Sleep disorders in Latin-American children with asthma and/or allergic rhinitis and normal controls.

BACKGROUND: Asthma and/or allergic rhinitis have been associated with sleep disorders. The aim of this study was to evaluate sleep disorders in Latin-American children (4-10 years) from nine countries, with persistent asthma (A) and/or allergic rhinitis (AR) and in normal controls (C). METHODS: Parents from 454 C children and 700 A and/or AR children followed up in allergy reference clinics completed the Children's Sleep Habits Questionnaire (CSHQ) which is a retrospective one-week questionnaire composed of 33 questions composed of seven subscales (bedtime resistance, sleep duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing and daytime sleepiness). The total scale of CSHQ and the subscales were compared between groups C and A+AR, A (n=285) vs. AR (n=390), and between controlled A (CA, n=103) vs. partially controlled/uncontrolled A (UA, n=182). RESULTS: The comparison between C and A+AR showed no significant differences in age (6.7 years vs. 7.0 years, respectively), mean Body Mass Index and total scale of CSHQ (53.3 vs. 63.2, respectively) and the subscales were significantly higher in the A+AR group. Comparison between groups A and AR, except for sleep anxiety, showed significantly higher values for CSHQ total scale (66.9 vs. 61.0, respectively) and subscales for group A. The UA group showed significantly higher values for total CSHQ scale and subscales in comparison to CA (71.1 vs. 59.4, respectively). CONCLUSIONS: Latin-American children with asthma and/or allergic rhinitis showed sleep disorders identified by the CSHQ when compared to normal controls. Despite being treated, asthma causes sleep impairment, especially when uncontrolled.

Sleep-related disorders in Latin-American children with atopic dermatitis: A case control study.

BACKGROUND: Atopic dermatitis (AD) has been associated with impairment of sleep. The aim of this study was to evaluate sleep disorders in AD Latin-American children (4-10 years) from nine countries, and in normal controls (C). METHODS: Parents from 454 C and 340 AD children from referral clinics answered the Children Sleep Habits Questionnaire (CSHQ), a one-week retrospective 33 questions survey under seven items (bedtime resistance, sleep duration, sleep anxiety, night awakening, parasomnias, sleep-disordered breathing and daytime sleepiness). Total CSHQ score and items were analysed in both C and AD groups. Spearman's correlation coefficient between SCORAD (Scoring atopic dermatitis), all subscales and total CSHQ were also obtained. RESULTS: C and AD groups were similar regarding age, however, significantly higher values for total CSHQ (62.2±16.1 vs 53.3±12.7, respectively) and items were observed among AD children in comparison to C, and they were higher among those with moderate (54.8%) or severe (4.3%) AD. Except for sleep duration (r=-0.02, p=0.698), there was a significant Spearman's correlation index for bedtime resistance (0.24, p<0.0001), sleep anxiety (0.29, p<0.0001), night awakening (0.36, p<0.0001), parasomnias (0.54, p<0.0001), sleep-disordered breathing (0.42, p<0.0001), daytime sleepiness (0.26, p<0.0001) and total CSHQ (0.46, p<0.0001). AD patients had significantly higher elevated body mass index. CONCLUSION: Latin-American children with AD have sleep disorders despite treatment, and those with moderate to severe forms had marked changes in CSHQ.

Influence of drying process and particle size of persimmon fibre on its physicochemical, antioxidant, hydration and emulsifying properties.

Persimmon, given its current surplus production, could be an alternative source for the extraction of certain interesting ingredients for the food industry and human health, such as fibre. Thus, the aim of this study was to analyse the influence of hot air and freeze-drying, as well as the particle size of fibre extracted from persimmon peels or pulp on their physicochemical, antioxidant, hydration and emulsifying properties, compared to commercial fibres (from peach, lemon, orange and apple). The results showed that both freeze-dried persimmon pulp and freeze-dried peel had better hydration properties and oil holding capacity than other fibres analysed, although the swelling capacity was higher for lemon fibre. Freeze-dried persimmon peel fibre showed higher values of emulsion stability than commercial fibres. Finally, the antioxidant activity of the smallest sized persimmon peel fibre obtained by freeze-drying was higher than that for lemon, orange and peach fibre.

[Risk factors for the deterioration of quality of life in critical trauma patients. Assessment at 6 and 12 months after discharge from the intensive care unit]. / Factores de riesgo de deterioro de calidad de vida en pacientes traumáticos críticos. Valoración a los 6 y 12 meses del alta de la unidad de cuidados intensivos.

OBJECTIVE: To evaluate factors influencing the deterioration of health-related quality of life (HRQoL) in trauma patients admitted to an ICU. DESIGN: A prospective observational study was carried out. SETTING: The combined medical/surgical ICU in a university secondary hospital with 24-hour neurosurgery service. PATIENTS: Trauma patients admitted to the ICU during a two-year period. HRQoL assessment prior to admission to the ICU, and at 6 and 12 months after discharge. MAIN VARIABLES: Demographic variables, type and severity of injury (AIS), severity (APACHE II, ISS, TRISS), length of stay, procedures, mortality and HRQoL according to the SF-36 and EQ-5D. RESULTS: We completed the monitoring of 110 patients that showed significant impairment of their HRQoL in all the dimensions assessed. According to the SF-36, physical role was more deteriorated at 12 months, but the mental component decreased more than the physical component after 6 months. The VAS scale of the EQ-5D decreased to 55 at 6 months (19) and increased to 66 at 12 months (17). In the multiple logistic regression analysis, the variables associated with poorer HRQoL were age > 45 years, TRISS > 10, previous porer quality of life, and serious injuries in the extremities. CONCLUSIONS: Patients showed marked deterioration of their HRQoL at 6 months, followed by overall improvement at 12 months, though without reaching their previous state. The factors that determine poorer quality of life include age, severity, previous HRQoL, and severe injuries in the extremities.

Implementation of a major trauma team. Analysis of activation and care times in patients admitted to the ICU.

OBJECTIVE: To analyze the factors associated with the activation of the severe trauma care team (STAT) in patients admitted to the ICU, to measure its impact on care times, and to analyze the groups of patients according to activation and level of anatomical involvement. DESIGN: Prospective cohort study of severe trauma admitted to the ICU. From June 2017 to May 2019. Risk factors for the activation of the STAT analysed with logistic regression and CART type classification tree. SETTING: Second level hospital ICU. PATIENTS: Patients admitted consecutively. INTERVENTIONS: No. MAIN VARIABLES OF INTEREST: STAT activation. Demographic variables. Injury severity (ISS), intentionality, mechanism, assistance times, evolutionary complications, and mortality. RESULTS: A total of 188 patients were admitted (46.8% of STAT activation), median age of 52 (37-64) years (activated 47 (27-62) vs not activated 55 (42-67) P = 0.023), males 84.0%. No difference in mortality according to activation. The logistic model finds as factors: care (16.6 (2.1-13.2)) and prehospital intubation (4.2 (1.8-9.8)) and severe lower extremity injury (4.4 (1.6-12.3)). Accidental fall (0.2 (0.1-0.6)) makes activation less likely. The CART model selects the type of trauma mechanism and can separate high and low energy trauma. CONCLUSIONS: Factors associated with STAT activation were prehospital care, requiring prior intubation, high-energy mechanisms, and severe lower extremity injuries. Shorter care times if activated without influencing mortality. We must improve activation in older patients with low-energy trauma and without prehospital care.

Erythema nodosum in kidney transplant recipient: a rare complication of pneumonia treatment.

Erythema nodosum (EN) is a cutaneous inflammatory reaction, usually reported in young women, but it is rarely observed among transplant patients. Localization in the lower extremities is typical, mostly involving the anterior surfaces of the legs. Several viral, bacterial, mycotic, and non-infectious etiologies, such as autommune disorders, drugs, inflammatory bowel diseases, sarcoidosis, pregnancy, and malignancies, have been found. We describe the case of a young woman kidney transplant recipient developing bilateral, erythematous, warm nodules localized on the anterior surface of her legs after antibiotic treatment for pneumonia with levofloxacin. Her immunosuppression was sirolimus and mycophenolate mofetil. EN was diagnosed by skin biopsy; microscopic examination showed septal panniculitis with granulomas. As a complete remission of the lesions was obtained in our patient after interruption of levofloxacin therapy, we suspect that levofloxacin was involved in the pathogenesis of EN. In fact, the management of EN is based on the treatment of underlying or associated conditions.

Influence of thermal treatment and storage on astringency and quality of a spreadable product from persimmon fruit.

The aim of this work was to develop osmodehydrated products from cubes of persimmon (var. Rojo Brillante), which could be spread as a jam but keeping the typical aroma, flavour and colour of fresh fruit. The application of a thermal treatment in the filling stage has been studied, with or without a later pasteurisation step at 90°C for 20min. These spreadable products were stored at room temperature or in refrigeration. The chemical composition, pH, aw, colour, astringency, antioxidant capacity and the growth of yeast, moulds and aerobic mesophiles were analysed after the manufacture process and throughout the storage (approximately 3.5months). Sensorial analyses were also performed after 24h of being prepared and after 49days of refrigeration. The product obtained without thermal treatment was the best since it maintained the characteristic persimmon colour better and showed higher antioxidant capacity. Furthermore, it was the best, according to the panel, not only for appearance but also for flavour.

Efficacy of topical hydrating and emollient lotion containing 10% urea ISDIN® plus dexpanthenol (Ureadin Rx 10) in the treatment of skin xerosis and pruritus in hemodialyzed patients: an open prospective pilot trial.

AIM: Dry skin and pruritus are common complication of end-stage renal diseases (ESRD), affecting up to 80% of dialysis patients. They are chronic, unpleasant skin manifestations with a strong negative impact on patients' quality of life, often inducing sleeplessness and mood disorders. The pathogenesis of skin xerosis (SX) and uraemic pruritus (UP) are multifactorial. Moisturizing emollients are commonly used for the treatment of SX and UP. Urea is used in dermatology due to its excellent hydrating and moisturizing properties. Urea is useful in all cases of dry skin and, depending on the concentration levels, will act as moisturizing or keratolitic agent. Ureadin Rx 10 is a topical hydrating and emollient lotion formulation. So far no data are available regarding the efficacy of topical application of urea in lotion in the treatment of SX and UP in dialysed patients. In a prospective open pilot trial we assessed the effect of topical 10% Urea ISDIN® plus dexpanthenol lotion in the treatment of SX and UP in dialyzed patients. METHODS: A total of 15 hemodialyzed patients (3 men; 12 women, mean age 66 years) with SX and UP were enrolled after their informed consent in the trial. Topical 10% Urea ISDIN® plus dexpanthenol (Ureadin RX; ISDIN) lotion (URx) was applied twice daily over the arm and the legs for 28 consecutive days. Primary outcomes were a 5-point SRRC Index score (evaluating scaling roughness, redness and cracks) and a 4-point itching score (IS) both measured at baseline and after 2 and 4 weeks of treatment. RESULTS: At baseline mean (SD) SRRC was 5 (2.3). After URx treatment SRRC significantly (P=0.0001) decreased to 1.6 (2.1) and to 0.9 (1.2) after two and four weeks respectively (a relative reduction of 82% at week 4). IS at baseline was 1.0 (1.4). URx reduced IS significantly (P=0.008) to 0.2 (0.5) at week 2 and to 0.06 at week 4 (a relative reduction of 94% at week 4). Local tolerability was excellent/good in 14 out of 15 patients. One patient reported mild burning sensation after application of the product. CONCLUSION: In this pilot trial topical application of 10% Urea ISDIN ® plus dexpanthenol lotion has shown to improve skin dryness and pruritus in haemodialysis patients.

Response to interferon in multiple sclerosis is related to lipid-specific oligoclonal IgM bands.

The objective of this study was to investigate whether the presence of lipid-specific oligoclonal IgM bands (LS-OCMB) in cerebrospinal fluid (CSF) influences the response to treatment with beta-interferon in relapsing-remitting multiple sclerosis (RRMS) patients. We performed a collaborative prospective study including RRMS patients with brain MRI and LS-OCMB studies performed before starting interferon treatment. The primary endpoint was the risk of having a relapse after treatment initiation. Secondary endpoints included relapse rate, relapse-rate reduction, proportion of relapse-free patients and proportion of patients with sustained disability increase during follow-up. One-hundred and two patients were included. After a mean follow-up of 37.4 months, the risk of suffering a relapse was two-fold higher in patients with LS-OCMB (hazard ratio 2.0, 95% confidence interval 1.1-3.8). LS-OCMB+ patients showed lower reduction in relapse rate (51.8% versus 80.8%; p < 0.0001), higher relapse rate in the first year (0.8 versus 0.2; p = 0.001), lower proportion of relapse-free patients (25% versus 61.3%; p = 0.003), and higher proportion of patients with sustained 1.0 increase in the Expanded Disability Status Score (45% versus 12.9%; p = 0.0003). In conclusion, LS-OCMB can have an influence on the response to interferon treatment in RRMS patients. They could be used as a biological marker to predict high inflammatory activity after treatment.

Arteriovenous fistula of the vertebral artery in a female infant with hypotonia and cephalocorporal disproportion.

BACKGROUND: Congenital arteriovenous fistulas are exceptional in childhood and imply a therapeutic challenge. CASE REPORT: A 9-month-old female infant was studied for cephalocorporal disproportion, hypotonia, progressive muscular atrophy and hyperreflexia. Computed tomography of the brain and electroencephalography were normal. Electromyographic patterns suggested proximal myopathic involvement. A continuous murmur with systolic reinforcement was audible in the neck. Angioresonance detected intracranial aneurysmal dilatations behind the bulbo-medullary junction and cerebral panangiography evidenced a direct vertebrovertebral fistula with extra- and intra-cranial varices and extreme medullary compression. Occlusion of the afferent vessel to the aneurismal sack was successfully achieved with a mixture of Histoacryl and 75% lipiodol via a microcatheter. CONCLUSION: Clinical signs of an arteriovenous fistula may be atypical. Considerable cephalocorporal disproportion and a bruit in the cervical or retromastoidal regions must suggest its existence. Complete obliteration with endovascular embolization permits somatic and neurological recovery.

[Incidence of alarm criteria and attitude towards patients with headache attended in emergency departments]. / Incidencia de criterios de alarma y actitud frente a los pacientes con cefalea atendidos en urgencias.

INTRODUCTION: Alarm criteria make it possible to identify persons who visit emergency services because of severe secondary headaches. AIMS: To determine the socio-demographic characteristics of the patients who visit emergency departments due to headache, the incidence of alarm criteria, treatment and the diagnosis after one year's follow-up. PATIENTS AND METHODS: We conducted a retrospective observational cross-sectional study of the persons attended in the emergency department of the Arnau de Vilanova Hospital between June 2014 and May 2015 due to headache. RESULTS: A total of 303 persons were identified, of whom 165 were finally included in the study. There was a predominance of women (66.7%). The mean age was 41.2 ± 15.9 years. Only 16.4% were referred from primary care and 52 (31.5%) presented alarm criteria. A computerised tomography head scan was performed in half of these cases, and lumbar puncture was carried out in four of them (7.7%). A serious cause of headache was found in four cases (2.4%). After one year of follow-up, three patients who did not initially visit because of alarm criteria were diagnosed with severe diseases of the central nervous system, and 23 (13.9%) returned to the emergency department for the same reason. CONCLUSIONS: Only one out of every two patients meets the alarm criteria. The proportion of severe secondary headache is really low. The multidisciplinary management of headache needs to be improved in our setting to prevent people visiting the emergency department due to primary headaches without any alarm criteria.

TITLE: Incidencia de criterios de alarma y actitud frente a los pacientes con cefalea atendidos en urgencias.Introduccion. Los criterios de alarma permiten identificar a las personas que consultan por cefaleas secundarias graves en los servicios de urgencias. Objetivo. Determinar las caracteristicas sociodemograficas de los pacientes que acuden a urgencias por cefalea, la incidencia de criterios de alarma, el tratamiento y el diagnostico tras un año de seguimiento. Pacientes y metodos. Estudio transversal retrospectivo y observacional de personas atendidas en el servicio de urgencias del Hospital Arnau de Vilanova entre junio de 2014 y mayo de 2015 por cefalea. Resultados. Se identifico a un total de 303 personas, de las cuales 165 se incluyeron finalmente en el estudio. Hubo un predomino de mujeres (66,7%). La edad media fue de 41,2 ± 15,9 años. Solo un 16,4% fue derivado desde atencion primaria y 52 (31,5%) presentaban criterios de alarma. En la mitad de estos casos se realizo una tomografia computarizada craneal, y en 4 (7,7%), una puncion lumbar. Se identifico una causa grave de la cefalea en 4 casos (2,4%). Tras un año de seguimiento, tres pacientes que inicialmente no consultaron por criterios de alarma fueron diagnosticados de enfermedades graves del sistema nervioso central, y 23 (13,9%) volvieron a urgencias por el mismo motivo. Conclusiones. Solo uno de cada dos pacientes cumple criterios de alarma. La proporcion de cefalea secundaria grave es realmente baja. Es necesario mejorar el abordaje multidisciplinar de la cefalea en nuestro ambito para evitar la consulta a urgencias por cefaleas primarias sin criterios de alarma.

Activation of soluble guanylate cyclase by nitric oxide is increased in lymphocytes from both rats chronically exposed to 2,5-hexanedione and workers chronically exposed to n-hexane.

Although occupational exposure to n-hexane induces neurotoxic effects in the central and peripheral nervous systems, the mechanisms of its neurotoxicity remain unclear. n-Hexane is metabolized to 2,5-hexanedione (2,5-HD), which is the neurotoxic agent and the indicator chosen for the biological monitoring of exposed workers. It has been previously reported that chronic exposure to 2,5-HD impairs the glutamate-nitric oxide-cyclic GMP pathway at the level of activation of soluble guanylate cyclase (sGC) enzyme by nitric oxide (NO), both in cultured neurons and in the cerebellum of rats in vivo. The aim of this study was to assess whether the activation of sGC by NO is also altered in lymphocytes from rats treated with 2,5-HD and/or workers chronically exposed to n-hexane. Lymphocytes were isolated from male Wistar rats treated with 2,5-HD in drinking water, and from blood samples from shoe-factory workers environmentally and chronically exposed to n-hexane. Urine samples were also collected from workers at the end of the shift in order to measure the urinary levels of 2,5-HD. Activation of sGC by NO was significantly higher (p<0.05) in lymphocytes from rats treated with 2,5-HD than in control rats. In isolated lymphocytes from exposed workers the activation of sGC by NO also increases (p<0.05) in contrast to the controls. The results presented here indicate that the activation of lymphocytes could be an indicator of the toxicity produced by being exposed to n-hexane, since the effects observed in workers chronically exposed to n-hexane are similar to those found in rats chronically treated with 2,5-HD in drinking water.

Removal of anti-Stokes emission background in STED microscopy by FPGA-based synchronous detection.

In stimulated emission depletion (STED) microscopy, the role of the STED beam is to de-excite, via stimulated emission, the fluorophores that have been previously excited by the excitation beam. This condition, together with specific beam intensity distributions, allows obtaining true sub-diffraction spatial resolution images. However, if the STED beam has a non-negligible probability to excite the fluorophores, a strong fluorescent background signal (anti-Stokes emission) reduces the effective resolution. For STED scanning microscopy, different synchronous detection methods have been proposed to remove this anti-Stokes emission background and recover the resolution. However, every method works only for a specific STED microscopy implementation. Here we present a user-friendly synchronous detection method compatible with any STED scanning microscope. It exploits a data acquisition (DAQ) card based on a field-programmable gate array (FPGA), which is progressively used in STED microscopy. In essence, the FPGA-based DAQ card synchronizes the fluorescent signal registration, the beam deflection, and the excitation beam interruption, providing a fully automatic pixel-by-pixel synchronous detection method. We validate the proposed method in both continuous wave and pulsed STED microscope systems.

Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis.

Nerve growth factor (NGF), essential for differentiation and survival of sympathetic neurons is suggested to play a role in differentiation or regression of neuroblastoma. Expression of mRNA for the trk protooncogene, encoding a tyrosine kinase receptor essential for functional NGF signal transduction, and mRNA for the low affinity NGF receptor (LNGFR) was examined in 45 neuroblastomas and 3 benign ganglioneuromas using Northern blot analysis. Expression of trk mRNA and LNGFR mRNA correlated with young age, favorable clinical stages, and absence of N-myc amplification. All children (n = 19) with neuroblastomas coexpressing mRNA for trk and LNGFR are alive 8-84 months from diagnosis, regardless of age and stage. In contrast, no child (n = 15) with tumor lacking trk mRNA is alive without disease. Three subsets of patients were distinguished, one favorable (trk+, LNGFR+, n = 19, 100% survival probability), one intermediate (trk+, LNGFR-, n = 11, 62.3% survival probability), and one unfavorable (trk-, LNGFR +/-, n = 15, 0% survival probability, P < 0.001). In widespread neuroblastoma stage IVS prone to spontaneous regression, three tumors coexpressing trk and LNGFR mRNAs regressed after no or minimal therapy while the remaining tumor expressing trk but not LNGFR mRNA progressed to a fatal outcome. It is concluded that neuroblastomas coexpressing mRNA for both NGF receptor subtypes are favorable tumors likely to differentiate or regress spontaneously or respond to conventional therapy. It is further hypothesized that loss of functional NGF receptors is an important step in tumorigenesis of undifferentiated malignant childhood neuroblastoma. For these unfavorable tumors current therapy remains futile and first-line innovative therapy is justified.

Effects of a single course of deferoxamine in neuroblastoma patients.

A phase II trial of a single 5-day course of deferoxamine in 9 patients with neuroblastomas was completed. Within 2 days of completion of treatment responses were observed in 7 of 9 patients and there was no drug toxicity. These responses were a decrease in bone marrow infiltration and, in one patient, a measurable reduction in her tumor mass. We conclude that deferoxamine given as an 8-h i.v. infusion daily for 5 days at 150 mg/kg/day has antitumor activity.

Lack of correlation between N-myc and MAX expression in neuroblastoma tumors and in cell lines: implication for N-myc-MAX complex formation.

Detectable levels of MAX messenger RNA were found in a set of human neuroblastoma tumors and established cell lines. MAX mRNA levels were independent of tumor stage and N-myc genomic amplification. By contrast, N-myc mRNA transcripts were detectable only in tumors with amplification of N-myc gene and in cell lines. Analysis by reverse transcriptase polymerase chain reaction and hybridization to specific oligodeoxynucleotide probes revealed approximately equal amounts of two MAX transcripts in all cases analyzed. Immunoprecipitations with a specific antibody to MAX detected two proteins of M(r) 21,000 and 22,000 in approximately equal amounts in all neuroblastoma lines regardless of N-myc amplification and/or expression. On the other hand, protein binding to the myc DNA consensus sequence correlated with N-myc expression in neuroblastoma cells. Thus, N-myc expression might be a limiting factor in the formation of the N-myc-MAX heterodimer in neuroblastomas.

A pharmacokinetic study of high-dose continuous infusion cisplatin in children with solid tumors.

The pharmacokinetics of cisplatin were investigated in 14 patients, aged 10 months through 13 years who were affected by solid malignant tumors. High-dose cisplatin (40 mg/m2/d) was administered with repeated courses for five days as a continuous intravenous (IV) infusion. Total platinum (Pt) levels in plasma and urine and free (protein-unbound) Pt levels in plasma ultrafiltrate were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES). Areas under the concentration v time curve (AUCs) for mean total and free Pt levels were calculated for the 120-hour period of infusion and for the 384 and 120 hours following its completion, respectively. Half-lives of total and free Pt in plasma were calculated for the 216 hours following completion of infusion in five patients at their first course. The fraction of the administered Pt dose excreted in urine as Pt was determined for the five-day period of infusion and seven-day period after its completion. A total of 36 courses were studied. Maximum average Pt levels were reached after 120 hours of infusion: at the first course, 3.22 and 0.17 micrograms/mL for total and free Pt, respectively. Platinum levels declined according to a biexponential model, with initial half-lives of 18.3 and 16.9 minutes, and terminal half-lives of 81.9 and 59.0 hours as determined for total and free Pt, respectively. In the second and third courses studied there was a progressive increase in mean Pt plasma levels. Consequently, the free drug exposure as measured by AUC increased in all patients with repeated courses: 47.7% for the second and 124.4% for the third course, when compared with the first. At the same time, the mean fraction of the dose excreted in the urine for the 12-day period considered, was 44.1% for the first course, 36.2% for the second, and 28.4% for the third. The progressive enhancement of tissue exposure to the free cytotoxic drug, resulting from a reduced renal clearance of Pt with sequential courses of cisplatin, produced mainly increased toxicity while therapeutic effect progressively diminished.