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From his unpublished juvenilia to The Young Duke (1831), Benjamin Disraeli tested his literary potential mainly through writing in the satirical, comic, or even farcical mode. One way or another, all his fictional works from 1826 to 1830 were meant to make people laugh, or at least smile, and appreciate the young author’s wit and humorous talent for irony and comic exaggeration. He sidelined this practice in the 1830s, when he mainly experimented with other narrative genres and modes of representation, eventually parading in Venetia (1837) a new sobriety of tone such as suited an aspiring Tory politician in the year of Victoria’s accession. Working within this developmental framework, my article sets out to investigate the young Disraeli’s penchant for laughter in connection with the fun-loving vein running in the family. It focuses on Vivian Grey, Part I, and relates it to Flim-Flams!, or, the Life and Errors of My Uncle and the Amours of My Aunt (1805), a quirky satirical ‘romance’ Isaac D’Israeli completed round about the time his eldest son was born. In highlighting the contextual similarities and carnivalesque qualities of the two works, the article offers an eccentric approach to the Romantic/early-Victorian generational changeover.

To date, little is known about the usefulness of ultra-high frequency ultrasound (UHF-US, 50–70 MHz) in clinical practice for the diagnosis of dysimmune neuropathies. We present a prospective study aimed at comparing UHF-US alterations of nerves and fascicles in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), distal CIDP (d-CIDP) and anti-MAG neuropathy and their relationships with clinical and electrodiagnostic (EDX) features. Twenty-eight patients were included (twelve CIDP, six d-CIDP and ten anti-MAG) as well as ten healthy controls. Each patient underwent neurological examination, EDX and UHF-US study of both median and ulnar nerves. UHF-US was reliable in differentiating immune neuropathies from controls when using mean and/or segmental nerve and/or fascicle cross-sectional area (CSA); furthermore, fascicle ratio (fascicle/nerve CSA, FR) was a reliable factor for differentiating d-CIDP from other types of polyneuropathies. Mean median nerve fascicle CSA, fascicle CSA and FR for the median nerve in the antecubital fossa and for the ulnar nerve in the midarm segment were able to distinguish CIDP from anti-MAG polyneuropathy, while ulnar nerve CSA in the mid-forearm differentiated between anti-MAG and d-CIDP. UHF-US offers information beyond simple nerve CSA and allows for a better characterization of the different forms of dysimmune neuropathies.

This poster describes logistical issues related to implementing a randomized, double- blinded, placebo-controlled Phase III interventional trial on the nine-valent HPV vaccine (9vHPV) among cisgender men and transgender women living with HIV, at the Mexico site. The trial seeks to demonstrate that 9vHPV reduces the incidence of persistent oral HPV infection (a surrogate for HPV-associated oropharyngeal cancer) with the 9 vaccine types. Five-hundred participants will be randomized in a 1:1 allocation to receive 9vHPV or placebo, stratified based on clinical site (Brazil, Mexico, Puerto Rico) and age. The team invites potential participants through local community organizations and public HIV clinics. People may be invited when waiting in line in the morning to get laboratory testing done, when they have an appointment for HIV care or through their treating physician or a community organizer. Initially, we worked at a single HIV clinic, although we did distribute study flyers to treating physicians at other clinics. As of mid-2022 we began enrolling at two additional clinics. Participants are prescreened when initially invited or by phone to prevent unnecessary trips for those ineligible. Once prescreened, participants are given an appointment for their first study visit; reminders about their first or other study visits are sent by text message 2-3 times before the appointment. Participants are provided with financial compensation in cash at each visit. We have implemented both study-wide mechanisms and additional locally-designed strategies and forms to guarantee quality control. For example, registering participant issues, study agent trail and persons invited, pre-screened and enrolled (including reasons for exclusion). Data is registered on paper forms and in a bespoke data base program (DatStat, designed at Moffitt Cancer Center). DatStat carries out the randomization (only the Mexico site pharmacist is unblinded) and requires a wireless internet connection, which can sometimes fail even though a router is installed by the study at each clinic. Vaccine and syringe importation can be time consuming and cause enrollment delays, given the need to acquire permissions for importation or problems getting the shipment out of Customs. Making sure shipments go through an airport with better functioning Customs offices is also important. Citation Format: Betania Allen-Leigh, Alejandra Portillo-Romero, Manuel Quiterio, Maribel Acosta, Abraham Rivera- Ramirez, Guillermina Sanchez, Aurelio Cruz, Tonatiuh Barrientos, Carlos Magis, Kimberly Isaacs-Soriano, Martha E. Abrahamsen, Margaret House, Emma Brofsky, Vikrant Sahasrabuddhe, Timothy Wilkin, Anna Giuliano, Luisa Villa, Eduardo Lazcano-Ponce. Logistical issues in implementing a clinical trial on oral cancer prevention through HPV vaccination: Implementation of Ulacnet201 in Mexico [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A002.

As importance and interest rises, the IVR continues to welcome other practitioners willing to contribute knowledge and experience to accelerate convergence and mainstreaming of Impact Valuation.

This paper aims to present an historical point of view and precisely exposes the reasons why the need for terminology has developed and gradually increased, without it nullifying the ability of scientists to invent words with freedom and imagination, sometimes even taking inspiration from literature, such as particle physicist Murray Gell-Mann (Nobel laureate 1969), who, for “quark”, was inspired by a passage from Joyce's Finnegans Wake.

Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

INTRODUCCION: Las dislipidemias son enfermedades asintomaticas causadas por concentraciones anormalmente elevadas de las lipoproteinas sanguineas; aumentan el riesgo de morbilidad y mortalidad, representan un problema de salud publica a nivel mundial como reportan los organismos sanitarios, su deteccion es de utilidad para la prevencion de las enfermedades cardiovasculares. El objetivo de este estudio fue determinar la prevalencia de dislipidemia en adultos del area urbana del canton Cuenca. METODOS: Se realizo un estudio descriptivo transversal; el universo lo conformaron 69 039 habitantes del area urbana de la ciudad de Cuenca. La muestra fue de tipo probabilistico, conformado por 384 personas. Se realizaron examenes de sangre que incluian: colesterol total, colesterol HDL, LDL y trigliceridos en ayunas, en el laboratorio de la Fundacion DONUM. La informacion se obtuvo por entrevista y observacion directa previo consentimiento informado. Los datos fueron analizados en el software SPSS Version 15, mediante medidas de frecuencias y tendencia central con un intervalo de confianza del 95%. RESULTADOS: El promedio de edad fue 51 anos, de los cuales el 71.9% fueron mujeres. La prevalencia de hipercolesterolemia fue 38.5%; en relacion al sexo existio predominio en las mujeres con 34.4%, en los hombres el 28.7%. La prevalencia de hipertrigliceridemia fue de 58.5%. CONCLUSIONES: Los resultados de este estudio permiten tener una vision real y actualizada de la prevalencia de este padecimiento a nivel local, lo que posibilitara plantear acciones de promocion de estilos de vida saludables priorizando la importancia del ejercicio y una alimentacion saludable, asi como actividades de prevencion a fin de evitarla aparicion de complicaciones. ABSTRACT BACKGROUND: Dyslipidemias are asymptomatic diseases caused by abnormally high blood lipoprotein levels; these entities significantly increase morbidity and mortality risk, representing a global public health problem. Early detection is useful for cardiovascular disease prevention. The aim of this study was to determine the prevalence of dyslipidemia in adults belonging to urban area of Cuenca. METHODS: A cross-sectional study was performed; the universe included 69.039 habitants of the urban area of Cuenca. The sample was probabilistic and conformed by 384 people. Fasting lipid panel were evaluated, including total cholesterol, HDL, LDL and triglycerides. Afterinformed consent information were obtained by interview and direct observation. The data were analyzed in SPSS Version 15, using frequencies and central tendency measures with 95% confidence interval. RESULTS: The average age was 51 years, 71.9% were women. The hypercholesterolemia prevalence was 38.5%, with a predominance in female patients 34.4% versus 28.7% in males. The prevalence of hypertriglyceridemia was 58.5%. CONCLUSIONS: The results gives a real and updated view of the local prevalence, this information allows proposing actions that promote healthy lifestyles, prioritizing the importance of exercise and diet, in order to avoid the complications.

Background: Reduction of tandemly arrayed D4Z4 repeats is diagnostic for facioscapulohumeral muscular dystrophy (FSHD). However, various clinical phenotypes have been observed in carriers of this molecular lesion. Currently their natural history is obscure. Methods: A prospective observational cohort study is conducted to quantify disease progression over five-year follow-up (2013-2016) in246 carriers of D4Z4 reduced alleles DRA with 1-10 RU from the Italian National Registry for FSHD recruited between January 10th, 2007 and December 20th, 2011. Participants were subdivided in probands (141, males 84) and relatives (105, males 52). Muscle impairment was measured as FSHD score and disease progression as ΔFSHD score. Clinical phenotypes were assessed and categorized on the basis of the Comprehensive Clinical Evaluation Form (CCEF). Findings: The highest ΔFSHD score (1·7) was found in subjects with full FSHD phenotype (category A) or with complex/atypical diseases (category D); subjects with incomplete clinical phenotype (category B) had lower ΔFSHD score (0·6, p

Bilateral cavernous carotid aneurysms (CCAs) represent a rare medical condition that can mimic other disorders. We present a rare case of bilateral CCAs simulating an ocular myasthenia. A 76-year-old woman presented with a history of fluctuating bilateral diplopia and unilateral ptosis, which led to the suspicion of ocular myasthenia. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain showed the presence of large bilateral aneurysms of the carotid cavernous tract. After an unsuccessful attempt with steroid therapy, the patient underwent endovascular treatment, with mild improvement. Bilateral CCAs can cause pupil sparing third nerve palsies and other cranial neuropathies which can mimic signs and symptoms of disorders of the neuromuscular junction. Therefore, the possibility of a vascular lesion simulating ocular myasthenia should be considered especially in older patients.

Here, we describe a new variant of necklace fibres with specific myopathological features that have not been described thus far. They were observed in two patients, from two independent families with identical DNM2 (dynamin 2) mutation (c.1106 G > A (p.Arg369Gln)), displaying mildly heterogeneous clinical phenotypes. The variant is characterized by lysosomal inclusions, arranged in a necklace pattern, containing homogenous material, devoid of myonuclei. The so-called necklace region has a certain characteristic distance to the sarcolemma. Electron microscopy, including three dimensional reconstructions of serial section images highlights their ultrastructural properties and relation to neighbouring organelles. This new pattern is compared to the previously reported patterns in muscle biopsies containing necklace fibres associated with MTM1- and DNM2-mutations.

Duchenne muscular dystrophy (DMD) is a lethal disease. The outcome measures used in numerous therapeutic trials include skeletal muscle biopsy. We studied the natural history of DMD from the standpoint of muscle histology with the aim of providing a reproducible tool for use in evaluating and comparing any histologic changes occurring in patients with DMD undergoing treatment and hence be able to determine how therapy modulates the histologic evolution of the disease.Three independent operators analyzed 56 muscle biopsies from 40 patients not treated with steroids, aged 1 to 10 years and 16 individuals treated with steroids, aged 7 to 10 years. We analyzed morphologic measures, normalized every measure for the average number of fibers observed for each year of age, and calculated intraclass correlation coefficients.The average proportion of connective tissue in patients not treated with steroids was 16.98% from ages 1 to 6 years and 30% from ages 7 to 10 years (p0.0001). The average proportion in patients treated with steroids was 24.90%. Muscle fiber area mirrored that of connective tissue in both groups.Having provided a reproducible tool for evaluation and comparison of histologic changes occurring in patients undergoing clinical trials, it was observed that at ages 6 to 7 years, fibrotic tissue rapidly peaks to 29.85%; this is a crucial moment when muscle tissue loses its self-regeneration ability, veering toward fibrotic degeneration. These data should be considered when deciding the most suitable time to begin therapy.

Rationale: Down syndrome (DS) is the most common chromosome disorder in live born infants, affecting several body systems, but usually sparing skeletal muscles. We present the case of a child with coexistence of DS and dystrophinopathy. Only 1 similar case has been reported so far. Patient Concerns: An 8-year-old boy with DS had a history of incidental finding of increased serum creatine kinase levels up to 1775 U/L (normal values 38–174 U/L). He presented no delay in motor development; at the neurological examination, no muscle weakness or fatigability was detected in 2 different evaluations performed over a 6-month period. Diagnoses: Skeletal muscle biopsy revealed marked dystrophic changes with patchy immunostaining for dystrophin. The Duchenne muscular dystrophy gene was screened for deletions by multiplex polymerase chain reaction, but no mutations were found. Sequence analysis of the Duchenne muscular dystrophy gene revealed a splice-site mutation c.1812+1G>A in intron 15 and confirmed a diagnosis of Becker muscular dystrophy. Interventions: The patient has started a specific physiotherapy that avoided any deterioration in motor development and muscular wasting. Outcomes: A multidisciplinary follow-up was initiated. The genetician that followed the patient for DS was supported by the neurologist, the physiotherapist, the pulmonologist, and the cardiologist. Lessons: This peculiar “double trouble” case exemplifies the value of careful clinical evaluation and adequate clinical experience to identify the concomitance of 2 different genetic syndromes in the same patient, and it points out the significance of muscular strength assessment in DS patients to make the most correct prognosis, and, consequently, to organize the best long-term care.

Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA. Setting Italy. Participants 66 index cases and 33 relatives carrying 1–3 DRA. Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk. Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment. Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.

Based on the 7-year experience of the Italian Clinical Network for FSHD, we revised the FSHD clinical form to describe, in a harmonized manner, the phenotypic spectrum observed in FSHD. The new Comprehensive Clinical Evaluation Form (CCEF) defines various clinical categories by the combination of different features. The inter-rater reproducibility of the CCEF was assessed between two examiners using kappa statistics by evaluating 56 subjects carrying the molecular marker used for FSHD diagnosis. The CCEF classifies: (1) subjects presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1–A3), (2) subjects with muscle weakness limited to scapular girdle or facial muscles (category B subcategories B1, B2), (3) asymptomatic/healthy subjects (category C, subcategories C1, C2), (4) subjects with myopathic phenotype presenting clinical features not consistent with FSHD canonical phenotype (D, subcategories D1, D2). The inter-rater reliability study showed an excellent concordance of the final four CCEF categories with a κ equal to 0.90; 95 % CI (0.71; 0.97). Absolute agreement was observed for categories C and D, an excellent agreement for categories A [κ = 0.88; 95 % CI (0.75; 1.00)], and a good agreement for categories B [κ = 0.79; 95 % CI (0.57; 1.00)]. The CCEF supports the harmonized phenotypic classification of patients and families. The categories outlined by the CCEF may assist diagnosis, genetic counseling and natural history studies. Furthermore, the CCEF categories could support selection of patients in randomized clinical trials. This precise categorization might also promote the search of genetic factor(s) contributing to the phenotypic spectrum of disease. Electronic supplementary material The online version of this article (doi:10.1007/s00415-016-8123-2) contains supplementary material, which is available to authorized users.

Wilfrid Scawen Blunt (1840–1922) was a member of the landed aristocracy well connected with the inner circle of late Victorian high society and high politics. He is known as a poet and a translator of Arabic poetry, as well as an adventurous traveller and an ardent anti-imperialist controversialist. He rates, in fact, as something of a precursor, and a fellow traveller, of J.A. Hobson. However, in the 1870s, at the beginning of his Arabophilia, he might have easily been mistaken for an ambitious patrician bent on making the East his ‘career’ (in the line of Disraeli's Tancred) at a time when the decline of Turkish religious and political authority over Islamic lands seemed to open up exciting opportunities for nations which were not ‘afraid of growing great’, as well as for enterprising individuals. It was only in 1881–82, through his commitment to the Egyptian nationalists, that his vague political sympathies were reshaped into a coherent critical attitude towards British colonial policies. Relying on Bl...

Non-technical summary The endothelium is a thin layer of cells lining the interior surface of the entire circulatory system. Endothelial progenitor cells (EPCs) have a crucial role in maintaining the integrity of the endothelium, as they are recruited from the bone marrow to sites of endothelial injury where they contribute to blood vessel formation and repair. The factors regulating EPC mobilization and trafficking remain incompletely understood. We evaluated the time-course effects of a single 4 h bout of severe hypoxic breathing (simulating 4100 m altitude) followed by 4 h restoration in room air. We show that hypoxia alone induces a rapid disappearance of EPCs from blood, probably sustained by a prompt cell marginalization followed by a late increase in EPC apoptosis. These observations may broaden our understanding of the mechanisms operated by EPCs to maintain endothelial homeostasis and may help to elucidate the potential role of EPCs in regenerative medicine.

Restoring blood flow to ischemic tissue is a prerequisite for treatment of ischemic diseases. Cell-based therapy based on bone marrow transplantation is a promising option for patients with critical limb ischemia (CLI). The efficacy of cell therapies to augment neovascularization seems to involve endothelial progenitor cells (EPCs); however, the mechanisms underlying the efficacy have not been fully elucidated. Herein we have described the case of a young patient with severe CLI, who experienced a 24-month beneficial clinical response to autologous bone marrow transplantation. The exceptional amelioration enabled him to perform standardized maximal treadmill exercise test that demonstrated lack of exercise-induced EPC mobilization, despite adequate stromal-derived factor 1 and vascular endothelial growth factor responses. Therefore, tissue ischemia is not sufficient to promote the recruitment of EPCs that have been demonstrated to be involved in the recovery from ischemia. The local implantation of marrow-derived elements may provide cells and/or trophic factors, which have the capacity to augment angiogenesis, opening new approaches to the etiopathogenesis of the disease.

Although the immune system is clearly capable of recognizing and eliminating tumor cells, it usually fails to provide adequate protective antitumor responses. It is becoming increasingly clear that modifications of dendritic cells (DCs), which are central regulators of immune responses, could be a strategy exploited by tumor cells to escape from immune control. This review focuses on the current understanding of DC defects occurring in cancer patients, mechanisms responsible for the induction of such defects, consequences of DC defects on antitumor immune response and current concepts of DC-based immunotherapy. An improved understanding of how tumors interact with DCs to escape from immune control may enable the design of improved DC-based immunotherapeutic strategies for patients with cancer.

The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively).To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA.We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015.We used histochemical, biochemical, and molecular techniques to examine the muscle samples.Respiratory chain activity and mitochondrial content.Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P .001), COX4 (26.6%; P .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P .05).Our results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.

Mitochondrial diseases are a heterogeneous group of progressive, genetically transmitted, multisystem disorders caused by impaired mitochondrial function. The disease course for individuals with mitochondrial myopathies varies greatly from patient to patient because disease progression largely depends on the type of disease and on the degree of involvement of various organs which makes the prognosis unpredictable both within the same family and among families with the same mutation. This is particularly, but not exclusively, true for mitochondrial disorders caused by mtDNA point mutations, which are maternally inherited and subject to the randomness of the heteroplasmy. For this reason, the prognosis cannot be given by single mitochondrial disease, but should be formulated by any single mitochondrial disease-related event or complication keeping in mind that early recognition and treatment of symptoms are crucial for the prognosis. The following approach can help prevent severe organ dysfunctions or at least allow early diagnosis and treatment of disease-related complications.

Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P

A síndrome de Cowden (SC) ou síndrome de múltiplos hamartomas (SMH) é genodermatose rara de herança autossômica dominante e expressividade variável. É caracterizada por múltiplas lesões hamartomatosas de origem ectodérmica , mesodérmica e endodérmica. O órgão mais acometido é a pele, e as lesões mucocutâneas estão presentes em proporção que varia de 99 a 100% dos casos. Esses sinais precedem o desenvolvimento do câncer em vários anos, servindo como importantes marcadores clínicos na identificação de pacientes com alto rico para desenvolver câncer da mama e tireóide. Devido a associações com malignidades internas o diagnóstico precoce é essencial. O locus gênico para SC foi identificado no cromossomo 10q22-23. As mutações no gene supressor tumoral, PTEN/MMAC1, localizado no cromossomo 10q23, têm sido implicadas no desenvolvimento do câncer mamário. Os autores relatam um caso dessa rara entidade. Trata-se de paciente do sexo masculino com quadro clínico característico dessa síndrome. Cowden's Syndrome (CS) or Multiple Hamartoma Syndrome (MHS) is a rare genodermatosis of autossomal-dominant inheritance with variable expressivity. It is characterized by multiple hamartomatous lesions of ectodermal, mesodermal and endodermal origins. The organ system that most consistently manifests this syndrome is the skin. Mucocutaneous lesions are present in 99 to 100% of cases. These signs precede the development of cancer by several years, and they serve as important clinical markers for identification of patients at high risk for malignancies of the breast or thyroid. Because of its potentially serious associations with internal malignancy, early and accurate diagnosis is essential. The gene locus for CS has been identified as chromosome 10 q22-23. Mutations in the human tumor suppressor gene, PTEN/MMAC1, located on the 10q23 chromosome, have been implicated in the development of breast cancer. The authors report a case of this rare entity, dealing with a male patient with the clinical characteristics of this syndrome.

Cell-mediated immunity and T-lymphocyte maturation are impaired in HIV-infected children. These abnormalities would be detected in HIV-uninfected offspring of HIV women (seroreverters [SR]) if HIV or its soluble proteins could cross the placental barrier. Immunophenotypic analyses were performed in 20 healthy HIV-uninfected newborns of HIV-infected mothers (SR), and in 14 healthy newborns of HIV-negative women (UC). The same analyses were performed in 3 groups of older children: SR (n = 41); UC (n = 15); and HIV-infected children (n = 25). Antigen-specific cells were evaluated with ELISpot and fluorimetric analyses; IL-7 serum concentration was measured by enzyme-linked immunosorbent assay (ELISA). Results showed that in SR newborns: (1) the CD4/CD8 ratio was reduced, (2) CD4+ and CD8+ naive T-cell percentages were decreased, (3) percentage of activated CD8+ T cells was increased, and (4) percentages of CD3+/4−/8− (DN) and DN/25−/44+ were augmented. These abnormalities were partially retained in older SR children. CD4+ and CD8+ HIV-specific cells were detected in a portion of newborn SRs but not in older SRs. Serum IL-7 was augmented both in newborn and older SRs. Cell-mediated immunity and T-cell maturation are altered even in HIV-uninfected newborns of HIV-infected mothers; these abnormalities persist over time. The biologic significance of these observations and potential subsequent clinical events should be investigated in larger cohorts of seroreverters.

Immune parameters were analyzed in peripheral blood mononuclear cells (PBMC) and cervical mucosa biopsy specimens of human immunodeficiency virus (HIV)-seronegative women sexually exposed to HIV (exposed seronegative [ESN]), HIV-infected women, and healthy women without HIV exposure. HIV was not detected in PBMC or cervical mucosa biopsy specimens of ESN women. However, interleukin (IL)-6, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha and -beta mRNA were elevated in PBMC and cervical mucosa biopsy specimens of ESN and HIV-infected women; CCR5 and CXCR4 mRNA were augmented in cervical mucosa biopsy specimens, but not in PBMC, of ESN and HIV-infected women; HIV-specific IFN-gamma-secreting cells were detected in vaginal washes of ESN and HIV-infected women; and phenotypic alterations were present in PBMC of ESN women. These results suggest that active HIV infection is not required for T cell activation; immune alterations occur in women in whom HIV infection cannot be detected virologically or clinically.

This article reports on a large longitudinal study, begun in 1993, of the natural history of human papillomavirus (HPV) infection and cervical neoplasia in a population of low-income women in São Paulo, Brazil, a city with one of the highest risks worldwide for cervical cancer. Known as the Ludwig-McGill cohort study, the epidemiological investigation focuses on persistent infection with oncogenic HPV types as the precursor event leading to cervical neoplasia. The objectives of this study are to: 1) study the epidemiology of persistent cervical HPV infection in asymptomatic women, 2) investigate whether persistent HPV infection increases risk of low-grade and high-grade cervical lesions, 3) search for determinants of persistent HPV infection, 4) search for molecular variants of HPV that may be associated with an increased risk of lesions, 5) investigate whether viral burden is correlated with persistent infections and with lesion risk, 6) study the antibody response to HPV as a predictor of persistence and lesion progression, and 7) examine the role of HLA typing and codon 72 p53 gene polymorphism in mediating HPV persistence and lesion severity. The study accrued 2 528 female subjects through March 1997. Subjects were followed up every 4 months in the first year, with twice-yearly return visits to take place in subsequent years. Participants undergo a questionnaire-based interview, have a cervical specimen taken for Pap cytology and HPV testing, and have a blood sample drawn for HPV antibody testing. A cervicography is performed once in the first year and every two years thereafter. In this article we describe the design and methods of the study, provide baseline cohort characteristics, and present a preliminary assessment of the prognostic value of baseline HPV status.Este artículo describe un amplio estudio longitudinal, iniciado en 1993, acerca de la historia natural de la infección por papilomavirus humanos (PVH) y las neoplasias cervicales en una población de bajos recursos económicos de São Paulo, Brasil, una de las ciudades con mayor riesgo de cáncer cervical en todo el mundo. Esta investigación epidemiológica, conocida como el estudio de cohorte Ludwig-McGill, se centra en la infección persistente por tipos oncogénicos de PVH como el acontecimiento precursor que conduce a la neoplasia cervical. Sus objetivos consistieron en: 1) estudiar la epidemiología de la infección cervical persistente por PVH en mujeres asintomáticas; 2) investigar si la infección persistente por PVH incrementa el riesgo de lesiones intraepiteliales escamosas cervicales de bajo y alto grado; 3) identificar los determinantes de la infección persistente por PVH; 4) buscar variantes moleculares de los PVH que puedan estar asociadas a un aumento del riesgo de lesiones; 5) determinar si la carga vírica está correlacionada con la infección persistente y el riesgo de lesiones; 6) averiguar si la respuesta de anticuerpos frente a los PVH permite predecir la persistencia de la infección y la progresión de las lesiones, y 7) investigar el papel de los tipos HLA y del polimorfismo del codón 72 del gen p53 como mediadores de la persistencia de los PVH y de la gravedad de las lesiones. Hasta marzo de 1997 se reclutaron 2 528 mujeres que fueron examinadas cada cuatro meses en el primer año y cada seis meses en los años subsecuentes. Las participantes se someten a una entrevista basada en un cuestionario; a la obtención de una muestra cervical para citología de Papanicolaou y detección de PVH, y a la extracción de una muestra de sangre para identificar anticuerpos anti-PVH. Además, en el primer año se les realiza una cervicografía, que después se repite cada dos años. En este artículo se describen el diseño y los métodos del estudio, se presentan las características basales de la cohorte y se realiza una evaluación preliminar del valor pronóstico del estado basal de los PVH.