Abacavir usage patterns and hypersensitivity reactions in the EuroSIDA cohort.

OBJECTIVES: Five to eight per cent of HIV-positive individuals initiating abacavir (ABC) experience potentially fatal hypersensitivity reactions (HSRs). We sought to describe the proportion of individuals initiating ABC and to describe the incidence and factors associated with HSR among those prescribed ABC. METHODS: We calculated the proportion of EuroSIDA individuals receiving ABC-based combination antiretroviral therapy (cART) among those receiving cART after 1 January 2009. Poisson regression was used to identify demographic, and current clinical and laboratory factors associated with ABC utilization and discontinuation. RESULTS: Between 2009 and 2016, of 10 076 individuals receiving cART, 3472 (34%) had ever received ABC-based cART. Temporal trends of ABC utilization were also heterogeneous, with 28% using ABC in 2009, dropping to 26% in 2010 and increasing to 31% in 2016, and varied across regions and over time. Poisson models showed lower ABC utilization in older individuals, and in those with higher CD4 cell counts, higher cART lines, and prior AIDS. Higher ABC utilization was associated with higher HIV RNA and poor renal function, and was more common in Central-East and Eastern Europe and lowest during 2014. During 779 person-years of follow-up (PYFU) in 2139 individuals starting ABC after 1 January 2009, 113 discontinued ABC within 6 weeks of initiation for any reason [incidence rate (IR) 14.5 (95% confidence interval (CI) 12.1, 17.5) per 100 PYFU], 13 because of reported HSR [IR 0.3 (95% CI 0.1, 1.0) per 100 PYFU] and 35 because of reported HSR/any toxicity [IR 4.5 (95% CI 3.2, 6.3) per 100 PYFU]. There were no factors significantly associated with ABC discontinuation because of reported HSR/any toxicity. CONCLUSIONS: ABC remains commonly used across Europe and the incidence of discontinuation because of reported HSR was low in our study population.

Diagnostic management of renal colic.

Renal colic is a common reason for presentation to emergency departments, and imaging has become fundamental for the diagnosis and clinical management of this condition. Ultrasonography and particularly noncontrast computed tomography have good diagnostic performance in diagnosing renal colic. Radiologic management will depend on the tools available at the center and on the characteristics of the patient. It is essential to use computed tomography techniques that minimize radiation and to use alternatives like ultrasonography in pregnant patients and children. In this article, we review the epidemiology, clinical and radiologic presentations, and clinical management of ureteral lithiasis.

Exploration of 19 serotoninergic candidate genes in adults and children with attention-deficit/hyperactivity disorder identifies association for 5HT2A, DDC and MAOB.

Attention-deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder in which different genetic and environmental susceptibility factors are involved. Several lines of evidence support the view that at least 30% of ADHD patients diagnosed in childhood continue to suffer the disorder during adulthood and that genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. Genetic, biochemical and pharmacological studies support the idea that the serotonin system participates in the etiology of ADHD. Based on these data, we aimed to analyze single nucleotide polymorphisms across 19 genes involved in the serotoninergic neurotransmission in a clinical sample of 451 ADHD patients (188 adults and 263 children) and 400 controls using a population-based association study. Several significant associations were found after correcting for multiple testing: (1) the DDC gene was strongly associated with both adulthood (P=0.00053; odds ratio (OR)=2.17) and childhood ADHD (P=0.0017; OR=1.90); (2) the MAOB gene was found specifically associated in the adult ADHD sample (P=0.0029; OR=1.90) and (3) the 5HT2A gene showed evidence of association only with the combined ADHD subtype both in adults (P=0.0036; OR=1.63) and children (P=0.0084; OR=1.49). Our data support the contribution of the serotoninergic system in the genetic predisposition to ADHD, identifying common childhood and adulthood ADHD susceptibility factors, associations that are specific to ADHD subtypes and one variant potentially involved in the continuity of the disorder throughout lifespan.

Adaptive behaviour in Angelman syndrome: its profile and relationship to age.

BACKGROUND: Angelman syndrome (AS) is a neurodevelopmental disorder usually caused by an anomaly in the maternally inherited chromosome 15. The main features are severe intellectual disability, speech impairment, ataxia, epilepsy, sleep disorder and a behavioural phenotype that reportedly includes happy disposition, attraction to/fascination with water and hypermotoric behaviour. METHOD: We studied the level of adaptive behaviour and the adaptive behavioural profile in the areas of 'motor skills', 'language and communication', 'personal life skills' and 'community life skills' in a group of 25 individuals with genetically confirmed AS, to determine whether there is a specific adaptive behaviour profile. RESULTS AND CONCLUSIONS: None of the individuals, whatever their chronological age, had reached a developmental age of 3 years. A specific adaptive behaviour profile was found, with 'personal life skills' emerging as relative strengths and 'social and communication skills' as weaknesses.

Distinct responses from bacterial, archaeal and fungal streambed communities to severe hydrological disturbances.

Stream microbes that occur in the Mediterranean Basin have been shown to possess heightened sensitivity to intensified water stress attributed to climate change. Here, we investigate the effects of long-term drought (150 days), storms and rewetting (7 days) on the diversity and composition of archaea, bacteria and fungi inhabiting intermittent streambed sediment (surface and hyporheic) and buried leaves. Hydrological alterations modified the archaeal community composition more than the bacterial community composition, whereas fungi were the least affected. Throughout the experiment, archaeal communities colonizing sediments showed greater phylogenetic distances compared to those of bacteria and fungi, suggesting considerable adaptation to severe hydrological disturbances. The increase in the class abundances, such as those of Thermoplasmata within archaea and of Actinobacteria and Bacilli within bacteria, revealed signs of transitioning to a drought-favoured and soil-like community composition. Strikingly, we found that in comparison to the drying phase, water return (as sporadic storms and rewetting) led to larger shifts in the surface microbial community composition and diversity. In addition, microhabitat characteristics, such as the greater capacity of the hyporheic zone to maintain/conserve moisture, tended to modulate the ability of certain microbes (e.g., bacteria) to cope with severe hydrological disturbances.

Chromatic and achromatic visual fields in relation to choroidal thickness in patients with high myopia: A pilot study.

PURPOSE: To analyse the relationship between the choroidal thickness and the visual perception of patients with high myopia but without retinal damage. METHODS: All patients underwent ophthalmic evaluation including a slit lamp examination and dilated ophthalmoscopy, subjective refraction, best corrected visual acuity, axial length, optical coherence tomography, contrast sensitivity function and sensitivity of the visual pathways. RESULTS: We included eleven eyes of subjects with high myopia. There are statistical correlations between choroidal thickness and almost all the contrast sensitivity values. The sensitivity of magnocellular and koniocellular pathways is the most affected, and the homogeneity of the sensibility of the magnocellular pathway depends on the choroidal thickness; when the thickness decreases, the sensitivity impairment extends from the center to the periphery of the visual field. CONCLUSIONS: Patients with high myopia without any fundus changes have visual impairments. We have found that choroidal thickness correlates with perceptual parameters such as contrast sensitivity or mean defect and pattern standard deviation of the visual fields of some visual pathways. Our study shows that the magnocellular and koniocellular pathways are the most affected, so that these patients have impairment in motion perception and blue-yellow contrast perception.

Sensitivity of laccase activity to the fungicide tebuconazole in decomposing litter.

The present study investigates the sensitivity of laccase activity to the fungicide tebuconazole (TBZ) in order to seek for new functional toxicity descriptors in aquatic microbial communities associated to decomposing litter. With this aim, we analyzed the sensitivity of laccase from the different microbial components (fungi and bacteria growing separately and in co-existence), as well as that of their corresponding enzyme fractions (cell bound and diffusible), forming microbial communities in Alnus glutinosa leaves. Results show that fungi are pivotal for laccase activity in leaves and that their activity is repressed when they co-exist with bacteria. The sensitivity of laccase activity to the TBZ was only detectable in leaves colonized by fungi separately (Alatospora acuminata populations), but absent in those colonized by bacteria separately and/or mixed fungi plus bacteria. Specifically, the increase of TBZ concentration enhances laccase activity in Alatospora acuminata populations but decreases ergosterol concentration as well as the amount of 18S RNA gene copies. This activity response suggests a detoxification mechanism employed by the fungus in order to reduce TBZ toxicity. Besides, enzyme fractioning showed that laccase activity in the cell bound fraction (76% of the total activity) was sensitive to the fungicide, but not that in the diffusible fraction (24% of total activity). Hence, TBZ would influence laccase activity in the presence of fungal cells but not in enzymes already synthesized in the extracellular space. The present study highlights the importance of the biological complexity level (i. e. population, community, ecosystem) when seeking for appropriate functional ecotoxicity descriptors in aquatic microbial communities.

Photoprotection and photoreception of intraocular lenses under xenon and white LED illumination.

OBJECTIVE: To analyze the photoprotection and phototransmission that various intraocular lenses (IOLs) provide under the illumination of a xenon (Xe) lamp and white LEDs (light emitting diode). METHODS: The spectral transmission curves of six representative IOLs were measured using a Perkin-Elmer Lambda 35 UV/VIS spectrometer. Various filtering simulations were performed using a Xe lamp and white LEDs. The spectral emissions of these lamps were measured with an ILT-950 spectroradiometer. RESULTS: The IOLs analyzed primarily show transmission of nearly 100% in the visible spectrum. In the ultraviolet (UV) region, the filters incorporated in the various IOLs did not filter equally, and some of them let an appreciable amount of UV through. The Xe lamp presented a strong emission of ultraviolet A (UVA), and its emission under 300nm was not negligible. The white LED did not present an appreciable emission under 380nm. CONCLUSIONS: The cut-off wavelength of most filters is between 380 and 400nm (Physiol Hydriol60C(®), IOLTECH E4T(®), Alcon SA60AT(®), Alcon IQ SN60WF(®)), so that their UV protection is very effective. Nonetheless, the IOL OPHTEC Oculaid(®) contains a filter that, when a Xe lamp is used, lets through up to 20% for 350nm and up to 15% for 300nm, which at this point is ultraviolet B (UVB). The OPHTEC(®) Artisan IOL has a transmission peak below 300nm, which must be taken into account under Xe illumination. White LEDs do not emit energy below 380nm, so no special protection is required in the UV region.

Human immunodeficiency virus (HIV) distribution in HIV encephalitis: study of 19 cases with combined use of in situ hybridization and immunocytochemistry.

Brains of 19 AIDS patients with HIV encephalitis were examined by immunohistochemistry and in situ hybridization using antisense HIV DNA and RNA probes. Double immunohistochemical labeling, using antibodies against viral and cell-type specific antigens, was utilized to study lesions in some brains. Other combined studies included use of in situ hybridization and immunohistochemical labeling of the same section, using antibodies against either viral or cell-type specific antigens. Hybridization signals were abundant and were concentrated mainly in the white matter. Heavy labeling was found in the subcortical white matter, the corpus callosum, the internal capsule, and white matter regions of the brainstem and cerebellum. Deeper cortical layers often contained cells with hybridized probe when the subcortical white matter was intensely labeled. HIV nucleic acid sequences were found almost exclusively in macrophages. Counts showed that 16-25% of macrophages contained viral antigens and exhibited hybridized HIV probe. Almost all of these macrophages contained proviral DNA, viral RNA and viral proteins; i.e. they were actively replicating HIV. We also examined brains from three AIDS cases without clinical or pathological evidence of HIV encephalitis; no HIV sequences or immunoreactive proteins were detected.

Spongiform encephalopathy in AIDS dementia complex: report of five cases.

We describe the morphological findings in the brain of five AIDS patients who died with a clinical diagnosis of dementia. We have found a spongiform change (small rounded vacuoles) in different parts of the brain and a similar but morphologically different sponginess, the status spongiosus, characterized by looser and coarser microcystic cavitations of the grey matter in which the tiny cysts and vacuoles are enmeshed by glial fibrils. At the ultrastructural level, round and oval clear spaces, divided by septae into several smaller ones, appeared in the neuropil. The pathogenesis of the majority of the vacuoles and cavitations is not clear yet but a focal loss of cortical neurons was evident and furthermore some of the vacuoles were identified as remnants of dendrites. The light and electron microscopic findings can not be interpreted as artefacts or as a simple edema of the brain and also can not be explained by the different infective complications. We have found spongiform alterations in all cases of clinically diagnosed dementia and therefore it seems obvious that these findings are quite frequent in AIDS dementia.

Influence of the contrast sensitivity function on the reaction time.

The reaction time (RT) vs spatial frequency (SF) curve is determined, using gratings from 1 to 40 c/deg, at seven different contrast levels between 0.95 and 0.02. The form of the RT/SF function: (a) replicated the inverse of the contrast sensitivity function (CSF) at near threshold contrast levels; (b) behaved differently at higher contrasts, exhibiting two branches at contrast close to 1. The interpretation is that there are two factors determining this function: (1) the transition from the operation of fast transient channels at low SF to the operation of slow sustained channels at high SF, the transition taking place within a narrow SF band close to 6 or 8 c/deg (depending on the subject) and (2) the contrast attenuation by the optical and neural transfer function, operating throughout the SF range. At high contrasts, the effect of the first factor can be clearly observed, because the effect of the second factor does not change with spatial frequency except in a region where the RT/SF function changes rapidly. At lower contrasts, however, the second factor becomes increasingly relevant while the first becomes less and less observable.

Implementations of a novel algorithm for colour constancy.

In agreement with the principles of the relativistic model proposed by Creutzfeldt et al., with the photometric rule (lightness anchoring rule) and with the influence of simultaneous contrast in the appearance of a visual scene, we propose a first-stage mechanism yielding substantial colour constancy. We have defined a set of first-stage colour descriptors, and to test their utility, we have performed a simulation using a Machine Vision System (MVS). The statistical stability of the descriptors for Munsell samples under different illuminants is good.

Influence of contrast on the recognition of defocused letters: a geometrical model.

We show how contrast (C) affects the recognition of defocused letters. To do this, the maximum distance (threshold distance) at which a subject, with an induced refraction of -5.5 D, can recognize a letter was determined. Our results show that when C = 1, the recognition threshold distance is such that the ratio eta/xi, between the pseudoimage of the letter (eta) and the blur circle (xi), corresponding to any point of the letter at this distance is about eta/xi = 2; the exact value depends on the difficulty of recognition, in agreement with previous experiments. This ratio represents the sharpness of the image in a geometrical treatment of image formation, providing a geometrical criterion for recognition. Reduction in contrast can be compensated by improving the geometrical sharpness; i.e. bringing the object closer to the subject's are point. Our results show that the increment of eta/xi as a function of the contrast is between C = 0.1 and 1.0. We suggest that a similar geometrical criterion for recognition could be used for any contrast (at least down to C = 0.1 and defocus > 1 D), provided that the proper value of eta/xi is used in each case. On this basis we propose a purely geometrical model, which agrees well with the data and predicts the relationships between tolerance to defocus, contrast and visual acuity; including the well-known relation between visual acuity and defocus when contrast is unity.

Complications following chemonucleolysis with collagenase.

Lumbar disc tissue from eight patients previously submitted to unsuccessful chemonucleolysis with collagenase was studied by light and scanning electron microscopy (SEM). Similar material from eight patients subjected to primary disc surgery served as control. The control discs revealed the characteristic signs of degeneration of collagen tissue, microcystic areas, and giant chondromas. However, the anulus fibrosus and the end-plates remained intact. Following chemonucleolysis with collagenase, "digestion" of the nucleus pulposus, the anulus fibrosus, and extensive damage to the end-plates, bone, ligaments, and epidural fat were seen.

Congenital disorders of glycosylation (CDG) may be underdiagnosed when mimicking mitochondrial disease.

Congenital disorders of glycosylation (CDG) and mitochondrial diseases are multisystem disorders with clinical characteristics that may overlap. We present four patients with CDG whose phenotypes suggested the diagnosis of a mitochondrial disease. Patients 1 and 2 are siblings with hemiplegic headache, stroke-like episodes, lactic acidaemia and history of maternal migraine; their initial clinical diagnosis was MELAS syndrome (mitochondrial encephalopathy, lactic acidosis and stroke-like episodes). Patient 3 suffers from ataxia, neuropathy, ophtalmoplegia and retinitis pigmentosa suggestive of NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. Patient 4 presented with neurological regression mimicking Leigh disease, with ptosis, myoclonus, ataxia and brainstem and cerebellar atrophy. Screening for mitochondrial disease including enzyme and mtDNA investigations on muscle biopsy were performed on Patients 1, 2 and 4 with normal results. However, evidence for a glycosylation disorder was substantiated by an increased carbohydrate deficient transferrin (CDT). The isoelectric focussing pattern of serum sialotransferrin was typical of CDG type I in Patients 1, 2 and 3 and was shifted towards the less sialylated bands in case 4. A deficiency of phosphomanomutase (PMM) confirmed the diagnosis of CDG-Ia in Patients 1, 2 and 3, who are compound heterozygous for mutations R141H/T237M (Patients 1 and 2) and R141H/P113L (Patient 3). In Patient 4, PMM activity was normal, and further enzymatic and molecular studies are underway. As the search for the primary defect in mitochondrial diseases is often unsuccessful, the pool of mitochondrial patients that remain without definite diagnosis might include CDG cases. Routine screening for CDG may avoid precocious invasive investigations.

Prevalence of coeliac disease in Down's syndrome.

OBJECTIVE: During the past decade, it has been shown that the association between Down's syndrome and coeliac disease is relatively frequent Prevalence rates of coeliac disease in patients with Down's syndrome reported by different authors are significantly higher than those found in the general population. The main purpose of this study was to assess the prevalence of coeliac disease in a series of subjects with Down's syndrome from our geographical area. DESIGN: A cross-sectional study. SETTING: Outpatient paediatric clinics of acute-care teaching hospitals in Barcelona, Spain. PARTICIPANTS: A total of 284 persons with Down's syndrome aged between 1 and 25 years were included in the study. In all cases, serum concentrations of antigliadin antibodies (AGAs) (Pharmacia CAP system enzyme-linked immunosorbent assay), antiendomysium antibodies (AEA) (indirect immunofluorescence) of immunoglobulin (Ig)A class or IgG class in cases of IgA deficiency were determined. Jejunal biopsy was offered to all patients with AEA positivity and to those with suggestive clinical manifestations of coeliac disease. In all patients, a clinical study was made to evaluate the presence and time-course of symptoms related to coeliac disease. MAIN OUTCOME MEASURES AND RESULTS: In 18 of the 284 subjects with Down's syndrome, aged between 2 and 15 years, coeliac disease was confirmed by jejunal biopsy. Accordingly, the minimum prevalence rate of coeliac disease was of 6.3%. Ninety-four percent (17/18) and 78% (14/18) of patients with the association Down's syndrome and coeliac disease showed AEA and AGA positivity, respectively. Fifteen patients with the association coeliac disease and Down's syndrome (15/18) showed clinical manifestations compatible with coeliac disease, with a predominance of intestinal symptoms (8/18) over those with atypical or extra-intestinal forms (7/18). Three patients had clinically silent forms of coeliac disease (3/ 18). CONCLUSIONS: Measurement of serum concentrations of AEA should be added to the list of screening tests for coeliac disease in patients with Down's syndrome, otherwise definite association between both diseases may pass unnoticed and diagnosis of coeliac disease be considerably delayed.

Vacuolar myelopathy in AIDS. A morphological analysis.

Between 1986 and 1988 we studied the spinal cord of 40 patients dying of AIDS. Transverse and longitudinal sections from a minimum of four levels of the spinal cord were examined by means of conventional histology, immunohistochemistry and electron microscopy. Out of 22 cases there were 6 showing a mild, 11 a moderate and 5 a severe myelopathy. Among these cases with severe myelopathy, vacuolar degeneration of the posterior, lateral, and anterior columns of the white matter, which are typical findings of vacuolar myelopathy (VM), were present. Cervical and thoracic cords were affected in all cases, the lumbal cord, however, in only two. Fusiform vacuoles, 30 to 180 microns in diameter and 200 to 500 microns in length, could be seen rising between the axolemma and the myelin sheath. Most of them were still containing an axon cylinder. Foamy phagocytic cells, phagocytosing axons of apparently preserved structure were found within the vacuoles. These foamy macrophages contained rests of axons in their cytoplasm. However, only one case with severe tissue disruption exhibited myelin debris as well. Our morphological findings suggest that in VM of AIDS a process of phagocytosis directed against the axon cylinders occurs simultaneously with vacuolar degeneration of the white matter of the spinal cord. The results suggest furthermore that VM, especially its moderate form, appears to be a more frequent condition than previously assumed.

Gliomatosis cerebri: clinical and histological findings.

The clinical and pathological data of ten patients with gliomatosis cerebri are compared with 48 well documented cases from the literature. The most striking clinical findings were behavioural and mental changes, seizures, motor weakness and headaches. Though diagnostic techniques have gained in sophistication, the clinical diagnosis of gliomatosis cerebri remains difficult. Laboratory and radiograph tests are mostly unconclusive. Expectations that computed tomography might lead to an accurate diagnosis were not fulfilled. Histological examination disclosed a diffuse proliferation of glial elements infiltrating normal nervous tissue with destruction of myelin sheaths, but only slight damage to neurons and axons. In two cases, areas typical of oligodendroglioma were also present. Glial fibrillary acidic protein staining showed in seven cases that most of the neoplastic cells were of astrocytic origin. In addition, GFAP negative neoplastic cells with the appearance of oligodendroglia and intermediate elements between astroglia and oligodendroglia and irregularly shaped naked nuclei of unidentified nature were found. On the basis of the two-stage theory of carcinogenesis, it is suggested that this disease might be the result of propagation of initiated glial elements which have not yet undergone the process of tumor conversion.

Severe toxoplasmic ventriculomeningoencephalomyelitis in two AIDS patients following treatment of cerebral toxoplasmic granuloma.

Two patients with acquired immunodeficiency syndrome (AIDS) who were successfully treated for cerebral toxoplasmosis presented a few weeks later with neurologic abnormalities. Brain CT scan showed ventricular dilatation, ependymitis, and meningoencephalitis. Both patients died despite extensive treatment. Neuropathological examination showed enlargement of the cerebral ventricles, severe ventriculoencephalitis with large ependymal and subependymal necrosis, and numerous pseudomembranes within the ventricle lumen. Microscopic examination revealed severe necrotizing ventriculoencephalitis, meningoencephalitis and myelitis. Immunohistochemical studies revealed the presence of miriads of tachyzoites within and around the necrotic areas. Such form of toxoplasmosis as a diffuse meningo-encephalo-ventriculo-myelitis appear unique to AIDS and, to our knowledge, have not been previously documented.

Anergic disseminated toxoplasmosis in a patient with the acquired immunodeficiency syndrome.

Cerebral toxoplasmosis is the most common cause of focal brain disease in patients with the acquired immunodeficiency syndrome. A 24-year-old human immunodeficiency virus-infected woman with two previous episodes of Pneumocystis carinii pneumonia presented with diarrhea and fever. Despite antibiotic treatment, septic shock developed, and she died 3 weeks after the symptoms began. Histologic and histochemical studies revealed an anergic toxoplasmosis with dissemination in all examined organs. There were multiple foci of toxoplasmic cysts and free tachyzoites, sometimes with minute areas of necrosis, but no inflammatory reaction at all. Since effective treatment of toxoplasmosis is available, the occurrence of this rare form of toxoplasmosis should be kept in mind.