Active and sham transcranial direct current stimulation (tDCS) improved quality of life in female patients with fibromyalgia.

PURPOSE: Fibromyalgia (FM) is a chronic pain syndrome with a strong impact on quality of life (QoL). Treatment of this condition remains a challenge, due to the scarce evidence for the effectiveness of the therapeutic approaches available. Current attention is focused on transcranial direct current stimulation (tDCS), which has yielded promising results for pain treatment. Rather than focusing only on pain relief, in this study, we aimed to determine how active or sham tDCS (over three cortical targets -the primary motor cortex, the dorsolateral prefrontal cortex and the operculo-insular cortex-) affect QoL in patients with FM. METHODS: Using a double-blind, placebo-controlled design, we applied fifteen tDCS sessions of 20' to initial 130 participants (randomized to any of the four treatment groups). We evaluated the QoL (assessed by SF-36) and the symptoms' impact (assessed by FIQ-R) in baseline, after treatment and at 6 months follow-up. RESULTS: All groups were comparable as regards age, medication pattern and severity of symptoms before the treatment. We found that QoL and symptoms' impact improved in all treatment groups (including the sham) and this improvement lasted for up to 6 months. However, we did not observe any group effect nor group*treatment interaction. CONCLUSIONS: After the intervention, we observed a non-specific effect that may be due to placebo, favoured by the expectations of tDCS efficacy and psychosocial variables inherent to the intervention (daily relationship with therapists and other patients in the clinic). Therefore, active tDCS is not superior to sham stimulation in improving QoL in FM.

Effects of intensity, attention and medication on auditory-evoked potentials in patients with fibromyalgia.

Fibromyalgia (FM) has been associated to an increased processing of somatosensory stimuli, but its generalization to other sensory modalities is under discussion. To clarify this, we studied auditory event-related potentials (AEPs) to stimuli of different intensity in patients with FM and healthy controls (HCs), considering the effects of attention mechanisms and medication. We performed two experiments: In study 1 (n = 50 FM, 60 HCs), the stimuli were presented randomly within the sequence; in study 2 (n = 28 FM, 30 HCs), they were presented in blocks of the same intensity. We analyzed intensity and group effects on N1-P2 amplitude and, only for the FM group, the effect of medication and the correlation between AEPs and clinical variables. Contrary to the expectation, the patients showed a trend of reduced AEPs to the loudest tones (study 1) or no significant differences with the HCs (study 2). Medication with central effects significantly reduced AEPs, while no significant relationships between the N1-P2 amplitude/intensity function and patients' symptoms were observed. The findings do not provide evidence of augmented auditory processing in FM. Nevertheless, given the observed effect of medication, the role of sensory amplification as an underlying pathophysiological mechanism in fibromyalgia cannot be discarded.

Neural correlates of cognitive dysfunction in fibromyalgia patients: Reduced brain electrical activity during the execution of a cognitive control task.

OBJECTIVES: Fibromyalgia (FM) is a generalized chronic pain syndrome of unknown aetiology. Although FM patients frequently complain of cognitive dysfunction, this is one of the least studied symptoms. Research on brain activity associated with the perceived cognitive impairment is particularly scarce. To address this gap, we recorded the brain electrical activity in participants during a cognitive control task. METHODS: Electroencephalograms (EEGs) were recorded in 19 FM patients and 22 healthy controls (all women) while they performed the Multi-Source Interference Task (MSIT). We analyzed the amplitude of the frontal N2 and parietal P3 components elicited in control and interference trials and their relation with reaction times. We also explored the relationship of perceived cognitive dysfunction, assessed using visual analogue scales (VAS) and the Memory Failures of Everyday (MFE-30) test, with N2 and P3 amplitudes. RESULTS: The N2 amplitudes were smaller in FM patients than in controls and were negatively associated with cognitive complaints. Unlike patients, healthy controls showed significant differences in the amplitude of P3 obtained from control vs. interference trials of the MSIT. Smaller N2 and P3 amplitudes were associated to longer reaction times. CONCLUSIONS: The findings suggest a reduction in frontal brain activity during performance of an interference task, which was associated with the patients' cognitive complaints. Findings on P3 suggest altered modulation of attention according to the task demands in FM patients. Deficits in flexibility in the allocation of attentional resources and cognitive control during complex tasks may explain the dyscognition reported by chronic pain patients.

Effect of the stop-signal modality on brain electrical activity associated with suppression of ongoing actions.

To clarify how the modality of stop signals affects the ability to suppress ongoing actions, we compared behavioural indices and event-related potentials (ERPs) recorded in healthy volunteers performing visual and auditory stop-signal tasks. Auditory stop signals were associated with faster reaction times and shorter stop-N2 and stop-P3 latencies. Given that the tasks did not differ in attentional/arousal processes (go-P3 or stop-P3 amplitudes) or motor preparation (LRP amplitude, onset or latency), our results suggest that stop signal modality mainly affects bottom-up sensory processes (faster auditory processing). The ERP waveform obtained by subtracting successfully stopped from unsuccessfully stopped trials showed similar amplitude and topography in both tasks, indicating that the strength of top-down processes related to inhibition was independent of modality. The findings contribute further knowledge about the variables associated with efficient inhibition and have practical implications for the design of settings or interventions to improve reactive inhibition.

Pain Expressions and Inhibitory Control in Patients With Fibromyalgia: Behavioral and Neural Correlates.

Fibromyalgia (FM) is a generalized chronic pain condition associated with a variety of symptoms, including altered cognitive and emotional processing. It has been proposed that FM patients show a preferential allocation of attention to information related to the symptoms of the disease, particularly to pain cues. However, the existing literature does not provide conclusive evidence on the presence of this attentional bias, and its effect on cognitive functions such as inhibitory control. To clarify this issue, we recorded the electroencephalographic activity of 31 women diagnosed with FM and 28 healthy women, while performing an emotional Go/NoGo task with micro-videos of pain, happy, and neutral facial expressions. We analyzed behavioral data, performed EEG time-frequency analyses, and obtained the event-related potentials (ERPs) N2 and P3 components in NoGo trials. A series of self-reports was also administered to evaluate catastrophic thinking and the main symptoms of fibromyalgia. Pain expressions were associated with longer reaction times and more errors, as well as with higher theta and delta power, and P3 amplitude to NoGo stimuli. Thus, behavioral and psychophysiological data suggest that increased attention to pain expressions impairs the performance of an inhibitory task, although this effect was similar in FM patients and healthy controls. N2 amplitude was modulated by type of facial expression (larger to pain faces), but only for the control group. This finding suggests that the presentation of pain faces might represent a smaller conflict for the patients, more used to encounter pain stimuli. No main group effects were found significant for N2 or P3 amplitudes, nor for time-frequency data. Using stimuli with greater ecological validity than in previous studies, we could not confirm a greater effect of attentional bias toward negative stimuli over inhibitory performance in patients with FM. Studying these effects allow us to better understand the mechanisms that maintain pain and develop intervention strategies to modify them.

Increased neural noise and impaired brain synchronization in fibromyalgia patients during cognitive interference.

Fibromyalgia (FM) and other chronic pain syndromes are associated with cognitive dysfunction and attentional deficits, but the neural basis of such alterations is poorly understood. Dyscognition may be related to high levels of neural noise, understood as increased random electrical fluctuations that impair neural communication; however, this hypothesis has not yet been tested in any chronic pain condition. Here we compared electroencephalographic activity (EEG) in 18 FM patients -with high self-reported levels of cognitive dysfunction- and 22 controls during a cognitive control task. We considered the slope of the Power Spectrum Density (PSD) as an indicator of neural noise. As the PSD slope is flatter in noisier systems, we expected to see shallower slopes in the EEG of FM patients. Higher levels of neural noise should be accompanied by reduced power modulation and reduced synchronization between distant brain locations after stimulus presentation. As expected, FM patients showed flatter PSD slopes. After applying a Laplacian spatial filter, we found reduced theta and alpha power modulation and reduced midfrontal-posterior theta phase synchronization. Results suggest higher neural noise and impaired local and distant neural coordination in the patients and support the neural noise hypothesis to explain dyscognition in FM.

Effects of genetic background on cardiovascular anomalies in the Ts16 mouse.

To investigate the genetic contribution to phenotypic variability in aneuploidy, we generated mice with trisomy 16 (Ts16) by mating [Rb(6.16)24Lub x Rb(16.17)7Bnr]F1 males with females from four inbred strains, BALB/cJ, C3H/HeJ, C57BL/6J, and DBA/2J. Among the four Ts16 strains that were generated, there were no significant differences in survival, weight, or length relative to euploid control littermates at either embryonic day (E) 14.5 or E17.5. All Ts16 fetuses at E14.5 had edema that ranged from mild to severe, increased amniotic fluid volume, and a thickened neck. At E17.5, Ts16 fetuses exhibited two distinct phenotypes, one with an edematous morphology and the other runt-like. None of these gross morphological abnormalities was strain-specific either in occurrence or frequency. At E10.5, there were pharyngeal arch artery (PAA) anomalies in all Ts16 embryos on the C3H/HeJ background, but none in trisomics on the other three backgrounds. However, at E17.5, there was in addition to ventricular and atrioventricular septal defects, a high frequency of aortic arch defects in Ts16 fetuses, irrespective of genetic background. Taken together, these findings indicate that there are at least two mechanistic responses to the presence of three copies of mouse chromosome 16 in the modeling of the cardiovascular system: one, development of PAA defects, is strongly influenced by genetic background; but the second, development of aortic arch anomalies in the absence of preexisting PAA anomalies, is not.

Cardiomyopathy in mice with paternal uniparental disomy for chromosome 12.

Mice inheriting both copies of MMU12 either maternally or paternally demonstrate imprinting effects. Whereas maternal uniparental disomy 12 (matUPD12) fetuses are growth retarded and die perinatally, paternal UPD12 (patUPD12) fetuses die during late gestation and exhibit placentomegaly and skeletal muscle maturation defects. To examine further the developmental consequences of UPD12, we intercrossed mouse stocks heterozygous for Robertsonian translocation chromosomes (8.12) and (10.12). We report that at 13.5-14.5 dg patUPD12 hearts exhibit increased ventricular diameter, thinner, less compact myocardium, and deep intertrabecular recesses when compared to controls. These data provide evidence for cardiac failure, a lethal condition, and suggest a role for an imprinted gene(s) in normal heart development.

Syntenic organization of the mouse distal chromosome 7 imprinting cluster and the Beckwith-Wiedemann syndrome region in chromosome 11p15.5.

In human and mouse, most imprinted genes are arranged in chromosomal clusters. Their linked organization suggests co-ordinated mechanisms controlling imprinting and gene expression. The identification of local and regional elements responsible for the epigenetic control of imprinted gene expression will be important in understanding the molecular basis of diseases associated with imprinting such as Beckwith-Wiedemann syndrome. We have established a complete contig of clones along the murine imprinting cluster on distal chromosome 7 syntenic with the human imprinting region at 11p15.5 associated with Beckwith-Wiedemann syndrome. The cluster comprises approximately 1 Mb of DNA, contains at least eight imprinted genes and is demarcated by the two maternally expressed genes Tssc3 (Ipl) and H19 which are directly flanked by the non-imprinted genes Nap1l4 (Nap2) and Rpl23l (L23mrp), respectively. We also localized Kcnq1 (Kvlqt1) and Cd81 (Tapa-1) between Cdkn1c (p57(Kip2)) and Mash2. The mouse Kcnq1 gene is maternally expressed in most fetal but biallelically transcribed in most neonatal tissues, suggesting relaxation of imprinting during development. Our findings indicate conserved control mechanisms between mouse and human, but also reveal some structural and functional differences. Our study opens the way for a systematic analysis of the cluster by genetic manipulation in the mouse which will lead to animal models of Beckwith-Wiedemann syndrome and childhood tumours.

AIDS knowledge and attitudes of health-care workers in Mexico.

AIDS threatens to spread rapidly in Mexico. In the present study, results of a survey of 204 Mexican employees in hospitals and doctors' offices indicated that those health-care workers were largely knowledgeable about the illness. A majority were willing to provide AIDS care, although they feared contagion. Multiple regression analyses indicated that (a) attitudes toward high-risk groups (intravenous drug users and homosexuals) and (b) fear of contagion were both related to intentions to provide care to AIDS patients.

PIP: A survey conducted in Ciudad Juarez, in the Mexican state of Chihuahua, investigated health care workers' (HCWs) AIDS knowledge, attitudes, and willingness to provide care to AIDS patients. Questioned were 171 HCWs employed in a public charity hospital and 33 from private physicians' offices. 24% of respondents were nurses and 22% were doctors; mean age was 28 years. On average, respondents answered 82% of the AIDS-related knowledge items correctly and 76% felt their education had prepared them to treat AIDS patients. Despite widespread awareness of the modes of HIV transmission and the universal precautions, 87% expressed concern about becoming infected with HIV through patient care. 81% indicated they were willing to treat AIDS patients. Most HCWs had positive (19%) or neutral (53%) attitudes toward homosexuals, but 44% expressed negative attitudes toward intravenous drug users. Multiple regression analysis found that attitude toward high-risk groups and fear of contagion, but not knowledge, were related to behavioral intention to provide AIDS care. This finding is consistent with research indicating that knowledge-based programs that fail to address the affective component of AIDS care are insufficient for changing AIDS care intentions and behaviors. Overall, AIDS patients in the border areas of Mexico, appear to be receiving more effective treatment than those in parts of the country with lower AIDS prevalence. Reports from the latter areas allege incidents of refusal to provide medical care to AIDS patients or the provision of substandard care.

Interspecies approaches for the analysis of parental imprinting during mouse development.

Genomic imprinting results in the functional specialization of the maternal and paternal genomes during development whereby offspring inherit only one active copy of a gene. Although the reason for its evolutionary genesis remains speculative, the consequences of genomic imprinting are evidenced by the failure of parthenogenetic and androgenetic development in mammals, and parental-specific effects in the etiology of a number of human diseases. While the precise molecular mechanism of imprinting is unknown, evidence suggests that the specialization of the parental genomes is established during gametogenesis when the parental genomes are epigenetically modified to reflect the parent of origin. To examine the epigenetic modification of specific imprinted genes and subsequent differential expression, an assay is required that can distinguish between the maternal and paternal alleles and their respective transcripts. During the past 5 years several strategies have been used to identify imprinted genes, ranging from the fortuitous disruption of specific parental alleles to subtraction hybridization between cDNAs from normal and parthenogenetic embryos. To study the developmental regulation of these imprinted genes during mammalian development, we describe a relatively simple interspecies "mRNA phenotyping" approach applicable to the analysis of allele-specific expression as well as the identification of candidate imprinted genes.

Imprinting mutation in the Beckwith-Wiedemann syndrome leads to biallelic IGF2 expression through an H19-independent pathway.

The Beckwith-Wiedemann syndrome (BWS) is genetically linked to chromosome 11p15.5, and a variety of observations suggest that deregulation of imprinted genes in this region is causally involved in the pathogenesis of the disease. It has been shown that in some patients without cytogenetic abnormalities the otherwise repressed maternal copy of the insulin-like growth factor 2 (IGF2) gene is expressed, leading to biallelic expression of IGF2. In some of these cases, this is accompanied by repression and DNA methylation of the maternal (otherwise active) copy of the neighbouring H19 gene. Hence, it is attractive to think that mutations may interfere with some aspect of H19 imprinting, thus leading to an inactive maternal allele, and indirectly to activation of the maternal IGF2 allele as reported in mice with an H19 gene deletion. However, no mutations have been identified so far in these patients. The only known mutations associated with BWS are maternally transmitted translocations, which are clustered in two locations centrometric to IGF2. The first cluster is 200-400 kb from IGF2 and the second is several megabases away. Hence, genes located far from the translocation breakpoints are potentially deregulated by them. Here we provide the first evidence of alteration of imprinting in a translocation family, with biallelic expression of IGF2 and altered DNA replication patterns in the IGF2 region. Interestingly, H19 imprinting was normal, suggesting an H19-independent pathway to biallelic IGF2 transcription. DNA methylation in IGF2 remained monoallelic, suggesting that the mutation in this family had uncoupled allele-specific methylation from expression.

Developmental regulation of genomic imprinting during gametogenesis.

Successful mammalian development requires both the male and female genomes. This is due in part to genomic imprinting, which results in offspring inheriting only one functional copy of a gene from either the mother or the father. Evidence suggests that this specialization of the parental genomes is established during gametogenesis when the imprint pattern inherited from the parent is switched to reflect the sex of the progeny. We used reverse transcription-PCR to analyze the allele-specific expression of Igf-2, Igf-2r, and H19 in the testes and ovaries of mice derived from an interspecies cross between Mus musculus and Mus spretus. Because of genomic imprinting, Igf-2 is expressed only from the paternal allele and Igf-2r and H19 only from the maternal allele, in most tissues. Although allele-specific expression was maintained in the neonatal testis and ovary, relaxation of imprinting was detected by 7 days after birth in the male and continued during testis development. In the female, relaxation of the Igf-2 and Igf-2r parental imprints was observed in the adult ovary and oocyte. These results (1) indicate that imprinted expression is relaxed during gametogenesis, presumably as a consequence or prerequisite of the imprinting mechanism, and (2) predict a subsequent imprinting event after which the allele-specific expression of Igf-2, Igf-2r, and H19 reflects the parent of origin.

Parental imprinting of the Mas protooncogene in mouse.

The Mas protooncogene on mouse chromosome 17 encodes a mitogenic G-protein-coupled cell surface receptor. We investigated the allele-specific expression pattern of the Mas gene on the basis of its proximity to the known imprinted gene for the insulin growth factor type II receptor (Igf2r). Phenotyping of mRNA demonstrated exclusive expression from the paternal allele in all embryonic tissues, including visceral yolk sac, between 11 and 12.5 days of gestation. By 13.5 days of gestation the paternal allele-specific expression of Mas was restricted to heart, tongue and visceral yolk sac, whereas all other tissues exhibited relaxation of the parental imprint. Our results demonstrate parental imprinting of Mas and suggest that the maternally inherited allele is transcriptionally repressed in a developmental and tissue-specific manner.

Spatially restricted imprinting of mouse chromosome 7.

Three of the four known imprinted genes (Igf-2, H19, and Snrpn) map to mouse chromosome 7. We used mRNA phenotyping to examine the tissue-specific transcription of Igf-1r, H-ras-1, and Gabrb3, which map to chromosome 7 between Snrpn and the Igf-2/H19 domain, and Myod-1, which maps proximal to Snrpn. We found that all of these genes were expressed by both parental alleles in tissues from day 1 neonates. The fact that imprinted genes can flank or map closely to genes that escape such epigenetic modification suggests that autosomal imprinting is not manifested globally along imprinted chromosomes but rather is spatially restricted, perhaps even defined by specific DNA consensus sequences or an "imprint box" associated with imprintable genes.

Subunidad beta de la gonadotropina corionica en el control de la enfermedad trofoblastica benigna. / Beta subunity of the corionic gonadotrophin in the control of benign throphoblastic disease

Se estudiaron 26 casos de enfermedad trofoblastica de curso benigno postevacuacion uterina de embarazo molar, analizando el comportamiento de la hormona gonadotropina corionica, mediante su determinacion en orina por metodo inmunologico asi como de la subunidad beta medida en suero por radioinmunoensayo. Con ambos metodos se observo descenso de los niveles hormonales hasta la negativizacion, la cual fue mas retardada y, por lo tanto, mas especifica en la subunidad beta, lo que es de gran importancia en la practica para demostrar ausencia de actividad trofoblastica