Rate-induced tracking for concave or d-concave transitions in a time-dependent environment with application in ecology.

This paper investigates biological models that represent the transition equation from a system in the past to a system in the future. It is shown that finite-time Lyapunov exponents calculated along a locally pullback attractive solution are efficient indicators (early-warning signals) of the presence of a tipping point. Precise time-dependent transitions with concave or d-concave variation in the state variable giving rise to scenarios of rate-induced tracking are shown. They are classified depending on the internal dynamics of the set of bounded solutions. Based on this classification, some representative features of these models are investigated by means of a careful numerical analysis.

Calidad de vida, comportamiento y actitudes hacia la queratosis actínica en España: estudio PIQA / Quality of Life, Behaviour and Attitudes towards Actinic Keratosis in Spain: The PIQA Study

OBJETIVO: El objetivo de este estudio fue examinar el conocimiento, el comportamiento y las actitudes de los pacientes hacia las lesiones de queratosis actínica (QA) y cómo esta enfermedad influye en la calidad de vida (CV). MÉTODOS: Estudio observacional de pacientes con lesiones de QA en España. La CV se evaluó con la versión española del Cuestionario de Calidad de Vida en pacientes con Queratosis Actínica (AKCV). El autoexamen de la piel, la exposición al sol y los hábitos y actitudes hacia el tratamiento de la QA quedaron registrados a través de diferentes cuestionarios. La adherencia al tratamiento fue valorada utilizando el test de Morisky-Green. Entre otras variables, la CV y la adherencia al tratamiento se compararon mediante la prueba de chi2 de Pearson y las pruebas ANOVA de un factor. También se llevó a cabo un análisis inferencial tanto de estas variables como de la duración del tratamiento. RESULTADOS: Se reclutaron un total de 1.240 pacientes (73,6 [10,5] años). En líneas generales, los pacientes que mostraron mayores niveles de preocupación también mostraron un mayor deterioro de la CV. La QA tuvo mayores efectos sobre la CV de las mujeres, sobre los pacientes que realizaban autoexploraciones de la piel, y sobre los que piensan que la QA es una enfermedad y/o creen que los hidratantes son capaces de prevenir el envejecimiento de la piel (p < 0,05). Tanto la adherencia como la duración del tratamiento guardaron una estrecha relación, ya que los pacientes con tratamientos de menos de una semana de duración tenían más probabilidades de mostrar una buena adherencia y una remisión completa de la QA (cociente de odds u odds ratio: OR [IC95%]: 6,25 [4,55-8,33] y 2,63 [1,96-3,45], respectivamente). CONCLUSIONES: Las preocupaciones que hay en torno a la QA se asocian, principalmente, al sexo y a que la QA se considera una enfermedad. Los más preocupados suelen tener una CV más baja y una buena adherencia al tratamiento. Una duración corta del tratamiento se asoció a una mejor adherencia y a una remisión completa de las lesiones de QA

OBJECTIVE: This study was aimed to examine patients' knowledge, behaviours and attitudes regarding actinic keratosis (AK) lesions and the impact of the disease on patients' quality of life (QoL). METHODS: Observational study of patients with AK lesions in Spain. QoL was evaluated with the validated version of Spanish AKQoL questionnaire. Skin self-examination, sun-exposure, habits and attitudes towards AK's treatment were recorded using different questionnaires. The adherence was assessed by means of the Morisky-Green test. Among other variables, QoL and adherence to treatment were compared by using Pearson's chi2 test and one-way ANOVA tests. Inferential analysis regarding such factors and length of treatment were also performed. RESULTS: A total of 1240 patients (73.6 [10.5] years old) were recruited. Overall, patients that showed higher levels of concern were also showed a higher impairment on QoL. AK had greater effects on women's QoL and those who performed skin self-examination, think that AK is a disease and/or believe that moisturizers can prevent skin aging ( P< .05). Adherence and length of treatment were strongly related, since patients with treatments intended for < 1 week were more likely to show good adherence and complete remission of AK (Odds Ratio [95% CI]: 6.25 [4.55-8.33] and 2.63 [1.96-3.45]), respectively). CONCLUSIONS: Concerns due to AK are mainly related to sex and to the consideration of AK as a disease. More concerned patients tend to have lower QoL and good adherence to treatment. Short length of treatment was associated with better adherence and complete remission of AK lesions

Quality of Life, Behaviour and Attitudes towards Actinic Keratosis in Spain: The PIQA Study. / Calidad de vida, comportamiento y actitudes hacia la queratosis actínica en España: estudio PIQA.

OBJECTIVE: This study was aimed to examine patients' knowledge, behaviours and attitudes regarding actinic keratosis (AK) lesions and the impact of the disease on patients' quality of life (QoL). METHODS: Observational study of patients with AK lesions in Spain. QoL was evaluated with the validated version of Spanish AKQoL questionnaire. Skin self-examination, sun-exposure, habits and attitudes towards AK's treatment were recorded using different questionnaires. The adherence was assessed by means of the Morisky-Green test. Among other variables, QoL and adherence to treatment were compared by using Pearson's χ2 test and one-way ANOVA tests. Inferential analysis regarding such factors and length of treatment were also performed. RESULTS: A total of 1240 patients (73.6 [10.5] years old) were recruited. Overall, patients that showed higher levels of concern were also showed a higher impairment on QoL. AK had greater effects on women's QoL and those who performed skin self-examination, think that AK is a disease and/or believe that moisturizers can prevent skin aging (P<.05). Adherence and length of treatment were strongly related, since patients with treatments intended for <1week were more likely to show good adherence and complete remission of AK (Odds Ratio [95%CI]: 6.25 [4.55-8.33] and 2.63 [1.96-3.45]), respectively). CONCLUSIONS: Concerns due to AK are mainly related to sex and to the consideration of AK as a disease. More concerned patients tend to have lower QoL and good adherence to treatment. Short length of treatment was associated with better adherence and complete remission of AK lesions.

Simultaneous ultrasound and microwave new reactor: detailed description and energetic considerations.

A new reactor in which microwaves (MW), delivered by a coaxial dipole antenna, and ultrasound (US), delivered by a metallic horn, can be simultaneously used in a liquid to perform different types of processes, widely referenced in literature, is presented in detail. Calibrations of thermal energy delivered to two liquids having very different dipolar moments (i.e. water and cyclohexane) using MW and US, both separately and simultaneously, are performed by employing the traditional calorimetric method. The main results are: (i) MW and US used simultaneously increase the thermal energy delivered to the two liquids with respect to their separate use, but differently using water or cyclohexane, and (ii) the total power absorbed by polar or non polar liquids is very different, both using MW and US.

Electric and magnetic fields do not modify the biochemical properties of FRTL-5 cells.

BACKGROUND: Electric and magnetic fields (EMF) might be involved in human disease and numerous research and scientific reviews have been conducted to address this question. In particular thyroid structural and functional alterations caused by various forms of non-ionizing radiation have been described. AIM: The aim of this study was to analyze the possible effects of EMF on thyroid, in particular we analyzed the effects caused by a GSM (Global System for Mobile Communications) signal (900 MHz) on cultured thyroid cells (FRTL- 5). MATERIAL AND METHODS: The experimental setup was designed in order to expose samples to a radiofrequency wave in well-controlled conditions. We used the FRTL-5 cell line, an epithelial monoclonal continuous cell line derived from Fisher rat thyroid tissue growing as monolayer, expressing the TSH receptor and the sodium-iodide symporter (NIS). FRTL-5 were subsequently irradiate for 24, 48, and 96 h with EMF (800-900 MHz, power-frequency of mobile communication systems) and iodide uptake and cAMP production were measured. RESULTS: The irradiation of cells with EMF at 900 Mhz for 24, 48, and 96 h did not influence the level of cAMP production and was not able to modify iodide accumulation in FRTL- 5 cells with respect to basal conditions. CONCLUSIONS: In conclusion, EMF do not seem to be able to interfere with the biochemical properties of FRTL-5 cells in vitro.

The XLMR gene ACSL4 plays a role in dendritic spine architecture.

ACSL4 is a gene involved in non-syndromic X-linked mental retardation. It encodes for a ubiquitous protein that adds coenzyme A to long-chain fatty acids, with a high substrate preference for arachidonic acid. It presents also a brain-specific isoform deriving from an alternative splicing and containing 41 additional N-terminal amino acids. To start to unravelling the link between ACSL4 and mental retardation, we have performed molecular and cell biological studies. By retro-transcription polymerase chain reaction analyses we identified a new transcript with a shorter 5'-UTR region. By immunofluorescence microscopy in embryonic rat hippocampal neurons we report that ACSL4 is associated preferentially to endoplasmic reticulum tubules. ACSL4 knockdown by siRNAs in hippocampal neurons indicated that this protein is largely dispensable for these cells' gross architectural features (i.e. axonal and dendritic formation and final length) yet it is required for the presence of normal spines. In fact, reduced levels of ACSL4 led to a significant reduction in dendritic spine density and an alteration in spine/filopodia distribution. The possible mechanisms behind this phenotype are discussed.

Diagnostic criteria for the Zappella variant of Rett syndrome (the preserved speech variant).

The preserved speech variant is the milder form of Rett syndrome: affected girls show the same stages of this condition and by the second half of the first decade are making slow progress in manual and verbal abilities. They walk without help, and may be able to make simple drawings and write a few words. Most of them can speak in sentences. Autistic behavior can often be observed. We previously described several cases in the pre-molecular era and subsequently reported a survey of 12 cases with MECP2 mutations. Seventeen new patients with the preserved speech variant and a proven MECP2 mutation have been clinically evaluated. Additional clinical data of our previously described cases are reported. These 29 preserved speech variant cases were compared with 129 classic Rett patients using a clinical severity score system including 22 different signs. There was both statistical and clinical evidence of the existence of this variant. On the basis of their abilities these girls can be distinguished as low-, intermediate- and high-functioning. Girls of the last two groups show a greater homogeneity: they speak in sentences, use their hands more easily, have normal somatic features, mild neurovegetative abnormalities, with autistic behavior in 76%, epilepsy in 30%, while girls of the first group are closer to classic Rett syndrome. The majority of patients carries either missense mutations (especially the p.R133C change) or late truncating mutations in the MECP2 gene. These results confirm the existence of this variant of Rett syndrome (Zappella variant), a clear example of progress of manual and verbal abilities, and not of a "preserved speech" and suggest corresponding diagnostic criteria.

A 2.6 Mb deletion of 6q24.3-25.1 in a patient with growth failure, cardiac septal defect, thin upperlip and asymmetric dysmorphic ears.

We report a female patient with neurodevelopmental delay and peculiar facial features. She has postnatal growth failure and an atrial septal defect. Patent duct arteriosis and tricuspidal insufficiency were also noted at birth. Characteristic facial features include medial flare eyebrows, dysmorphic helix of the right ear, cupshaped left ear, anteverted nares, long and smooth philtrum, thin upper lip, high vaulted palate. Array-CGH analysis demonstrated the presence of a 2.6 Mb deletion in 6q24.3-25.1. The phenotypic features of this case are very similar to those previously reported in a patient with a 7Mb overlapping deletion, pointing to a specific new syndrome. Twenty-two genes are present in the common critical deleted region. Among them, there is the PPP1R14C gene that encodes for KEPI, a PKC-potentiated inhibitory protein for type-1 Ser/Thr protein phosphatase. Its selective distribution in brain and heart well correlates with developmental delay and cardiac anomalies observed in the patient.

Retinoblastoma and mental retardation microdeletion syndrome: clinical characterization and molecular dissection using array CGH.

We describe three patients with retinoblastoma, dysmorphic features and developmental delay. Patients 1 and 2 have high and broad forehead, deeply grooved philtrum, thick anteverted lobes and thick helix. Patient 1 also has dolicocephaly, sacral pit/dimple and toe crowding; patient 2 shows intrauterine growth retardation and short fifth toe. Both patients have partial agenesis of corpus callosum. Patient 3 has growth retardation, microcephaly, thick lower lip and micrognathia. Using array-comparative genomic hybridization (CGH), we identified a 13q14 de novo deletion in patients 1 and 2, while patient 3 had a 7q11.21 maternally inherited deletion, probably not related to the disease. Our results confirm that a distinct facial phenotype is related to a 13q14 deletion. Patients with retinoblastoma and malformations without a peculiar facial phenotype may have a different deletion syndrome or a casual association of mental retardation and retinoblastoma. Using array-CGH, we defined a critical region for mental retardation and dysmorphic features. We compared this deletion with a smaller one in a patient with retinoblastoma (case 4) and identified two distinct critical regions, containing 30 genes. Four genes appear to be good functional candidates for the neurological phenotype: NUFIP1 (nuclear fragile X mental retardation protein 1), HTR2A (serotonin receptor 2A), PCDH8 (prothocaderin 8) and PCDH17 (prothocaderin 17).

The Italian XLMR bank: a clinical and molecular database.

Mental retardation (MR) is a nonprogressive condition characterized by a significant impairment of intellectual capabilities with deficit of cognitive and adaptive functioning and onset before 18 years. Mental retardation occurs in about 2 to 3% of the general population and it is estimated that 25 to 35% of the cases may be due to genetic causes. Among these "genetic" MR, 25 to 30% are probably due to mutations in a gene on the X chromosome (X-linked mental retardation, XLMR). Given the genetic heterogeneity of XLMR, the availability of a considerable number of patients with accurate phenotypic classification is a crucial factor for research. The X-linked Mental Retardation Italian Network, which has been active since 2003, has collected detailed clinical information and biological samples from a vast number of MR patients. Collected samples and clinical information are inserted within the XLMR bank, a comprehensive molecular and clinical web-based database available at the address http://xlmr.unisi.it. The database is organized in three distinct parts. Part I and II contain several electronic schedules to register information on the family, the phenotypic description, the photographs, and a 20 sec movie of the patient. Part III allows the registration of molecular analyses performed on each case; samples and clinical data are usable via password-restricted access. Clinical and molecular centers interested in joining the network may request a password by simply contacting the Medical Genetics of the University of Siena. The XLMR bank is an innovative biological database that allows the collection of molecular and clinical data, combines descriptive and iconographic resources, and represents a fundamental tool for researchers in the field of mental retardation.

[Intravenous immunoglobulin therapy: ELISA measurement of antidesmogleins 1 and 3 in three patients with pemphigus vulgaris]. / Terapia con inmunoglobulinas intravenosas: medición seriada mediante ELISA de anticuerpos antidesmogleína 1 y 3 en tres pacientes con pénfigo vulgar.

Intravenous immunoglobulin therapy (IVIg) has been used in the treatment of autoimmune bullous diseases unresponsive to conventional therapy in recent years. The action mechanism, which is not well known, suggests a wide spectrum of immunoregulation. In the last five years, several studies on patients with unresponsive pemphigus vulgaris with a clinical and serological outcome after IVIg administration in 80%-90% of cases have been published. We report the case of 3 patients with pemphigus vulgaris in whom we measured autoantibody titers to desmoglein 3 and 1 during 8 months. In spite of the clinical improvement, no significant decrease in antibody concentration was observed. Therapy with IVIg, although it has clinical benefit, did not decrease antibody values in our patients and thus it may need to be combined with immunosuppressant that inhibit pathogen antibody production.

Terapia con inmunoglobulinas intravenosas: medición seriada mediante ELISA de anticuerpos antidesmogleína 1 y 3 en tres pacientes con pénfigo vulgar / Intravenous immunoglobulin therapy: ELISA measurement of antidesmogleins 1 and 3 in three patients with pemphigus vulgaris

La terapia con inmunoglobulinas intravenosas (IgIV) es utilizada en los últimos años en pacientes con enfermedades ampollosas autoinmunes resistentes a la terapia convencional. Su mecanismo de acción, no bien conocido, supone un amplio espectro de inmunorregulación. En los últimos 5 años se han publicado varios trabajos en pacientes con pénfigo vulgar resistente con un beneficio clínico y serológico en el 80%-90% de los casos. Presentamos 3 casos de pénfigo vulgar con determinación seriada mediante la técnica de ELISA de anticuerpos antidesmogleína 1 y 3 (AcDsG1 y AcDsG3) durante un período de 8 meses en los que, a pesar de la mejoría clínica, no se objetivó disminución significativa en la concentración de anticuerpos. La terapia con IgIV, aun con beneficio clínico, no disminuyó en nuestros pacientes las cifras de anticuerpos y por ello debería quizá combinarse con inmunosupresores que inhiban la producción de anticuerpos patógenos

Intravenous immunoglobulin therapy (IVIg) has been used in the treatment of autoimmune bullous diseases unresponsive to conventional therapy in recent years. The action mechanism, which is not well known, suggests a wide spectrum of immunoregulation. In the last five years, several studies on patients with unresponsive pemphigus vulgaris with a clinical and serological outcome after IVIg administration in 80%-90% of cases have been published. We report the case of 3 patients with pemphigus vulgaris in whom we measured autoantibody titers to desmoglein 3 and 1 during 8 months. In spite of the clinical improvement, no significant decrease in antibody concentration was observed. Therapy with IVIg, although it has clinical benefit, did not decrease antibody values in our patients and thus it may need to be combined with immunosuppressant that inhibit pathogen antibody production

[Clinical and genetic features of the Alport 'syndromes']. / Le 'sindromi' di Alport: dalla clinica alla genetica.

Alport syndrome (ATS) is a clinically and genetically heterogeneous progressive nephropathy often associated with deafness and/or ocular lesions. The histological aspect is characterized by thinning, thickening and splitting of the glomerular basement membrane (GBM). Alport syndrome is caused by mutations in COL4A3 gene (type IV collagen, alfa-3 chain), or COL4A4 gene (type IV collagen, alfa-4 chain) or COL4A5 gene (type IV collagen, alfa-5 chain) genes. Alport syndrome accounts for 1-2% of renal failure cases in Europe, and for 2-3% of transplanted patients in United States. This review focuses on the three types of Alport syndrome which differ in the clinical progression and in the mode of inheritance. The common X-linked form is caused by mutations in the COL4A5 gene and it accounts for 85% of cases. The autosomal dominant and the autosomal recessive forms are caused by mutations in either COL4A3 or COL4A4 genes. The autosomal recessive form which is responsible for the 10-15% of Alport cases, has been known since several years. On the contrary, the autosomal dominant form has only recently been identified in some families. Furthermore, this review will focus on the difficulties encountered during the genetic counselling related to the differential diagnosis between Alport syndrome and Thin Basement Membrane Disease (TBMD). We will report direct experiences of our group showing the difficulties to give an exact prognosis and a correct recurrence risk to the family.

Analgesic effect of He-Ne (632.8 nm) low-level laser therapy on acute inflammatory pain.

OBJECTIVE: The aim of this study was to evaluate the analgesic effect of the low level laser therapy (LLLT) with a He-Ne laser on acute inflammatory pain, verifying the contribution of the peripheral opioid receptors and the action of LLLT on the hyperalgesia produced by the release of hyperalgesic mediators of inflammation. BACKGROUND DATA: All analgesic drugs have undesired effects. Because of that, other therapies are being investigated for treatment of the inflammatory pain. Among those, LLLT seems to be very promising. MATERIAL AND METHODS: Male Wistar rats were used. Three complementary experiments were done. (1) The inflammatory reaction was induced by the injection of carrageenin into one of the hind paws. Pain threshold and volume increase of the edema were measured by a pressure gauge and plethysmography, respectively. (2) The involvement of peripheral opioid receptors on the analgesic effect of the laser was evaluated by simultaneous injection of carrageenin and naloxone into one hind paw. (3) Hyperalgesia was induced by injecting PGE2 for the study of the effect of the laser on the sensitization increase of nociceptors. A He-Ne laser (632.8 nm) of 2.5 J/cm2 was used for irradiation. RESULTS: We found that He-Ne stimulation increased the pain threshold by a factor between 68% and 95% depending on the injected drug. We also observed a 54% reduction on the volume increase of the edema when it was irradiated. CONCLUSION: He-Ne LLLT inhibits the sensitization increase of nociceptors on the inflammatory process. The analgesic effect seems to involve hyperalgesic mediators instead of peripheral opioid receptors.

Acrokeratosis paraneoplastica: Bazex syndrome.

Bazex syndrome is a paraneoplastic dermatosis characterized by acral psoriasiform lesions associated with an underlying neoplasm. We present the case of a 64-year-old patient that was diagnosed with squamous cell lung carcinoma after being evaluated for lesions compatible with paraneoplastic acrokeratosis. With a high frequency Bazex syndrome is the earliest marker of an underlying subclinical neoplasm. An early suspicion is of the outmost importance in order to perform a prompt diagnosis of an underlying malignancy. We propose a diagnostic algorithm upon suspicion of acrokeratosis paraneoplastica and review the pathogenesis of this entity.

CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms.

BACKGROUND: Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterised by a wide spectrum of clinical manifestations. Both the classic form and preserved speech variant of Rett syndrome are due to mutations in the MECP2 gene. Several other variants of Rett syndrome have been described. In 1985, Hanefeld described a variant with the early appearance of convulsions. In this variant, the normal perinatal period is soon followed by the appearance of seizures, usually infantile spasms. We have observed two patients with signs of Rett syndrome showing acquired microcephaly and stereotypic midline hand movements. The disease started with generalised convulsions and myoclonic fits at 1.5 months in the first patient and with spasms at 10 days in the other, suggesting a diagnosis of the Hanefeld variant. In these patients, MECP2 point mutations and gross rearrangements were excluded by denaturing high performance liquid chromatography and real time quantitative PCR. The ARX and CDKL5 genes have been associated with West syndrome (infantile spasms, hypsarrhythmia, and mental retardation). METHODS: Based on the clinical overlap between the Hanefeld variant and West syndrome, we analysed ARX and CDKL5 in the two girls. RESULTS: We found frameshift deletions in CDKL5 in both patients; one in exon 5 (c.163_166delGAAA) and the other in exon 18 (c.2635_2636delCT). CDKL5 was then analysed in 19 classic Rett and 15 preserved speech variant patients, all MECP2 negative, but no mutations were found. CONCLUSION: Our results show that CDKL5 is responsible for a rare variant of Rett syndrome characterised by early development of convulsions, usually of the spasm type.