Topical and Oral Roflumilast in Dermatology: A Narrative Review. / Roflumilast tópico y oral en dermatología. Una revisión narrativa.

Oral roflumilast is a phosphodiesterase-4 inhibitor approved for the prevention of exacerbations of chronic obstructive pulmonary disease and chronic bronchitis. In dermatology, topical roflumilast is authorized by the US Food and Drug Administration for the treatment of plaque psoriasis and mild to moderate seborrheic dermatitis. Several studies have described the off-label use of roflumilast in dermatology, including a randomized controlled trial showing its usefulness in the treatment of psoriasis; case reports and small series have also reported successful outcomes in hidradenitis suppurativa, recurrent oral aphthosis, nummular eczema, lichen planus, and Behçet disease. Roflumilast has a favorable safety profile, similar to that of apremilast, and it is considerably cheaper than new generation drugs and even some conventional immunosuppressants. We review the pharmacokinetics and pharmacodynamics of topical and oral roflumilast and discuss potential adverse effects and both approved and off-label uses in dermatology. Roflumilast is a promising agent to consider.

Clinical relevance of interictal dysphoric disorder and its impact on quality of life in drug-resistant epilepsy.

OBJECTIVE: This study aims to assess the prevalence of Interictal Dysphoric Disorder (IDD) in drug-resistant epilepsy (DRE) and to describe its clinical and psychopathological profile, including personality, as well as its impact on quality of life (QOL). METHOD: A retrospective cross-sectional study from an Epilepsy Unit from January 2007 to December 2017. All patients were diagnosed with DRE. Patients underwent a battery of tests (HADS, SCL-90R, PDQ-4+, QOLIE-31) and a psychiatrist assessed the presence of Axis-I disorders and IDD. Statistical procedures were carried out using R-4.0.1 software. RESULTS: A total of 282 patients were included. A statistically significant association was found between IDD and mood and anxiety disorders (p < 0.001 and p < 0.05 respectively), and between IDD and higher scores in all HADS and SCL-90-R items compared to subjects without IDD (p < 0.001). A statistically significant association was also found between IDD and obsessive-compulsive, borderline and depressive personality disorder (p < 0.05). Scores in all QOLIE-31 items except for 'medication effects' were significantly lower in subjects with IDD compared with subjects without IDD (p < 0.001). CONCLUSIONS: In DRE, IDD subjects show differences in the psychopathological profile and QOL scores compared to subjects without a diagnosis of IDD. An early diagnosis of IDD could facilitate prompt interventions which might positively impact QOL.

Spanish-dementia knowledge assessment scale (DKAS-S): psychometric properties and validation.

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of cognitive impairment. Community knowledge of the disease has proven to be a very important aspect of the development of interventions and the evaluation of their effectiveness. However, it is necessary to have standardized and recognized tools in different languages. The aim of the current study was to develop a cross-cultural adaptation of the Spanish Dementia Knowledge Assessment Scale (DKAS-S) and to assess their psychometric properties with cohorts of health students and professional and non-professional caregivers of AD patients from several regions of Spain. METHODS: We developed and translated the DKAS into Spanish following the forward-back-forward translation procedure. Then, we performed a cross-sectional study to assess the validity, reliability and feasibility of the DKAS-S. We also performed an analysis to obtain test-retest reliability measures. The study was performed in four medical centres across three regions in Spain. From May to September 2019, we administered the scale to students, professional and non-professional caregivers; including a subgroup of non-professional caregivers of patients with early-onset AD (< 65 years). RESULTS: Eight hundred forty-six volunteer participants completed the DKAS-S: 233 students (mean age 26.3 ± 9.2 years), 270 professional caregivers (mean age 42.5 ± 11.7 years) and 343 non-professional caregivers of AD patients. (mean age was 56.4 ± 13.16). The DKAS-S showed good internal consistency (Cronbach's α = 0.819) and good test-retest reliability (time 1: 28.1 ± 8.09 vs time 2: 28.8 ± 7.96; t = - 1.379; p = 0.173). Sensitivity to change was also significant in a subgroup of 31 students who received education related to AD and dementias between each administration (time 1: 25.6 ± 6.03) to (time 2: 32.5 ± 7.12; t = - 5.252, p = 0.000). The validity of the construct was verified by confirmatory factor analysis, although there were challenges in the inclusion of some items in the original 4 factors. CONCLUSIONS: The 25-item DKAS-S showed good psychometric properties for validity and reliability and the factorial analysis when it was administered to a population of students and professional and non-professional caregivers. It was a useful instrument for measuring levels of knowledge about dementia in Spanish population.

Clinico-pathological findings in natural cases of "mascadera" in goats.

"Mascadera" is a chronic emaciating neuropathy affecting goats; it produces significant economic losses in many regions and its cause is unknown. Here, the histological lesions found in 15 animals naturally affected by the disease are described. Complete necropsy was performed and tissue samples were collected for histopathological study. Severe atrophy of the masseter and buccinator muscles and tongue was observed, as well as vacuolar degeneration of neurons in the nuclei of the trigeminal, facial, and glossopharyngeal nerves. No relevant lesions were observed in other tissues. These findings and the clinical signs are consistent with those observed by other authors in animals spontaneously and experimentally intoxicated with Prosopis juliflora. The disease may be due to consumption of a similar species present in our country that is still unknown. Further research on the etiology and pathogenesis of this disease is needed to establish appropriate prevention guidelines.

Spontaneous photosensitization by Heterophyllaea pustulata Hook. f. (Rubiaceae), in sheep from Northwestern Argentina.

Heterophyllaea pustulata Hook. f. (Rubiaceae) is a phototoxic plant. It grows in the Andean area of northwest of Argentina, and it causes significant economic losses in the livestock. This plant induces dermal lesions by photosensitization probably due to its content of photosensitizing anthraquinones. This paper describes an outbreak of poisoning in Corriedale sheepfold, which had an incidence of 49%. Ear skin biopsies and blood samples were collected of six affected animals. Liver enzymes remained within the reference limits. Histopathologically, a deep necrotizing dermatitis was identified in all samples. H. pustulata was identified in the areas of grazing. Anthraquinone concentration in leaves was 0.84% p/p, expressed as rubiadin. All findings allow us to conclude that the diagnosis is a primary photosensitization. Huge regional economic losses could be attributed to H. pustulata poisoning, although its toxicity has been little studied.

Immunohistochemical expression of growth factors in the follicular wall of normal and cystic ovaries of sows.

The expression of growth factors was evaluated immunohistochemically in normal and cystic ovaries of sows. The immunohistochemically stained area (IHCSA) was quantified by image analysis to analyse the expression of these proteins in the follicular wall of secondary, tertiary and cystic follicles. IGF-I immunoreactivity was strong in the granulosa cell layer (GC), moderate in the theca interna (TI) and mild in the theca externa (TE) of the normal follicles. There was severe reduction of the labelling to IGF-I in the GC of the follicular and luteinized cysts. In the normal follicles, the reactivity for IGF-II was very similar to pattern noted in IGF-I. There was reduction of the IHCSAs in the GC of the follicular and luteinized cysts, but the decrease was not significant. The staining of the IGF-II in the TI and TE of the cysts was increased, in comparison with normal follicles. The IHCSAs for VEGF were higher in the GC and TE of the normal follicles in contrast to TI, but this difference was noted only in the tertiary follicle. The VEGF reactivity increased in the GC of the cysts, in relation to normal follicles. The results of the current study show that the formation of ovarian cysts in sows is associated with alterations in the immunohistochemical expression of some growth factors.

Intermediate filament proteins expression and carbohydrate moieties in trophoblast and decidual cells of mature cat placenta.

The aim of this study was to characterize cytoskeletal intermediate filament proteins and glycoconjugates of syncytiotrophoblast, cytotrophoblast and decidual cells of feline endotheliochorial placenta. Samples from 12 normal pregnant female cats, after 45 ± 5 days of gestation, were obtained removing the uterine horns by hysterectomy. Sections were processed for routine observation and for immunohistochemistry using anticytokeratin, antivimentin and antidesmin antibodies. In addition, lectin histochemistry was performed using a panel of several biotinylated lectins to characterize glycosides expression profile. Cytotrophoblast and syncytiotrophoblast showed immunoreactivity only with acidic and basic cytokeratins. Decidual cells were only positive to vimentin, consistent with their origin from endometrial fibroblasts. Trophoblast expressed a broad population of glycans, highly exposing terminal N-acetyl glucosamine residues and non-sialylated galactose and N-acetyl galactosamine oligomers. Oligosaccharides bound by Phaseolus vulgaris erythroagglutinin were the only highly branched N-linked residues evidenced in cats, and they were restricted to the syncytium. Unlike results reported on humans, mice and rats on lectin affinity of decidual cells, sialid acids and complex N-linked oligosaccharides were not demonstrated in cats. Glycosylation of proteins determines many of their final properties, thus becoming essential for the embryo-maternal dialogue during implantation and placentation. Changes in glycosylation pattern have been related to pathological pregnancies in other species. Hence, the knowledge about glycosylation profile of the normal cat placenta may lead to a better understanding of both normal and pathological reproductive events.

Comparison of water- vs. land-based exercise for improving functional capacity and quality of life in patients living with and beyond breast cancer (the AQUA-FiT study): a randomized controlled trial.

BACKGROUND: Patients living with and beyond breast cancer frequently exhibit several side effects that can impact quality of life and physical functioning way beyond diagnosis and cancer therapies. Traditional on-land exercise has shown to be effective in reducing several symptoms of BC but little is known about the role of water-based exercise in improving physical and psychological well-being. OBJECTIVES: To compare land- vs. water-based exercise training for BC survivors to improve Health-Related Quality of Life (HRQoL), cancer-related fatigue (CRF), physical functioning, body composition and physical activity in patients with BC. METHODS: A randomised, parallel group (1:1) controlled trial was conducted between 2020 and 2022. Patients were randomly allocated to complete a similar exercise training twice weekly during 12 weeks either on land (LG) using traditional gym equipment or in a swimming pool (WG) using body-weight exercises and water-suitable accessories. Both groups were supervised and monitored by an experienced physiotherapist. Main outcome was HRQoL (EORTC QLQ C30 and B23 module) and CRF measured with the Piper Scale. Secondary variables included functional capacity with the 6 Minutes Walking Test (6MWT), upper and lower body strength (handgrip strength and 30″ Sit-to-Stand (STS) test), body composition and objectively measured physical activity. RESULTS: 28 patients were assessed and randomised during the study period. One patient did not receive the allocated intervention due to skin issues and one patient was dropped out during the intervention. A significant effect of time was found for both symptom severity (F(2,52) = 6.46, p = 0.003) and overall functioning (F1.67,43.45 = 5.215, p =0 .013) but no interaction was found between group and time. No effects were reported for CRF. Similar findings were reported for functional capacity (time effect F1.231,32.019 = 16.818, p < 0.001) and lower body strength (time effect F2,52 = 15.120, p < 0.001) as well as fat mass (time effect F2,52 = 4.38, p = 0.017). Notably, a significant time per group interaction was reported for physical activity (F2,52 = 6.349, p =0.003) with patients in the WG significantly improving PA levels over time while patients in the LG exhibited a marked decreased. CONCLUSIONS: Exercise training either in water or on land can decrease symptom severity and improve functionality and body composition. Water-based training seems more effecting than land-based exercise to improve physical activity patterns over time.

Effects of different anesthetics in the murine model of EHV-1 infection.

Mice are commonly used as an experimental model to investigate the Equid herpesvirus 1 (EHV-1) infection. This model easily reproduces the disease, and the clinical signs are more or less similar to those observed in the horse, the natural host. During natural infection, the acute course of respiratory infection is mandatory for the development of adaptive immune response. Since interactions between EHV-1 and anesthetics are possible, the study investigated whether the early events of murine pulmonary immune response could be affected by different anesthetics. Therefore, mice were experimentally infected with a unique EHV-1 strain under the effects of ether, ketamine/xylazine, or isoflurane. Clinical signs and histopathological lesions in the lungs were described, and the cell death and proliferation rates of sham-inoculated or infected animals were quantified using immunohistochemistry. Clinical signs were more severe in animals anesthetized with ether. Qualitative differences in the recruited inflammatory cells were observed following application of anesthesia. The level of infection between the infected groups was not statistically significant. However, lungs from ketamine/xylazine-anesthetized animals showed the highest cell death rates, whereas those from isoflurane-anesthetized animals showed the highest proliferation rates. It has been emphasized that anesthetics alone or their interactions with EHV-1 modify the response against the infection. An appropriate selection of the anesthetic during experimental studies is relevant to minimize wrong conclusions.

Lectin-binding pattern in ovarian structures of rats with experimental polycystic ovaries.

Numerous experimental models in different species have been developed for the study of polycystic ovarian syndrome. In this study, we used a model of induction of polycystic ovaries (PO) in rats by exposure to constant light to study the distribution and variations of glycosylated residues present in the different ovarian structures. Seven biotinylated lectins were used (Con-A, WGA, DBA, SBA, PNA, RCA and UEA-I) on tissue sections, and detection was performed using the streptavidin/peroxidase method. In tissue sections was observed an increase in affinity for Con-A in the granulosa and theca interna of growing follicles and cysts in animals with PO in relation to the control group. Follicular cysts showed higher affinity for WGA and RCA-I which growing follicles in the same group, and there was a decrease in affinity for PNA in the cysts in relation to the growth of follicles in both groups. Atretic follicles in both groups showed greater labelling with lectins PNA, SBA and RCA-I in relation to healthy follicles. It could also be noted that the zona pellucida of cystic follicles lost the affinity for the lectin Con-A. There was no staining on follicles in any category with the lectins DBA and UEA-I, although it was staining in the corpus luteum (control group) and in the mesothelium and interstitial glands of both groups with DBA. These observations probably reflect changes in the glycosaminoglycans present in the different ovarian compartments or in the glycosylation of cellular components essential for proper follicular dynamics.

Acute hepatitis C in a patient receiving etanercept.

According to the literature, the use of tumor necrosis factor (TNF) inhibitors in patients with chronic hepatitis C infection is safe and effective. There have been no reports, however, of primary infection with the hepatitis C virus during treatment with a biologic agent. We report the case of a patient with long-standing moderate to severe psoriasis who developed acute hepatitis C while being treated with etanercept. Biologic therapy was continued and the infection was successfully treated with pegylated interferon, which achieved a sustained virologic response. Etanercept did not have a negative impact on disease outcome or on response to antiviral treatment.

Association between depressive and anxious symptoms with cognitive function and quality of life in drug-resistant epilepsy.

•Depressive/anxious disorders and cognitive impairment are frequent comorbidities in epilepsy and have a more deleterious effect in DRE.•Studies concerning the relationship between anxiety and depression and cognitive performance in DRE are scarce.•Higher scores in HADS are associated with lower QOLIE-31 scores and might be considered as predictors of QOL in DRE.•A relationship between anxious and depressive symptoms -measured with HADS and SCL-90R- and cognition might not exist.•There remains an unexplored study area regarding this relationship which requires more attention to improve the assessment of DRE.

Results from a national survey on the management of primary hyperparathyroidism.

BACKGROUND: Management of primary hyperparathyroidism (PHPT) continues to be challenging. At the Third International Workshop on PHPT, recent data on this disease were reviewed and new clinical recommendations were developed. There are few data on the influence of new guidelines in clinical practice. AIM: We designed an online survey that was sent to all Spanish hospital endocrinology services. METHODS: The questionnaire included 28 questions about diagnosis and management of PHPT. Ninety-nine of 131 sites (76%), giving health coverage to 70% of Spanish population, completed the survey. RESULTS: The reported incidence of PHPT was 9.95/100,000 person-years. Heighty percent of patients were asymptomatic. Each center performed a median (Q1, Q3) of 12 (6, 20) parathyroidectomies/year. The median (Q1, Q3) percentage of curative interventions (at first trial) was 90% (80, 95). The main reasons for not performing surgery were, by decreasing frequency: surgery contraindication, patient's refusal, loss of monitoring, limited surgery experience. Localization techniques were used in 83% of cases. The main criteria for parathyroidectomy in asymptomatic patients were Ca≥2.875 mmol/l (79%), Tscore ≤-2.5 SD at any site (91%), age <50 yr (80%) and glomerular filtration rate <60 ml/min/1.73 m 2 (82%). Minimally invasive surgery was performed in 42% of centers. Frequency of biochemistry and bone density determinations for non-surgically managed patients was in accordance with international guidelines. CONCLUSIONS: The clinical practice of Spanish endocrinologists is consistent with the recommendations of the guidelines from the Third International Workshop for the management of PHPT.

Unilateral orchidectomy in mature cats is not followed by compensatory hypertrophy.

The aim of this study was to describe the effect of unilateral orchidectomy on testicular characteristics of mature domestic cats. Five, 1- to 2-year-old, cross-bred male cats were unilaterally orchidectomized on day 0 (right) and day 60 (left). The testes were processed for histological and immunohistochemical evaluation and groups compared by Student's t-test. No significant differences (p > 0.05) were found between testes groups for any of the gross (volume and gonadosomatic index) and microscopic (tubular diameters, axis, area, length and perimeter, germinal epithelium height, spermatogonias, spermatocytes, spermatids, spermatozoa, Sertoli and Leydig cells, intertubular compartment, lumen, cellular debris, tubular- intertubular proportion and basement membrane) parameters assessed. According to these biometric and morphometric results, mature cats do not develop compensatory hypertrophy within 60 days of unilateral orchidectomy.

Comparison of physical activity and sedentary behaviours between young haemophilia A patients and healthy adolescents.

In recent studies, adolescent haemophilia A patients and healthy adolescents have been encouraged to participate in physical activity (PA) based on its many established health benefits. However, none of the studies to date has used objective measures of PA and sedentary behaviour. The aims of the current study included: (i) to determine the amount and intensity of habitual PA among haemophilia A and healthy adolescents, and in haemophilia A patients with and without bleeding episodes in the previous year, and (ii) to identify the type and determine the time spent in sedentary activities in which both groups participate to obtain a broadened view of their daily activities. A total of 41 adolescent haemophiliacs and 25 healthy adolescents, between the ages of 8 and 18 years, participated in this cross-sectional study. A triaxial accelerometer was used to measure PA and the Adolescent Sedentary Activity Questionnaire to assess sedentary behaviours among members of both groups. Adolescent haemophilia A patients showed a higher daily mean time engaged in light, moderate and moderate-to-vigorous PAs relative to their healthy counterparts (P < 0.001). Patients who had experienced bleeding episodes during the previous year also spent more time participating in vigorous PAs than healthy adolescents (P = 0.002). With regard to sedentary behaviours, healthy adolescents spent more time listening to music than haemophilia A adolescents (P = 0.003), whereas haemophilia A adolescents spent more time watching TV (P < 0.001) and playing videogames (P = 0.003) than healthy counterparts. Findings suggest that increased participation in moderate intensity PAs and reduced sedentary behaviours should be recommended among adolescents with haemophilia A.

Histopathological, immunohistochemical, lectinhistochemical and molecular findings in spontaneous bovine abortions by Campylobacter fetus.

Bovine campylobacteriosis (BC) is a venereal disease caused by Campylobacter fetus characterized by temporary infertility with mild endometritis, early embryonic death and occasional abortions. The objectives of this study were to describe and identify C. fetus in spontaneous bovine abortion on the basis of histopathological, immunohistochemical, lectinhistochemical and polymerase chain reaction (PCR) techniques. The most frequent foetal lesion was neutrophilic bronchopneumonia and interstitial pneumonia. Other commonly observed lesions included non-suppurative interstitial enteritis, hepatitis, pericarditis, myositis, myocarditis, and meningitis. In this study, C. fetus fetus was phenotypically classified in all bovine foetuses from lungs and abomasal fluids. Immunohistochemistry (IHC) staining revealed positive stained Campylobacter organisms with typical morphology. Lectin binding patterns not showed great differences between the infected and the non-infected groups. The most important changes were a minor peanut agglutinin (PNA) and DBA binding in the alveolar cells of the lungs and DBA globet cells in some of the C. fetus-positive foetuses. Individual variations in each lectin binding pattern complicate the evaluation of the lectins results. All foetuses positive to IHC were positive by PCR. Better efficiency of PCR was obtained from abomasal fluids than from lung tissues. The association of culture and phenotypic techniques with histopathology, IHC and PCR allowed a better characterization and description of BC.

Massive intrasplenic arterial thrombosis in a patient with chronic ITP during the development of an Evans syndrome.

Long-term safety and efficacy of eltrombopag in adults with persitent/chronic primary immune thrombocytopenia (ITP) evaluated in EXTEND study, showed a high response rate (80%) but, in the clinical safety study, it was observed that 6% of the patients presented venous and arterial thrombotic events. In addition, in the course of the disease, autoimmune hemolytic anemia (Evans syndrome, ES) may occur and could increase the risk of thrombosis. We report an interesting case of splenic rupture due to massive intrasplenic arterial thrombosis in the course of ES in a patient with chronic ITP treated with eltrombopag. The purpose of this case report is to highlight the potential increase in thrombotic risk that may involve the use of eltrombopag in hemolysis situations in patients with ITP.

Calbindin D28k expression and the absence of apoptosis in the cerebellum of Solanum bonariense L-intoxicated bovines.

Solanum bonariense intoxication is characterized by cerebellar neuronal vacuolation, degeneration, and necrosis. Cerebellar Purkinje cells seem especially susceptible, but more research is needed to determine the pathogenesis of neuronal necrosis and the mechanism of Purkinje cell susceptibility. Calbindin D28k (CbD28k) is highly expressed in Purkinje cells and has been used as a marker for normal and degenerative Purkinje cells. The goal of this study was to describe S bonariense-induced disease by ascertaining Purkinje cell-specific degenerative changes using CbD28k expression and to correlate this with apoptosis in Purkinje cells, as determined using TUNEL (transferase-mediated dUTP-biotin nick end-labeling) and ultrastructural changes. In all cases, an increase in both dose and duration of S bonariense intoxication resulted in a decrease in the number of Purkinje cells. CbD28k immunohistochemistry was an excellent marker for Purkinje cells because immunoreactivity did not change in normal or degenerative tissues. This finding suggests that excessive calcium excitatory stimulation does not induce rapid neuronal degeneration and death. As found in previous studies, TUNEL tests and electron microscopy suggest that Purkinje cell degeneration and death are not occurring via an apoptotic process. These findings suggest that S bonariense poisoning induces progressive Purkinje cell death that is not mediated by excitotoxicity or apoptotic activation.