Dermatological Symptoms Research Articles

The effectiveness of the combined use of fractional microneedle rf-therapy and pharmacophoresis of hyaluronic acid in the treatment of patients with atrophic scars

Background. The formation of scar tissue is a fairly physiological process, in most cases aimed at closing the skin defect in order to preserve the bodys homeostasis. Correction methods for atrophic scars include laser technology, radiofrequency therapy, injection methods and topical therapy.
 Arm: the formation of scar tissue is a fairly physiological process, in most cases aimed at closing the skin defect in order to preserve the bodys homeostasis. Correction methods for atrophic scars include laser technology, radiofrequency therapy, injection methods and topical therapy.
 Methods. There were 56 patients with atrophic scar. Depending on the therapeutic complex for the correction of аtrophic scar, 3 groups were formed: group 1 ― the combined use of RF-therapy for the pharmacophoresis of hyaluronic acid, group 2 ― radio frequency microneedle therapy, group 3 ― the pharmacophoresis of hyaluronic acid. In the work, the Dermatological Symptom Scale Index (DSSI), which was assessed before and after treatment, was adapted to evaluate clinical symptoms.
 Results. In accordance with the total value of the DSSI, a more significant dynamics was observed in group 1, regardless of the type of AR (subgroups 1A and 1B). DSSI in the 1A subgroup decreased by 80.8% (p0.01), in the 1B group by 82.4% (p0.01). DSSI in the 2A subgroup decreased by 32.3% (p0.01), in the 2B group by 61.4% (p0.01). DSSI in the 3A subgroup decreased by 62.3% (p0.01), in the 3B group by 33.7% (p0.01). In group 1, where the combined treatment was carried out, a more pronounced efficacy was noted than when applying the components of the technique, which did not depend on the type of cicatricial deformity. In group 2, after the application of RF-therapy, the effectiveness was expressed to a much lesser extent, and the most significant results were obtained in patients with post-traumatic atrophic scars. In group 3, after a course of pharmacophoresis of a hyaluronic acid preparation, positive dynamics was observed to a greater extent with hormone-dependent scars.
 Conclusions. The results of the study showed that the most effective method is the combined use of RF-therapy and the pharmacology of hyaluronic acid, at the same time with post-inflammatory (post-traumatic) atrophic scars, monotherapy with the use of radiofrequency microneedles is possible, with hormone-dependent atrophic scars, monotherapy of pharmacophoresis of hyaluronic acid is possible.

Cutaneous Pedal Manifestations in Patient With Hepatitis C Virus-Associated Cryoglobulinemia: Case Report and Review of Literature.

Cryoglobulinemia is an uncommon blood dyscrasia that can manifest itself in the lower extremity. Due to the insidious nature of this disease, dermatological symptoms and ulcerations can easily be mistaken for more common entities. The authors present an overview of cryoglobulinemia and a case report of a patient with lower extremity manifestations of this disorder. This can provide specific guidance on the steps necessary to accurately establish the diagnosis of cryoglobulinemia or rule it out and pursue other etiologies causing lower extremity ulceration.

Difficulties in differential diagnosis of cutaneous manifestations in patients with coronavirus infection

Patients with severe SARS-CoV-2 infection (COVID-19) and multiple comorbidities should be monitored for possible adverse reactions to prescribed drugs, including drug eruptions (DE) at any stage of treatment. Below, we describe a clinical case of a 92-year-old female patient with severe PCR-confirmed COVID-19. The patient was treated with amoxicillin/clavulanic acid, moxifloxacin, acetylcysteine, and sodium enoxaparin. On day 9 into treatment, the patient developed moderately itching macular rashes showing a tendency to coalesce, but overall showed no signs of deterioration. On day 15, the rashes regressed, following a short course of dexamethasone and chloropyramine. This kind of skin reaction might have been provoked by β-lactams and fluoroquinolones included in the treatment regimen, a secondary bacterial infection, compromised immunity due to advanced age, and high viral load associated with dermatological symptoms. Delayed onset of skin symptoms might be regarded as a marker of COVID-19 severity.

Zapalenie tętnic Takayasu — obraz kliniczny, diagnostyka i leczenie

Systemic vasculitis is a heterogeneous group of diseases of a not fully understood etiology. The common feature is the development of immune-mediated inflammation in the vessel walls, which can lead to the weakening of the wall and formation of aneurysms or occlusion of the lumen, resulting in tissue ischemia. Skin lesions may be present in many conditions of this group. In small and medium vessel vasculitis, the skin may be directly affected by the pathological process. On the other hand, in large vessel vasculitis dermatological symptoms develop secondarily to the involvement of larger vessels. Clinical manifestations, diagnosis and treatment of Takayasu arteritis (TA), classified according to the International Chapel Hill Consensus Conference from 2012 in the group of large vessel vasculitis, are discussed in this article. The aim of the paper is to draw attention to the cutaneous lesions that may raise suspicion of systemic vasculitis. In patients with TA, Raynaud’s phenomenon (especially unilateral), finger necrosis, digital clubbing, erythema nodosum-like lesions or pyoderma gangrenosum-like lesions, erythema induratum, purpuric or necrotic eruptions, livedo reticularis and superficial phlebitis may be observed.

Extrapulmonary Clinical Manifestations in COVID-19 Patients.

.COVID-19 manifestations in symptomatic patients can be in the form of pneumonia, acute respiratory syndrome, and multiple organ dysfunction as well. Renal complications, gastrointestinal dysfunctions, endocrine system disorders, myocardial dysfunction and arrhythmia, neurological dysfunctions, dermatological symptoms, hematological manifestations, and thromboinflammation are among the reported extrapulmonary complications. Moreover, the presence of coagulopathy, excessive and dysregulated immune responses, and autoimmunity by COVID-19 patients is considerable. The pathogenesis of infection entails the entry of the virus via receptors on cells, principally angiotensin-converting enzyme 2 receptors. Direct virus damage coupled with indirect effects of viral infection including thromboinflammation, dysfunction of the immune system, and dysregulation of the renin–angiotensin system leads to multiple organ failure. This review outlines the extrapulmonary organ–specific complications and their pathophysiology and epidemiology.

Timing of PCR and antibody testing in patients with COVID-19–associated dermatologic manifestations

Timing of PCR and antibody testing in patients with COVID-19–associated dermatologic manifestations

An introduction to the assessment and management of psychodermatological disorders

SUMMARYPsychodermatology is an emerging field at the interface between psychiatry, psychology and dermatology. There is a strong bidirectional relationship between a number of dermatological disorders and psychiatric disorders. This article provides an overview of psychiatric disorders with dermatological symptoms, and dermatological disorders with secondary psychophysiological consequences. The principles of management and our insights into establishing a psychodermatology service in the UK are discussed.

Late infantile form of multiple sulfatase deficiency.

SummaryMultiple sulfatase deficiency (MSD) is a lysosomal storage disorder (LSD) that results in the accumulation of sulfate esters which go on to cause neurological deterioration and mental delay, skin changes, and dysmorphism. The disease can be categorized into three subtypes based on the age of onset: neonatal, late infantile, or juvenile. Our patient is a 2.5-year-old girl, the only child of a healthy couple. Prior to the presentation of the disease, she had not been noted to have any previous health complications. The condition began at the age of 6 months with developmental regression and global hypotonia. Following thorough evaluation and testing, the patient was diagnosed with severe late infantile MSD, although some features, such as minimal mental deterioration, minimal dysmorphic facial features, and minimal organ enlargement, did not fully correlate with the diagnosis, since in cases of severe forms of the condition these features are almost always quite marked. The unexpected minimalism of some of the patient’s MSD signs in spite of the severity of her MSD condition made her case worth further studying.Learning points:Treating dermatologic signs and symptoms greatly eased our patient’s discomfort.We would suggest the use of appropriate supportive treatment for symptom management regardless of the life expectancy of the patient.As regards the diagnosis of MLD, given that in some cases the patient may present with irregular features of the condition, a genetic evaluation may be useful for accurate diagnosis.If motor function impairment is followed by dermatologic involvement, as seen in our patient and in many cases in the literature, MSD must be considered, and additional tests should be done to rule it out.

Multiple Chemical Sensitivity Syndrome: A Principal Component Analysis of Symptoms.

Multiple Chemical Sensitivity (MCS) is a chronic and/or recurrent condition with somatic, cognitive, and affective symptoms following a contact with chemical agents whose concentrations do not correlate with toxicity in the general population. Its prevalence is not well defined; it mainly affects women between 40 and 50 years, without variations in ethnicity, education and economic status. We aimed to assess the core symptoms of this illness in a sample of Italian patients. Two physicians investigated different symptoms with a checklist compilation in 129 patients with MCS (117 women). We conducted a categorical Principal Component Analysis (CATPCA) with Varimax rotation on the checklist dataset. A typical triad was documented: hyperosmia, asthenia, and dyspnoea were the most common symptoms. Patients also frequently showed cough and headache. The CATPCA showed seven main factors: 1, neurocognitive symptoms; 2, physical (objective) symptoms; 3, gastrointestinal symptoms; 4, dermatological symptoms; 5, anxiety-depressive symptoms; 6, respiratory symptoms; 7, hyperosmia and asthenia. Patients showed higher mean prevalence of factors 7 (89.9%), 6 (71.7%), and 1 (62.13%). In conclusion, MCS patients frequently manifest hyperosmia, asthenia, and dyspnoea, which are often concomitant with other respiratory and neurocognitive symptoms. Considering the clinical association that is often made with anxiety, more studies are necessary on the psychosomatic aspects of this syndrome. Further analytical epidemiological studies are needed to support the formulation of aetiological hypotheses of MCS.

Update on dermatomyositis in adults.

Dermatomyositis (DM) in adults has a prevalence of 6-7 per 100,000 population per year. This dedicated compact overview was prepared due to an increasing incidence as well as an often underestimated systemic involvement and new developments in myositis-specific antibodies (MSA). The spectrum of clinical dermatological and systemic symptoms is described. Related diagnostic procedures are depicted, and therapeutic regimens based on the German S2k guidelines and the current literature are presented. The urgency of an early diagnosis is emphasized as about 30% of patients with DM manifest a tumor. Etiopathology is often associated with pulmonary fibrosis, and inflammation of myositis can cause irreversible muscle damage. Clinical signs and correct interpretation of serological markers can deliver valuable information on the extent of DM, and provide an indication for further diagnostic procedures, prognosis and choice of therapy.

Anxiety sensitivity and social anxiety in adults with psychodermatological symptoms.

Many dermatology patients experience social anxiety symptoms; however, few studies have investigated vulnerabilities contributing to this distress. Anxiety sensitivity (AS), or the fear of the consequences of anxiety, warrants consideration given its association with social anxiety and dermatological symptoms, respectively. The purpose of this investigation was to investigate the role of AS in social anxiety symptoms in two samples of adults with psychodermatological conditions. AS social, but not physical or cognitive, concerns were hypothesized to demonstrate unique associations with social anxiety symptoms after controlling for relevant variables. Participants completed self-report measures online (Study 1) or in-person (Study 2). Study 1 included 164 participants with active skin conditions (Mage = 31.88; 69.5% female; 83.5% White), and Study 2 included 63 dermatology outpatients (Mage = 51.49; 70.7% female; 65% White). Results revealed AS social concerns was a unique factor contributing to social anxiety symptoms in both samples. This study demonstrates replication, and the findings suggest heightened concerns about the negative consequences related to visible skin conditions may worsen social anxiety symptoms in individuals with psychodermatological conditions. Despite limitations, this study informs the conceptualization of co-occurring psychological and dermatological conditions and highlights the need to evaluate the efficacy of brief AS interventions among patients with psychodermatological conditions.

Matrix stimulation in chronic pruritus: A randomized controlled study.

Chronic pruritus is one of the main symptoms in dermatology. We investigated a new intervention for chronic pruritus by neurostimulation through matrix electrodes. In this randomized controlled trial, 29 patients with chronic pruritus caused by a variety of dermatological diseases were allocated to an experimental group (EG; n=14, 4-Hz neurostimulation of the itching area through matrix electrodes) or the control group (CG; n=15, placement of matrix electrodes without neurostimulation). Outcome measures were the itching sensation as measured by a Numerical Rating Scale immediately after the intervention and the intermediate effect measured by the average itching sensation on the day before the intervention compared with the average itching sensation on day 1, 2 and 3 after the intervention. Regarding the short-term effect on itching, the anova showed a significant interaction effect for the 5-min stimulation with a larger reduction in the EG with a large effect size of d=1.10. The average reduction in itching intensity was 78.2% for the EG compared with 34.3% for the CG. For the intermediate effect, no significant interaction was found (F=1.721, P=0.199). Comparing the itching sensation at day 0 with day 3, the interaction effect showed a statistical trend toward a greater reduction in the EG (F=3.178, P=0.086; statistical trend, d=0.69). This study proved that neurostimulation through matrix electrodes is effective in the short-term reduction of itching in patients with chronic pruritus caused by dermatological diseases. Additional studies are needed with larger patient pools and covering longer study periods.

Psychiatric comorbidity in individuals with bullous pemphigoid and all bullous disorders in the Danish national registers

BackgroundBullous pemphigoid (BP) is an autoimmune blistering skin disease that takes a profound physical and mental toll on those affected. The aim of the study was to investigate the bidirectional association between BP and all bullous disorders (ABD) with a broad array of psychiatric disorders, exploring the influence of prescribed medications.MethodsThis nationwide, register-based cohort study encompassed 6,470,450 individuals born in Denmark and alive from 1994 to 2016. The hazard ratios (HRs) of a subsequent psychiatric disorder in patients with BP/ABD and the reverse exposure and outcome were evaluated.ResultsSeveral psychiatric disorders were associated with increased risk of subsequent BP (4.18-fold for intellectual disorders, 2.32-fold for substance use disorders, 2.01-fold for schizophrenia and personality disorders, 1.92–1.85-1.49-fold increased risk for organic disorders, neurotic and mood disorders), independent of psychiatric medications. The association between BP and subsequent psychiatric disorders was not significant after adjusting for BP medications, except for organic disorders (HR 1.27, CI 1.04–1.54). Similar results emerged with ABD.ConclusionPsychiatric disorders increase the risk of a subsequent diagnosis of BP/ABD independent of medications, whereas medications used for the treatment of BP/ABD appear to account for the subsequent onset of psychiatric disorders. Clinically, an integrated approach attending to both dermatological and psychiatric symptoms is recommended, and dermatologists should remain vigilant for early symptoms of psychiatric disorders to decrease mental health comorbidity.

Dermatological Manifestations in Patients With SARS-CoV-2: A Systematic Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been initially defined as a disease of the respiratory tract; however, with the increasing number of patients and announcing that the virus became a pandemic, new systemic clinical manifestations are observed, including dermatological manifestations. However, the identification and characteristics of these manifestations are still controversial. This review article aims to evaluate the medical literature and explore the dermatological clinical manifestations in patients with SARS-CoV-2. The literature was reviewed through MEDLINE®, Ovid, PubMed®, and Embase®. Searching terms included were a combination of "dermatological" OR "skin" AND "symptoms" OR "manifestations" AND "SARS-CoV-2". The following step was filtering the results to include only original research studies investigating the different types of skin and dermatological clinical manifestations in patients with SARS-CoV-2. A total of 879 studies were retrieved. Following the exclusion of studies on animals and including only studies on humans, 32 studies emerged. Altogether, seven studies were identified as eligible, covering 555 patients with SARS-CoV-2 who had dermatological symptoms. Three studies were retrospective, two studies were prospective, and two studies were case series. Different types of dermatological lesions can occur in patients with SARS-CoV-2, most commonly erythema, urticaria, and varicella-like rash. Dermatological manifestations with SARS-CoV-2 can be misdiagnosed with other conditions. Further studies with robust design are needed.

Vipera snakebite in Europe: a systematic review of a neglected disease.

In 2009, snakebites were included in the list of the World Health Organization (WHO) neglected diseases. Dermatological literature lacks current and up-to-date articles about snakebites and their management, despite the fact that dermatologists, especially from rural hospitals, can be called into the emergency room to consult the management of suspected snakebites. In this systematic review, we highlighted the main clinical and laboratory aspects of snakebites from Vipera spp. in Europe, by reviewing 3574 studies initially retrieved from PubMed, Embase and Cochrane CENTRAL databases. Of these, 78 were finally included in the systematic review. We found that the most involved taxon was V.berus in 63.3% and the most involved anatomic site of the bite was the upper limbs 53.1% with fang marks reported in 90.5%. The mean age of the patients was 32.9years, and bites were slightly more common among males (58.2%). A wound washing was performed in 86.9% of cases before the hospitalization. The most frequently reported grade of envenomation was G2 (42.2%). In addition to local dermatological symptoms (extended erythema, oedema, cutaneous necrosis, hives, purpura, petechiae, acute compartment syndrome), numerous systemic symptoms have also been reported, including fatigue (14.4%), pain (75.3%), fever (49.2%), direct anaphylactoid reaction (5.3%), anxiety (60.8%), cranial nerve neurotoxicity (14.8%), dysesthesia/paraesthesia (7.9%), vomiting (33.7%), abdominal pain (23.3%), diarrhoea (15.4%), dyspnoea (6.3%), proteinuria (10.6%) and haematuria (9.3%). Secondary infections were present in 3.5% and disseminated intravascular coagulation in 3.1% of cases, and fasciotomy was performed in 4.2% cases, while an amputation in 6.9%. Only 0.9% of patients died. Antivenom was administered in 3053 cases. In conclusion, there is a pressing need for robust multi-centre randomized control trials, standardized protocol for snakebite management and antivenom administration across Europe and a National snakebite register for each European country.

Tofacitinib in psoriatic arthritis patients: skin signs and symptoms and health-related quality of life from two randomized phase 3 studies.

BackgroundPsoriatic arthritis (PsA) is a chronic, systemic immune‐mediated inflammatory musculoskeletal disease. The onset of dermatologic symptoms often precedes rheumatic manifestations. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA that has been shown to improve dermatologic symptoms in patients with PsA.ObjectivesTo investigate the efficacy of tofacitinib in improving dermatologic endpoints in adult patients with active PsA.MethodsThis analysis included data from two placebo‐controlled, double‐blind, phase 3 studies in patients with active PsA and an inadequate response (IR) to ≥1 conventional synthetic disease‐modifying antirheumatic drug (csDMARD) who were tumor necrosis factor inhibitor (TNFi)‐naïve (OPAL Broaden; NCT01877668) or an IR to ≥1 TNFi (OPAL Beyond; NCT01882439). Patients had active plaque psoriasis at screening and received a stable dose of one csDMARD during the study. Patients were randomized to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or placebo (to Month 3). Dermatologic endpoints: Psoriasis Area and Severity Index (PASI) total score; PASI90 overall; PASI75 and PASI90 by baseline PASI severity; Physician’s Global Assessment of Psoriasis; Nail Psoriasis Severity Index; Dermatology Life Quality Index total and sub‐dimension scores; Itch Severity Item; and Patient’s Global Joint and Skin Assessment‐Visual Analog Scale‐Psoriasis question.ResultsIn patients with active PsA, including those stratified by mild or moderate/severe dermatologic symptoms, greater improvements from baseline and percentage of responders were observed in tofacitinib‐treated patients vs. placebo for the majority of analyzed dermatologic endpoints at Months 1 and 3, and improvements were maintained to Month 12 in OPAL Broaden and Month 6 in OPAL Beyond. Similar effects were observed in adalimumab‐treated patients vs. placebo in OPAL Broaden across dermatologic endpoints.ConclusionsTofacitinib provides a treatment option for patients with active PsA, including the burdensome dermatologic symptoms of PsA.

Extravascular Dermal Trypanosomes in Suspected and Confirmed Cases of gambiense Human African Trypanosomiasis.

BackgroundThe diagnosis of gambiense human African trypanosomiasis (gHAT) typically involves 2 steps: a serological screen, followed by the detection of living trypanosome parasites in the blood or lymph node aspirate. Live parasites can, however, remain undetected in some seropositive individuals, who, we hypothesize, are infected with Trypanosoma brucei gambiense parasites in their extravascular dermis.MethodsTo test this hypothesis, we conducted a prospective observational cohort study in the gHAT focus of Forecariah, Republic of Guinea. Of the 5417 subjects serologically screened for gHAT, 66 were enrolled into our study and underwent a dermatological examination. At enrollment, 11 seronegative, 8 unconfirmed seropositive, and 18 confirmed seropositive individuals had blood samples and skin biopsies taken and examined for trypanosomes by molecular and immunohistological methods.ResultsIn seropositive individuals, dermatological symptoms were significantly more frequent, relative to seronegative controls. T.b. gambiense parasites were present in the blood of all confirmed cases (n = 18) but not in unconfirmed seropositive individuals (n = 8). However, T. brucei parasites were detected in the extravascular dermis of all unconfirmed seropositive individuals and all confirmed cases. Skin biopsies of all treated cases and most seropositive untreated individuals progressively became negative for trypanosomes 6 and 20 months later.ConclusionsOur results highlight the skin as a potential reservoir for African trypanosomes, with implications for our understanding of this disease’s epidemiology in the context of its planned elimination and underlining the skin as a novel target for gHAT diagnostics.

The spectrum of COVID-19–associated dermatologic manifestations: An international registry of 716 patients from 31 countries

BackgroundCoronavirus disease 2019 (COVID-19) has associated cutaneous manifestations.ObjectiveTo characterize the diversity of cutaneous manifestations of COVID-19 and facilitate understanding of the underlying pathophysiology.MethodsCase series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies.ResultsThe registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients.LimitationsWe cannot estimate incidence or prevalence. Confirmation bias is possible.ConclusionsThis study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were nonspecific, whereas others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology.

Гострі пероральні та інгаляційні отруєння талієм і їх віддалені наслідки (огляд літератури та дані власних досліджень)

Aim of the Research. To generalize modern literature data on the toxicity of thallium compounds (Tl+), the mechanisms of their toxic effects and to analyze the prevalence of acute Tl+ poisonings in recent years abroad and in Ukraine. Compare the features of the clinical manifestations and outcome of Tl+ intoxications with the dose received and the content of Tl+ in biological media. Methods and Materials. A scientific analysis of literature data and our own observations on the prevalence, characteristics of clinical manifestations and outcomes of acute poisoning with thallium compounds was carried out. Results. An increase in the prevalence of single and group cases of acute Tl+ poisoning in recent years both abroad and in Ukraine has been revealed. It was established that among the clinical manifestations of Tl+ poisoning, neurological disorders, gastrointestinal and dermatological symptoms predominate, the severity of which in most cases depends on the content of Tl+ in biological media, mainly in urine and nails. Conclusions. Diagnosis of acute Tl+ poisoning in most cases is delayed or posthumous. When combining previous gastrointestinal and dermatological disorders with painful paresthesias and ascending sensory and motor disorders of innervation in the lower and upper extremities, it is necessary to conduct a chemical-analytical determination of Tl in the patient’s biological media to exclude or confirm intoxication. Key Words: thallium, mechanisms of toxic effects, acute poisoning, diagnostics.

Injuria cerebral aguda causada por oclusión de gran vaso por COVID–19

En la pandemia de la enfermedad por el coronavirus 2019 (COVID-19) causada por el virus SARS-CoV2, la mayoría de los pacientes presentan síntomas generales y respiratorios, algunos cuadros atípicos gastrointestinales, cardiovasculares, dermatológicos o neurológicos. Se reporta el caso de un paciente varón de 40 años, sin ningún antecedente epidemiológico importante, diagnosticado de COVID 19 por prueba rápida inmunológica, quien presenta un accidente cerebro vascular isquémico súbito. En el estudio tomográfco cerebral sin contraste se evidenció un área extensa isquémica, en el hemisferio cerebral izquierdo en territorio de la arteria cerebral media, acompañado de edema. En los pacientes con COVID-19, infectados por coronavirus SARS-CoV2, debe tenerse en cuenta la posibilidad de que el paciente presente accidente cerebrovascular (ACV), para permitir un manejo adecuado y oportuno.