-400) as a plasticizer. On the basis of an initial phase solubility study, the maximum concentration of Soluplus® possible was used for developing the inserts. An optimized formulation was obtained using a 32-factorial design. Two factors at three levels were used to design the ocular inserts. Soluplus® (X 1) and the plasticizer, PEG-400 (X 2), were set as the independent variables at various levels, and the Rel4h (drug release in 4 h, Y 1) and tensile strength (Y 2) were set as the dependent variables. A pre-formulation study was conducted to select suitable materials. RESULTS: Various physico-chemical parameters of the optimized formulation, including the tensile strength and folding endurance, were studied using FT-IR, DSC, XRD, and SEM. An in vitro dissolution study was conducted to determine the amount of drug released. There was no redness, swelling, or watering of the rabbit eye. CONCLUSION: It was concluded that the ocular inserts of the poorly soluble nepafenac developed using a graft-co-polymer enhanced the solubility and utilization of the drug for a prolonged period.

Telangiectatic Matting is Associated with Hypersensitivity and a Bleeding Tendency.

OBJECTIVE: The aim was to investigate the pathogenesis of telangiectatic matting (TM) and identify possible risk factors. METHODS: This study had two parts. The clinical records of consecutive patients were retrospectively analysed to identify risk factors for TM. In the second part, the haemostatic and coagulation profile of the subset of patients with TM were analysed and compared with controls using standard coagulation tests, platelet function and a global assay of coagulation (rotational thromboelastometry, ROTEM). RESULTS: In 352 consecutive patients presenting to a phlebology practice, 25 patients had TM (7.1%). All 25 patients were female with the median age of 45 (27-57) years. A comprehensive medical history was taken. Among 27 possible risk factors assessed, statistically significant associations included recurrent epistaxis, easy bruising, hypersensitivity (eczema, hives, hay fever, and rhinitis), previous treatment with sclerotherapy or endovenous laser for lower limb veins, and a family history of telangiectasias. Variables not associated with TM included oral contraceptive intake, hormone replacement therapy, and age. The haemostatic and coagulation profile of 12 patients (6 male and 6 female) with TM did not differ significantly from those without TM. CONCLUSION: TM is associated with both hypersensitivity and a bleeding tendency. This study revealed no significant increase in the incidence of haemostatic abnormalities in patients with TM compared with the control group. Given the significant association with hypersensitivity disorders, the underlying mast cell hyper-reactivity may contribute to both hypersensitivity and a bleeding tendency and predispose patients to TM.

Detection of Beta-Human Papillomavirus in a Child With Polyomavirus-Associated Trichodysplasia Spinulosa.

Viral associated trichodysplasia spinulosa (VATS) is a rare cutaneous eruption characterized by folliculocentric papules, keratin spicules, and alopecia associated with trichodysplasia spinulosa-associated polyomavirus (TSPyV) infection. We report a case of a 6-year-old male child who presented with a generalized papular eruption during chemotherapy for acute lymphoblastic leukemia. The papules were tested for human papillomavirus (HPV) DNA by nested polymerase chain reaction (PCR) and TSPyV using PCR and gene sequencing studies. The lesions were positive for TSPyV by PCR combined with sequencing and showed high copy number with real-time PCR, and beta-papillomavirus was identified by PCR and sequencing. Immunohistochemistry revealed inner root sheath keratinocytes expressing nuclear HPV L1 capsid antigen. To our knowledge, this is the first case of concomitant productive HPV and TSPyV infection in a VATS-affected patient. The presence of HPV may be coincidental, however, further studies are needed to establish whether specific HPV genotypes influence the development of abnormal inner root sheath trichohyalin granules found in VATS.

Beta Human Papillomavirus Infection Is Prevalent in Elephantiasis and Exhibits a Productive Phenotype: A Case-Control Study.

Elephantiasis is considered a cutaneous region of immune deficiency with cobblestone-like surface caused by a wart-like eruption. Verrucosis is a diffuse human papillomavirus (HPV) infection linked to immunodeficiency disorders. The objective of this study was to examine the prevalence of HPV infection in lymphedema and its pathogenic role in elephantiasis. A retrospective case-control study was performed examining lymphedematous skin and controls of peritumoral normal skin. HPV infection was evaluated at the DNA, protein, and histopathologic levels by polymerase chain reaction, immunohistochemistry, and light microscopy, respectively. Overall, 540 HPV DNAs were detected in 120 of 122 cutaneous samples (median 4 HPV DNAs per sample, range 0-9). Compared with controls, no differences existed in type or number of HPVs identified. Instead, a diverse spectrum of HPV-related histopathologies were evident, likely reflecting the multiplicity of HPV genotypes detected. Most notably, increasing histopathologic lymphedema stage significantly correlated with markers of productive HPV infection such as altered keratohyaline granules and HPV L1 capsid expression. Limitations of this study are the absence of normal skin controls not associated with neoplasia or subclinical lymphedema, and lack of assessment of HPV copy number per keratinocyte infected. In conclusion, productive HPV infection, not HPV type or numbers detected, distinguished lymphedematous skin from controls. These findings support the theory that lymphedema creates a region of depressed immunity that permits productive HPV infection, manifested clinically by diffuse papillomatosis, characteristic of elephantiasis.

Subcutaneous nodules are associated with cardiovascular events in patients with rheumatoid arthritis: results from a large US registry.

Subcutaneous nodules are the most common conspicuous extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) is the leading cause of death in patients with RA. The objective of this study is to examine the possibility of a relationship between subcutaneous nodules and "first ever" cardiovascular disease event, i.e., myocardial infarction (MI), stroke, or cardiovascular death in a large registry-cohort of patients with RA. Patient information was collected from the CORRONA registry from October 2001 to September 2011. A total of 26,042 patients with RA were studied for the presence or absence of subcutaneous nodules. Cox proportional hazards regression models were constructed to estimate the hazard ratios (HR) for CVD events in relation to subcutaneous nodules at baseline. Three statistical models were used to examine the association between subcutaneous nodules and CVD: Model A adjusted for age and sex associated risk, model B adjusted for traditional CV risk factors, and model C adjusted for factors in models A and B plus underlying RA-specific measures. The definition of primary exposure was "subcutaneous nodules at baseline." A total of 3908 patients had subcutaneous nodules at baseline. Of the 566 total composite CVD events, 138 occurred in the group that had SCN at baseline. Incidence rate-ratio values (patients with subcutaneous nodules at baseline vs. no subcutaneous nodules at baseline) for composite CVD events, MI, stroke, and cardiovascular death were 1.55, 1.65, 1.37, and 1.68, respectively. Adjusted HR values (95 % CI) for composite CVD events based on "subcutaneous nodules-status at baseline" (primary exposure) were as follows: 1.35 (1.11-1.63) for model A, 1.25 (1.03-1.52) for model B, and 1.03 (0.831-1.277) for model C. Subcutaneous nodules were associated with increased CVD events in RA. This association persisted after adjusting for age, sex, and traditional CV risk factors.

Delayed onset of the Jarisch-Herxheimer reaction in doxycycline-treated disease: a case report and review of its histopathology and implications for pathogenesis.

The Jarisch-Herxheimer reaction (JHR) is a transient inflammatory syndrome triggered hours after the start of antibiotic treatment of spirochete infections, namely syphilis. Clinically, JHR manifests as an abrupt onset of constitutional symptoms and exacerbation of cutaneous lesions that resolve without intervention. JHR's pathogenesis is unclear and it is histopathologically rarely reported. Herein, the authors report a 47-year-old woman, with solitary erythema migrans and positive Lyme disease serology, who presented for medical care 14 days after commencement of doxycycline therapy. She complained of malaise, facial flushing, gingival erythema, and acquisition of additional plaques characterized by swelling, increased erythema, pruritus, and exfoliative scale. Punch biopsies demonstrated subacute to chronic spongiotic psoriasiform reaction patterns with a superficial lymphocytic infiltrate. By Borrelia-specific immunohistochemistry, spirochetes were found in the deep dermis, unassociated with inflammation, and focally in the upper spinous layer, associated with spongiosis. Borrelia burgdorferi DNA was detected by nested polymerase chain reaction. Doxycycline was discontinued, and symptoms and signs resolved within a few days. Liberation of endotoxin-like materials (eg, lipoproteins) from degenerating spirochetes and concomitant cytokine production is the suspected cause of JHR and supported by the finding of lesional spirochetes. Alternatively, a reversal reaction with a delayed-type hypersensitivity reaction is also a plausible cause based on spirochetes found in the lymphocytic spongiotic dermatitis.

Adolescent Onset of Localized Papillomatosis, Lymphedema, and Multiple Beta-Papillomavirus Infection: Epidermal Nevus, Segmental Lymphedema Praecox, or Verrucosis? A Case Report and Case Series of Epidermal Nevi.

Herein, we report the case of a 12-year-old female who noted the recent onset of an oval, circumscribed, 10-cm papillomatous plaque affecting the thigh and vulva that showed histologic signs of lymphedema without evidence of secondary lymphedema. The sequencing of genes associated with a delayed onset of lymphedema or epidermal nevi (EN) - GATA2 and GJC2, and HRAS and KRAS, respectively - showed wild-type alleles. Polymerase chain reaction for human papillomavirus (HPV) DNA demonstrated infections with 15 HPV genotypes. Evidence of productive HPV infection, HPV capsid expression, and cytopathic changes was detected. At the 6-month follow-up, no evidence of recurrence was found after complete excision. The analysis of a consecutive series of 91 EN excision specimens revealed that 76% exhibited histologic evidence of lymphostasis. Notably, multiple acrochordon-like EN, which most closely resembled this case, showed similar signs of localized lymphedema. The late onset and evidence of lymphedema favors the diagnosis of congenital unisegmental lymphedema. However, the clinical findings and epidermal changes point to the diagnosis of EN. Moreover, localized verrucosis also accurately describes this patient's cutaneous findings. Based on the above evidence, we postulate that an abnormal development of lymphatics may play a primary role in the pathogenesis of some types of EN and facilitate productive HPV infection.