The differing pathophysiologies that underlie COVID-19-associated perniosis and thrombotic retiform purpura: a case series.

BACKGROUND: There are two distinctive acral manifestations of COVID-19 embodying disparate clinical phenotypes. One is perniosis occurring in mildly symptomatic patients, typically children and young adults; the second is the thrombotic retiform purpura of critically ill adults with COVID-19. OBJECTIVES: To compare the clinical and pathological profiles of these two different cutaneous manifestations of COVID-19. METHODS: We compared the light microscopic, phenotypic, cytokine and SARS-CoV-2 protein and RNA profiles of COVID-19-associated perniosis with that of thrombotic retiform purpura in critical patients with COVID-19. RESULTS: Biopsies of COVID-19-associated perniosis exhibited vasocentric and eccrinotropic T-cell- and monocyte-derived CD11c+ , CD14+ and CD123+ dendritic cell infiltrates. Both COVID-associated and idiopathic perniosis showed striking expression of the type I interferon-inducible myxovirus resistance protein A (MXA), an established marker for type I interferon signalling in tissue. SARS-CoV-2 RNA, interleukin-6 and caspase 3 were minimally expressed and confined to mononuclear inflammatory cells. The biopsies from livedo/retiform purpura showed pauci-inflammatory vascular thrombosis without any MXA decoration. Blood vessels exhibited extensive complement deposition with endothelial cell localization of SARS-CoV-2 protein, interleukin-6 and caspase 3; SARS-CoV-2 RNA was not seen. CONCLUSIONS: COVID-19-associated perniosis represents a virally triggered exaggerated immune reaction with significant type I interferon signaling. This is important to SARS-CoV-2 eradication and has implications in regards to a more generalized highly inflammatory response. We hypothesize that in the thrombotic retiform purpura of critically ill patients with COVID-19, the vascular thrombosis in the skin and other organ systems is associated with a minimal interferon response. This allows excessive viral replication with release of viral proteins that localize to extrapulmonary endothelium and trigger extensive complement activation.

Electrodialytic treatment of secondary mining resources for raw materials extraction: Reactor design assessment.

The sustainability of mining activities is compromised due to the high amounts of mining residues generated that have to be disposed of, often in open dams, that may cause environmental deterioration, e.g. release of toxic elements to water supplies. These residues are, however, secondary resources of raw materials. In the case of Panasqueira mine, they even are a source of tungsten, considered a critical raw material. The present work aims to assess the electrodialytic process efficiency for raw materials extraction from Panasqueira mine residues. Experiments were performed with 2 and 3-compartment electrodialytic reactors, applying current intensities between 50 and 100 mA, from 4 to 14 days, and sample suspensions enhanced with NaCl or effluent. Additionally, control experiments with no current application were carried out. The results showed that a 3-compartment reactor operating at 100 mA, with NaCl as supporting electrolyte, presented the highest extraction of copper (13%), tin (10%), tungsten (13%) and arsenic (63%).

Clinical evaluation of the synbiotic Prodefen Plus® in the prevention of the antibiotic-associated diarrhoea in subjects requiring antibiotic treatment.

Prodefen® is a dietary food supplement formulated as a synbiotic that has shown additional benefit to the standard supportive therapy in the management of acute viral diarrhoea in children. There is scarce evidence of this synbiotic in adults. The objective of this randomised double blind placebo-controlled clinical trial was to evaluate the efficacy and safety of Prodefen Plus® in the prevention of antibiotic-associated diarrhoea (AAD) in an adult population requiring either antibiotic treatment for an oral infection or antibiotic prophylaxis for a dental surgical procedure in a dental consultation. 151 subjects were randomised to the active (synbiotic) or control arm (placebo) for 14 days. There was a significantly higher reduction in the AAD incidence, and an improvement in the stool consistency in the active group. A higher reduction in both the frequency and duration of the diarrhoea episodes in the active group was also observed, as it was an improved perception of the diarrhoea severity. Overall, the study medication was well tolerated. In conclusion, results from this study confirm the beneficial effect of the synbiotic administered as adjuvant therapy in preventing the antibiotic-associated diarrhoea.

S100B as a new fecal biomarker of inflammatory bowel diseases.

OBJECTIVE: S100 proteins are demonstrated to exert a protective role in the gastrointestinal tract. In the present study, we investigated whether S100B protein, that is typically expressed by enteroglial cells, is detectable in feces and could be a useful noninvasive indicator of gut chronic inflammation. PATIENTS AND METHODS: This clinical prospective study included n=48 patients suffering Crohn's disease (CD) or ulcerative colitis (UC) and non IBD-controls. The clinical disease activity was evaluated using Harvey-Bradshaw or Mayo Score Index while the diagnosis of IBD was defined based on standard endoscopic and histological criteria. S100B and calprotectin were extracted and analyzed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: Unlike calprotectin, S100B was significantly decreased in both CD and UC compared to non IBD-patients. The strongest quantitative alterations of S100B were detected concomitantly with signs of active or quiescent disease, including high/normal expression of fecal calprotectin, mucosal damage/cryptitis, mucin depletion and inflammatory infiltrate, as defined by endoscopic evaluation and histological analysis. At the onset of disease and under no Infliximab-based therapy, the lowest was detected suggesting that S100B in feces could have a potential diagnostic value for IBD. CONCLUSIONS: Testing for S100B and calprotectin could be a useful screening tool to better predict IBD activity.

Sustainability of construction materials: Electrodialytic technology as a tool for mortars production.

The reduction of tap water consumption in all activity sectors, including the building industry, is crucial to the sustainability of water resources. Effluents from wastewater treatment plants have the potential to replace freshwater in the construction sector but they contain a critical mixture of impurities, which hampers their use in mortars production. In this work, the viability of using effluent as an alternative to potable water for the production of mortars, after electrodialytic treatment, was assessed. Electrodialytic technology (ED-T) is a proven technique for decontamination of porous and aqueous matrices. ED-T experiments were conducted with 500 mL of effluent for 6, 12 and 24 h, with a current intensity of 25 mA. The results showed that after ED-T 6 h, the removal efficiencies of critical components were above 85% of their initial concentrations. Mortar properties such as setting time, workability, flexural strength, compressive strength and morphology were obtained for 100% effluent and tap water/effluent mixtures (50:50) with and without ED-T pre-treatment. The mortars with the ED-T treated effluent showed similar initial setting times and workability, higher flexural and compressive strength compared to the mortars reference.

Angiolymphoid hyperplasia with eosinophilia of the nail unit.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a distinctive lymphocyte rich vasoformative proliferation comprising epithelioid-appearing endothelial cells with partially canalized capillary vessels in a lymphohistiocytic and eosinophil rich environment. ALHE presents clinically as single or multiple pink-brown dome-shaped papules or nodules, most commonly on the ear and peri-auricular area, followed by the face, and scalp. ALHE involving the subungual unit is rare with only 5 previously reported cases and all involved the underlying bone. The authors describe a case of a painful subungual nodule of the left 1st fingernail in a 48-year-old woman. An excisional biopsy was performed confirming a diagnosis of ALHE. There was no bone involvement and immediately following excision of the tumor, there was complete resolution of her symptoms. Our patient's presentation expands upon the clinical and histopathological spectrum of subungual ALHE.

Benign atrophic papulosis (Köhlmeier-Degos disease): the wedge-shaped dermal necrosis can resolve with time.

BACKGROUND: Atrophic papulosis is a rare thrombo-occlusive disease, characterized by the appearance of multiple atrophic porcelain-white skin papules, with a surrounding erythematous rim, which are histologically consisting of wedge-shaped necrosis of the dermis. OBJECTIVE: It consists of two variants: (i) the benign atrophic papulosis (BAP) only involving the skin and (ii) the malignant atrophic papulosis (MAP) also involving several internal organs with a cumulative five-year survival rate of approx. 55%. While the probability of only having a BAP at onset is approximately 70%, increasing to 97% after 7 years of monosymptomatic cutaneous course, no close long-term follow-up of the development of the skin lesions has been reported. METHODS: We present a precise visual documentation of the evolution of the disseminated skin lesions in a female patient with BAP spanning over two decades. RESULTS: A considerable improvement and/or clinical resolution of the majority of the lesions disputing the scarring character of the atrophic porcelain-white skin papules has been detected. CONCLUSION: BAP not only exhibits an excellent prognosis, but resolution of lesions can also occur after a considerable period of time.

Hydrogel coated mesh decreases tissue reaction resulting from polypropylene mesh implant: implication in hernia repair.

PURPOSE: Use of polypropylene mesh (PPM) in hernia repair is associated with tissue reactivity. We examined, in a rat model, a novel non-biodegradable hydrogel coated PPM which may allow for decreased inflammation and a decreased foreign body reaction. METHODS: Through a dorsal midline incision, a 2 cm × 2 cm section of PPM (either coated or uncoated) was placed on the fascial surface 1.5 cm from the incision on the dorsal wall of Sprague-Dawley rats. At 2 and 12 weeks after placement, the PPM and surrounding tissue were harvested. A board-certified dermatopathologist examined H&E stained slides for fibrosis and foreign body reaction. In addition, tissues were stained for apoptotic cells, oxidative damage, macrophages, fibroblasts, neovascularization and metalloproteases. RESULTS: At 2 and 12 weeks, there was a greater than 95 % decrease in foreign body giant cells in coated PPM samples compared to uncoated; fibrosis was decreased by 50 %. At 2 and 12 weeks, oxidative damage, fibroblast accumulation, apoptosis and macrophages were significantly decreased in coated PPM samples compared to uncoated PPM. CONCLUSION: These results demonstrate that a non-biodegradable hydrogel coating of PPM led to significant reduction in foreign body reaction, oxidative stress and apoptosis compared to uncoated PPM in vivo, and suggest that this coating could be clinically useful in hernia repair.

Pharmacokinetics and preliminary efficacy of two vaginal gel formulations of ultra-low-dose estriol in postmenopausal women.

OBJECTIVES: To investigate the pharmacokinetics, safety and preliminary effectiveness of ultra-low-dose estriol vaginal gel formulations (20 µg/g (T1) and 50 µg/g (T2)) compared to Ovestinon® (estriol 500 µg/0.5 g (R)) and placebo in postmenopausal women. METHODS: Forty-three volunteers were randomly assigned to received T1, T2, R or placebo once daily for 21 days. Absorption of estriol after single and multiple administration was analyzed. Cytological changes in the vagina, tolerability and safety were also investigated. RESULTS: Thirty-six women were included in the pharmacokinetic analysis. Systemic absorption was lower with test formulations (AUC0-t: 171.65 ± 80.18 (T1) and 406.75 ± 199.53 (T2) pg/ml × h) than with Ovestinon® (1221.97 ± 549.06 pg/ml × h). Estriol exposure of the test formulations after multiple administration (AUCss: 36.33 ± 30.52 (T1) and 73.71 ± 46.86 (T2) pg/ml × h) was significantly lower than after single-dose administration and not significantly different between them. In contrast, the exposure after repeated administration of Ovestinon® was considerable and not statistically different from levels after single administration. All estriol formulations produced similar improvement in the vaginal maturation value, while placebo showed a small and not significant change. Overall safety and acceptability were good. CONCLUSIONS: Estriol 20 and 50 µg/g formulations, while showing a comparable capacity for reversing vaginal atrophy, present a highly favorable safety profile, producing a very low systemic absorption of estriol and significantly lower than that of Ovestinon®.

Laparoscopy shows superiority over endoscopy for early detection of malignant atrophic papulosis gastrointestinal complications: a case report and review of literature.

BACKGROUND: The malignant form of atrophic papulosis (Köhlmeier-Degos disease) is a rare thrombo-occlusive vasculopathy that can affect multiple organ systems. Patients typically present with distinctive skin lesions reflective of vascular drop out. The small bowel is the most common internal organ involved, resulting in considerable morbidity and mortality attributable to ischemic microperforations. Determination of the presence of gastrointestinal lesions is critical in distinguishing systemic from the benign, cutaneous only disease and in identifying candidates for treatment. CASE PRESENTATION: We describe an 18 year old male who first presented with cutaneous atrophic papulosis but became critically ill from small bowel microperforations. He had an almost immediate and dramatic response to treatment. Prior to his presentation with acute abdomen he had upper and lower endoscopy showing areas of nonspecific patchy erythema. At laparotomy, innumerable characteristic lesions with central pearly hue and erythematous border were seen. PubMed was used for a literature search using the keywords malignant atrophic papulosis, Degos disease, endoscopy, laparoscopy and laparotomy. This search yielded 200 articles which were further analyzed for diagnostic procedures and findings. Among the 200 articles we identified only 11 cases in which endoscopy was performed. Results of endoscopy and laparotomy in our patient with malignant atrophic papulosis were compared to those in the literature. Endoscopy of the gastrointestinal tract has shown gastritis and non-specific inflammation whereas laparoscopy shows white plaques with red borders on the serosal surface of the small bowel and the peritoneum. From personal communications with other physicians worldwide, we identified three additional unpublished cases in which endoscopy revealed only minimal changes while laparoscopy showed dramatic lesions. From our experience the endoscopic findings are often subtle and nonspecific, whereas laparascopy or laparotomy will reveal pathognomic lesions on the serosal surface of the intestine. CONCLUSION: Our report contrasts the endoscopic and laparoscopic findings in malignant atrophic papulosis which suggest laparoscopy is the more powerful means of detecting gastrointestinal involvement. Imaging studies may serve as a key indicator of systemic progression. Based on our experience, laparoscopy should be performed when there is a high index of suspicion for gastrointestinal malignant atrophic papulosis, even if endoscopic examination is non-diagnostic or normal.

Schizophrenia through the carers' eyes: results of a European cross-sectional survey.

Schizophrenia is a serious mental disorder affecting approximately 29 million people worldwide. The ideal treatment and care of patients with schizophrenia should be provided by a multidisciplinary 'team' involving psychiatrists, nurses and other healthcare professionals, together with carers and patients. In light of the key role carers play in the care of patients with schizophrenia, the present survey was designed to assess the opinions of family members and friends of patients with schizophrenia across Europe and to ascertain their attitudes towards the illness, medication and adherence to medication. Among carers participating in this survey, there was widespread awareness of the issues involved in supporting patients with schizophrenia and the importance of their role in improving poor adherence to medication. Three differences in opinion emerged between the views of carers and psychiatrists; psychiatrists rely more on the patient themselves when assessing adherence than carers would recommend; in contrast to psychiatrists, many carers believe the illness itself contributes to non-adherence; two thirds of carers think that schizophrenia medication damages health (higher than estimated by psychiatrists). The findings from the present survey, taken together with the results from the Adherencia Terapéutica en la Esquizofrenia surveys of psychiatrists and nurses, support the need for a collaborative approach to the issue of treatment nonadherence. In particular, healthcare professionals should recognize the valuable contribution that family carers can make to improve treatment adherence and consequently clinical outcomes for patients with schizophrenia. Schizophrenia carries a significant burden for families providing care. The Adherencia Terapéutica en la Esquizofrenia (ADHES) carers' survey was designed to assess the opinions of family and friends of patients with schizophrenia across Europe and ascertain their attitudes towards the illness, medication and adherence to medication. A questionnaire-based cross-sectional survey of 138 carers across 16 European countries. Interpretation of results was based on a descriptive comparison of responses. Carers recognized the importance of medication to help patients get better (76%) and improve their quality of life (76%) and relationships (74%). Sixty-seven per cent believed medication damages general health. Sixty-five per cent reported that treatment adherence was a burden for patients. Thirty-eight per cent indicated that it was a daily struggle to get patients to take their medication. Fifty per cent perceived that medication administered every few weeks rather than daily was quite/very important. Ninety-three per cent agreed on the importance of family support to boost adherence, with education and information deemed important for families and patients. Carers rely less on the patient themselves when assessing adherence than psychiatrists. The burden faced by carers and patients in taking medication provides an opportunity for healthcare professionals to provide support in a multidisciplinary 'team' involving psychiatrists, nurses and carers.

Imatinib mesylate (Gleevec™) in the treatment of diffuse cutaneous systemic sclerosis: results of a 24-month open label, extension phase, single-centre trial.

OBJECTIVES: We aimed to assess the long-term safety and tolerability of imatinib in diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this open-label, single-arm, extension-phase clinical trial, patients continued imatinib for 24 months following 12 months of initial treatment. RESULTS: Seventeen patients were enrolled. Forty of 92 adverse events (AE) and 0/6 serious (S) AEs were possibly related to medication. The MRSS decreased from a median of 21 to 16, (p=0.002). CONCLUSIONS: This study demonstrates long-term safety and tolerability of imatinib in a substantial proportion of patients with dcSSc. This is important in evaluating the relevance of this therapy in a chronic disease such as SSc.

Eculizumab prevents recurrent antiphospholipid antibody syndrome and enables successful renal transplantation.

Renal transplantation in patients with antiphospholipid antibodies has historically proven challenging due to increased risk for thrombosis and allograft failure. This is especially true for patients with antiphospholipid antibody syndrome (APS) and its rare subtype, the catastrophic antiphospholipid antibody syndrome (CAPS). Since a critical mechanism of thrombosis in APS/CAPS is one mediated by complement activation, we hypothesized that preemptive treatment with the terminal complement inhibitor, eculizumab, would reduce the extent of vascular injury and thrombosis, enabling renal transplantation for patients in whom it would otherwise be contraindicated. Three patients with APS, two with a history of CAPS, were treated with continuous systemic anticoagulation together with eculizumab prior to and following live donor renal transplantation. Two patients were also sensitized to human leukocyte antigens (HLA) and required plasmapheresis for reduction of donor-specific antibodies. After follow-up ranging from 4 months to 4 years, all patients have functioning renal allografts. No systemic thrombotic events or early graft losses were observed. While the appropriate duration of treatment remains to be determined, this case series suggests that complement inhibitors such as eculizumab may prove to be effective in preventing the recurrence of APS after renal transplantation.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

Human rhinovirus infections of the lower respiratory tract in hematopoietic stem cell transplant recipients.

BACKGROUND: Human rhinoviruses (HRVs) are a common cause of upper respiratory infection (URI) in hematopoietic stem cell transplant (HSCT) recipients; yet, their role in lower respiratory illness is not well understood. METHODS: We performed a retrospective chart review of HSCT recipients with HRV infection from the time molecular detection methods were implemented at our institution in 2008. Factors associated with proven or possible HRV pneumonia at the first HRV detection were evaluated by univariate and multivariate analysis. We then characterized all episodes of proven and possible HRV pneumonia from the initial HRV infection through a 1-year follow-up period. RESULTS: Between 2008 and 2011, 63 HSCT recipients had ≥1 documented HRV infections. At first HRV detection, 36 (57%) patients had HRV URI and 27 (43%) had proven or possible HRV pneumonia; in multivariate analysis, hypoalbuminemia (odds ratio [OR] 9.5, 95% confidence interval [CI] 1.3-71.7; P = 0.03) and isolation of respiratory co-pathogen(s) (OR 24.2, 95% CI 2.0-288.4; P = 0.01) were independently associated with pneumonia. During the study period, 22 patients had 25 episodes of proven HRV pneumonia. Fever (60%), cough (92%), sputum production (61%), and dyspnea (60%) were common symptoms. Fifteen (60%) episodes demonstrated bacterial (n = 7), fungal (n = 5), or viral (n = 3) co-infection. Among the remaining 10 (40%) cases of HRV monoinfection, patients' oxygen saturations ranged from 80% to 97% on ambient air, and computed tomography scans showed peribronchiolar, patchy, ground glass infiltrates. CONCLUSIONS: HRV pneumonia is relatively common after HSCT and frequently accompanied by bacterial co-infection. As use of molecular assays for respiratory viral diagnosis becomes widespread, HRV will be increasingly recognized as a significant cause of pneumonia in immunocompromised hosts.

Follicular cutaneous squamous cell carcinoma: an under-recognized neoplasm arising from hair appendage structures.

BACKGROUND: Cutaneous squamous cell carcinoma (SCC) with no demonstrable point of epidermal origin is problematic as it raises consideration of metastatic SCC histologically. There are rare case reports and series of SCC arising from the wall of hair follicle structures. Such lesions have been termed follicular SCC (FSCC). OBJECTIVES: To investigate the clinicopathological features of FSCC. METHODS: We prospectively collected cases of follicular SCC over a 5-year period. Follicular SCC is defined as a cutaneous SCC deriving from a pre-existing hair follicle structure. Lesions were considered to represent 'hybrid' SCCs if an interfollicular epidermal origin was also demonstrated; SCCs with > 50% of the origin from interfollicular epidermis were excluded. Histological features and clinical information were evaluated. RESULTS: We identified 61 cases of follicular SCC arising in 60 patients from a database of 5212 cutaneous SCCs encountered over the same time period by the same authors. There were 49 pure follicular SCCs and 12 hybrid lesions. The male to female ratio was 44 : 16; the mean age was 74 years (range 44-93). Follicular SCC represents 1·2% of all primary SCCs. Biopsies of such lesions, if the appendage structure of origin is not represented, are histologically indistinguishable from metastatic SCC. CONCLUSIONS: Recognition of this under-reported form of SCC is essential if an inappropriate diagnosis of metastatic SCC, with potentially harmful and inappropriate therapy and investigation, is to be avoided.

Cutaneous melanoma arising from a cesarean delivery skin scar.

A 41-year-old pregnant African-American woman noticed rapid growth of her cesarean delivery skin scar beginning at 14-week gestation. Skin biopsy, which was performed at 31 weeks, revealed poorly differentiated cutaneous melanoma. At 34 weeks, she underwent repeat cesarean delivery with tumor excision, pelvic lymphadenectomy and abdominal wall reconstruction. Locally advanced disease and anatomical limitations prevented attainment of negative surgical margins. Despite adjuvant chemotherapy and radiation, she died 1 year after diagnosis. Deferring biopsy of a suspicious skin lesion during pregnancy may have delayed the diagnosis of melanoma in this case and possibly affected the long-term outcome.