Different types of abstract concepts: evidence from two neurodegenerative patients.

The observation of neurological patients showing selective impairments for specific conceptual categories contributed in the development of semantic memory theories. Here, we studied two patients (P01, P02), affected, respectively, by the semantic variant of Primary Progressive Aphasia (sv-PPA) and Cortico-Basal Syndrome (CBS). An implicit lexical decision task, including concrete (animals, tools) and abstract (emotions, social, quantity) concepts, was administered to patients and healthy controls.P01 and P02 showed an abolished priming effect for social and quantity-related concepts, respectively. This double dissociation suggests a role of different brain areas in representing specific abstract categories, giving insights for current semantic memory theories.

Multifunctional scaffolds for biomedical applications: Crafting versatile solutions with polycaprolactone enriched by graphene oxide.

The pressing need for multifunctional materials in medical settings encompasses a wide array of scenarios, necessitating specific tissue functionalities. A critical challenge is the occurrence of biofouling, particularly by contamination in surgical environments, a common cause of scaffolds impairment. Beyond the imperative to avoid infections, it is also essential to integrate scaffolds with living cells to allow for tissue regeneration, mediated by cell attachment. Here, we focus on the development of a versatile material for medical applications, driven by the diverse time-definite events after scaffold implantation. We investigate the potential of incorporating graphene oxide (GO) into polycaprolactone (PCL) and create a composite for 3D printing a scaffold with time-controlled antibacterial and anti-adhesive growth properties. Indeed, the as-produced PCL-GO scaffold displays a local hydrophobic effect, which is translated into a limitation of biological entities-attachment, including a diminished adhesion of bacteriophages and a reduction of E. coli and S. aureus adhesion of ∼81% and ∼69%, respectively. Moreover, the ability to 3D print PCL-GO scaffolds with different heights enables control over cell distribution and attachment, a feature that can be also exploited for cellular confinement, i.e., for microfluidics or wound healing applications. With time, the surface wettability increases, and the scaffold can be populated by cells. Finally, the presence of GO allows for the use of infrared light for the sterilization of scaffolds and the disruption of any bacteria cell that might adhere to the more hydrophilic surface. Overall, our results showcase the potential of PCL-GO as a versatile material for medical applications.

Deep learning for MYC binding site recognition.

Motivation: The definition of the genome distribution of the Myc transcription factor is extremely important since it may help predict its transcriptional activity particularly in the context of cancer. Myc is among the most powerful oncogenes involved in the occurrence and development of more than 80% of different types of pediatric and adult cancers. Myc regulates thousands of genes which can be in part different, depending on the type of tissues and tumours. Myc distribution along the genome has been determined experimentally through chromatin immunoprecipitation This approach, although powerful, is very time consuming and cannot be routinely applied to tumours of individual patients. Thus, it becomes of paramount importance to develop in silico tools that can effectively and rapidly predict its distribution on a given cell genome. New advanced computational tools (DeeperBind) can then be successfully employed to determine the function of Myc in a specific tumour, and may help to devise new directions and approaches to experiments first and personalized and more effective therapeutic treatments for a single patient later on. Results: The use of DeeperBind with DeepRAM on Colab platform (Google) can effectively predict the binding sites for the MYC factor with an accuracy above 0.96 AUC, when trained with multiple cell lines. The analysis of the filters in DeeperBind trained models shows, besides the consensus sequence CACGTG classically associated to the MYC factor, also the other consensus sequences G/C box or TGGGA, respectively bound by the SP1 and MIZ-1 transcription factors, which are known to mediate the MYC repressive response. Overall, our findings suggest a stronger synergy between the machine learning tools as DeeperBind and biological experiments, which may reduce the time consuming experiments by providing a direction to guide them.

Mortality and cause of death among psychiatric patients: a 20-year case-register study in an area with a community-based system of care.

BACKGROUND: Most mortality studies of psychiatric patients published to date have been conducted in hospital-based systems of care. This paper describes a study of the causes of death and associated risk factors among psychiatric patients who were followed up over a 20-year period in an area where psychiatric care is entirely provided by community-based psychiatric services. METHOD: All subjects in contact with the South Verona Community-based Mental Health Service (CMHS) over a 20-year period with an ICD-10 psychiatric diagnosis were included. Of these 6956 patients, 938 died during the study period. Standardized mortality ratios (SMRs) and Poisson multiple regressions were used to assess the excess of mortality in the sample compared with the general population. RESULTS: The overall SMR of the psychiatric patients was 1.88. Mortality was significantly high among out-patients [SMR 1.71, 95% confidence interval (CI) 1.6-1.8], and higher still following the first admission (SMR 2.61, 95% CI 2.4-2.9). The SMR for infectious diseases was higher among younger patients and extremely high in patients with diagnoses of drug addiction (216.40, 95% CI 142.5-328.6) and personality disorders (20.87, 95% CI 5.2-83.4). CONCLUSIONS: This study found that psychiatric patients in contact with a CMHS have an almost twofold higher mortality rate than the general population. These findings demonstrate that, since the closure of long-stay psychiatric hospitals, the physical health care of people with mental health problems is often neglected and clearly requires greater attention by health-care policymakers, services and professionals.

Graphene oxide touches blood: in vivo interactions of bio-coronated 2D materials.

Graphene oxide is the hot topic in biomedical and pharmaceutical research of the current decade. However, its complex interactions with human blood components complicate the transition from the promising in vitro results to clinical settings. Even though graphene oxide is made with the same atoms as our organs, tissues and cells, its bi-dimensional nature causes unique interactions with blood proteins and biological membranes and can lead to severe effects like thrombogenicity and immune cell activation. In this review, we will describe the journey of graphene oxide after injection into the bloodstream, from the initial interactions with plasma proteins to the formation of the "biomolecular corona", and biodistribution. We will consider the link between the chemical properties of graphene oxide (and its functionalized/reduced derivatives), protein binding and in vivo response. We will also summarize data on biodistribution and toxicity in view of the current knowledge of the influence of the biomolecular corona on these processes. Our aim is to shed light on the unsolved problems regarding the graphene oxide corona to build the groundwork for the future development of drug delivery technology.

Hepatic and cardiac and iron overload detected by T2* magnetic resonance (MRI) in patients with myelodisplastic syndrome: A cross-sectional study.

INTRODUCTION: Transfusion-dependent anemia and iron overload are associatedwith reduced survival in myelodysplastic syndrome (MDS). This cross-sectional study aimed to evaluate the prevalence of hepatic and cardiac overload in patients with MDS as measured by T2* magnetic resonance imaging (MRI), and its correlation with survival. METHODS: MDS or chronic myelomonocytic leukemia patients had iron overload evaluated by T2* MRI. HIO was considered when hepatic iron concentration ≥ 2 g/mg. Cardiac iron overload was considered with a T2*-value < 20 ms. RESULTS: Among 71 patients analyzed, median hepatic iron concentration was 3.9 g/mg (range 0.9-16 g/mg), and 68%of patients had hepatic iron overload. Patients with hepatic iron overload had higher mean ferritin levels (1182 ng/mL versus 185 ng/mL, p < 0.0001), transferrin saturation (76% versus 34%, p < 0.0001) and lower survival rates. Median cardiac T2*value was 42 ms (range 19.7-70.1 ms), and only one patienthad a T2* value indicative of cardiac iron overload. CONCLUSIONS: Hepatic iron overload is found in two thirds of patients, even in cases without laboratory signs of iron overload. Hepatic iron overload by T2* MRI is associated with a decreased risk of survival in patients with MDS.

The gene for a novel human lamin maps at a highly transcribed locus of chromosome 19 which replicates at the onset of S-phase.

A previously described human DNA fragment which is replicated early in S-phase of HL-60 cell DNA (C. Tribioli, G. Biamonti, M. Giacca, M. Colonna, S. Riva, and A. Falaschi, Nucleic Acids Res. 15:10211-10232, 1987) was used to screen a genomic library in lambda Ch28. A clone which contained a 13.7-kb insert (L30E) found to code for several transcripts was isolated. The transcription of L30E DNA exhibited a complex pattern and a tissue-specific and proliferation-dependent type of regulation. The data were consistent with two tandemly arranged transcription units, the 3' end of one separated from the 5' end of the other by a sequence of about 600 bp containing an active promoter. The isolation and sequencing of L30E-specific cDNAs permitted identification of two genes, one of which encoded a B-type human lamin (analogous to mouse lamin B2). L30E DNA was mapped by in situ hybridization at the G-negative subtelomeric band p13.3 of chromosome 19. Interestingly, in synchronized HL-60 cells, L30E DNA is replicated in the first minute of S-phase. Replication of the lamin gene early in S-phase may reflect a coupling between early replication and transcription of genes for S-phase-specific proteins such as lamins.

Presence of transcription signals in two putative DNA replication origins of human cells.

We describe the purification and cloning of human DNA replicated at the onset of S phase in HL60 cells synchronized with aphidicolin. A survey of the overall structural properties of these sequences did not show any distinctive features except for an enrichment in Cot0 DNA. The two longer fragments were completely sequenced and studied in more detail. Both were shown to contain transcriptional signals associated with promoters and/or enhancers, such as the binding sites of Sp1, T antigen and nuclear factor III. In one instance, a binding site for a known cellular transcription factor (USF/MLTF) was located inside the sequence by footprinting. Accordingly, by CAT assay and Northern blot, the same sequence was shown to contain an active promoter. The significance of these findings with respect to the role of transcription in initiation of DNA replication at the origin is discussed. None of the tested fragments exhibited autonomously replicating sequence (ARS) activity in transfected cells. The problems connected with the detection of ARS activity in human cells are critically examined.

Effects of carbamazepine on pituitary-adrenal function in healthy volunteers.

Carbamazepine (CBZ) is a widely used therapeutic agent in seizure, pain, and mood disorders. Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro, limited data suggest that systemic CBZ induces pituitary-adrenal activation. Few data are available to reconcile these effects or clarify their mechanism(s), particularly in healthy human subjects. We report here a study of basal ACTH and cortisol secretion and their responses to ovine CRH administration in nine healthy volunteers, studied both during repeated (2-3 weeks) administration of CBZ and while medication free. CBZ significantly increased mean 24-h urinary free cortisol (mean +/- SE, 197 +/- 17 vs. 137 +/- 24 nmol/day; P less than 0.02) and evening basal total plasma cortisol (113 +/- 17 vs. 83 +/- 14 nmol/L; P less than 0.05) as well as cortisol-binding globulin-binding capacity (497 +/- 36 vs. 433 +/- 28 nmol/L; P less than 0.01). Despite the CBZ-induced hypercortisolism, plasma ACTH responses to CRH during CBZ treatment remained robust, rather than being suppressed by basal hypercortisolism. In fact, during CBZ treatment, we noted a positive correlation between the increase in basal plasma cortisol and the increase in the plasma ACTH response to CRH (r = 0.65; P less than 0.05). We also observed a reduction in cortisol-binding globulin-binding capacity after CRH administration (315 +/- 25 vs. 433 +/- 28 nmol/L; P less than 0.001), which was accentuated by CBZ treatment (342 +/- 19 vs. 497 +/- 36 nmol/L; P less than 0.001; magnitude of fall, -155 +/- 22 nmol/L on CBZ vs. -118 +/- 11 nmol/L off CBZ; P less than 0.05). We conclude that CBZ increases plasma cortisol secretion in healthy volunteers independent of its effect on plasma cortisol-binding capacity. This pituitary-adrenal activation seems to reflect a pituitary, rather than a hypothalamic, effect of CBZ. Hence, despite CBZ-induced hypercortisolism, the ACTH response to CRH remained robust in direct proportion to the CBZ-induced rise in basal plasma cortisol. Thus, we propose that the increased cortisol secretion observed during CBZ treatment reflects a relative inefficacy of glucocorticoid negative feedback at the pituitary. This pituitary-driven increase in cortisol secretion combined with the expected reduction in centrally directed CRH secretion could contribute to the anticonvulsant properties of CBZ.

Plasma interleukin-1 beta and tumor necrosis factor concentrations in obsessive-compulsive disorders.

Plasma interleukin-1 beta (Il-1 beta) and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured twice, at a 48-hour interval, in 27 drug-free obsessive-compulsive patients (12 women and 15 men) and in 27 sex-age-matched healthy controls. Il-1 beta and TNF-alpha concentrations were significantly lower in patients than in controls, whereas there were no differences in either group between men and women, between the samples of the two days, or, in the patients, between those who had and those who had not been previously treated with psychopharmacologic drugs.

Cognitive impairment and (CTG)n expansion in myotonic dystrophy patients.

BACKGROUND: Myotonic dystrophy (DM) is a genetic multisystemic disease with muscular, endocrine, ocular, cardiac and cognitive impairment. The molecular basis of the disease has been identified in an unstable base triplet (CTG)n repeat located in the 3' untranslated region of the miotonin protein-kinase (MT-PK) gene on the long arm of chromosome 19. Cognitive impairment could be a direct expression of this genetic alteration at the central nervous system (CNS) level rather than a consequence of the neuromuscular impairment. To explore this hypothesis, we tested a group of genetically diagnosed, adult onset DM, of their nonaffected relatives (NAR), of patients with spinal muscle atrophy (SMA), and of normal controls using the Wechsler Adult Intelligence Scale (WAIS). METHODS: Seventeen adult-onset DM patients, 9 NAR, 10 SMA patients and 20 unrelated normal controls (NC) were studied. Clinical, neuromuscular and neuropsychiatric evaluation, which included WAIS and the Schedule for Affective Disorders and Schizophrenia (SADS), were performed on the four groups. DM, NAR and NC were also assessed by a neurophysiological (P300) evaluation. A DNA analysis was performed in DM and in NAR to measure presence and magnitude of CTG expansion. RESULTS: We found a statistically significant difference between verbal (p < .0003), nonverbal (p < .0001) and total (p < .0001) IQ of DM patients compared to IQs of NAR, SMA and NC. Seven out of 11 WAIS subtests were significantly and consistently lower in DM patients compared to SMA and/or NC. In DM patients there was a statistically significant negative correlation between nonverbal (r = -.68; p < .002) and total (r = .59; p < .01) IQ and (CTG)n. Patients with DM had a significantly lower P300 amplitude compared to NAR and NC. CONCLUSIONS: Our study indicates that in DM there is a mild but significant cognitive impairment which correlates with the degree of CTG expansion and it is not dependent on the neuromuscular impairment; however further studies with larger groups of patients and controls are suggested to confirm our results, due to the small sample size and to a possible effect of educational level in our patients.

A repeated element in the human lamin B2 gene covers most of an intron and reiterates the exon/intron junction.

Nuclear lamins are intermediate filament-type proteins forming a fibrillar meshwork that underlies the inner nuclear membrane. We have previously reported the identification of the human lamin B2 gene that maps to the subtelomeric band p13.3 of chromosome 19 in close proximity of a human DNA replication origin. Here we report the identification within the human lamin B2 gene of a novel repeated element (variable number of tandem repeats: VNTR) that appears to have a very recent origin, being absent in the genome of mouse and primates such as cercopitheques, lemurs and macaques. The VNTR is adjacent to exon 8 of the lamin B2 gene which, albeit encoding the nuclear localization signal of the protein, is highly divergent both at amino acid and nucleotide level among species. Moreover the VNTR, characterized by a repeated unit of about 100 bp, covers most of intron 8 of the gene and reiterates both the last 7 bp of the upstream exon and the exon/intron junction. RT-PCR experiments carried out on HeLa cell RNA suggest that none of the downstream junctions is used during the processing of the lamin B2 pre-mRNA.

Searching for replication origins in mammalian DNA.

The attempts at identifying precise replication origins (ori) in mammalian DNA have been pursued mainly through physico-chemical and biochemical approaches, in view of the essential failure of the search for autonomously replicating sequences in cultured cells. These approaches involve the mapping of short stretches of nascent DNA, the identification of the regions where either leading or lagging strands switch polarity, or the localization of replication intermediates by two-dimensional gel electrophoresis. Due to the complexity of animal cell genomes, most of these studies have been performed on amplified domains and with the use of synchronization procedures. The results obtained have been controversial. In order to avoid the use of experimental procedures potentially affecting the physiological mechanism of DNA replication, we have developed a method for the localization of ori in single-copy loci in exponentially growing cells. This method entails the absolute quantification of the abundance of selected DNA fragments along a genomic region within samples of newly synthesized DNA by competitive polymerase chain reaction (PCR); the latter is immune to all the uncontrollable variables which severely affect the reproducibility of conventional PCR. The application of this method to SV40 ori-driven plasmid replication precisely identifies the known ori localization. Using the same approach, we have mapped an ori for bi-directional DNA replication in a 13.7-kb locus of human chromosome 19 encoding lamin B2.

The lithium loading dose method in a clinical setting.

The lithium loading dose method developed by Cooper and associates resulted in achievement of therapeutic concentrations in 29 of 30 psychiatric inpatients. Fewer lithium determinations were required than in 30 other inpatients treated with the traditional trial-and-error technique.

The metyrapone test in depressed males.

Hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis in depression has received considerable attention, particularly in the now numerous studies utilizing the dexamethasone suppression test. The possibility of HPA axis hypoactivity in this population however has not been similarly explored. To examine this latter possibility, the metyrapone test, a well-established neuro-endocrine assay for determining pituitary reserve, was administered to ten endogenously depressed males and ten matched controls. Consistent with the findings of an earlier study on ten female depressives, one of the depressed males but none of the controls showed clear evidence of HPA axis hypoactivity. This suggests that HPA axis dysfunction in depressives may be more complex than originally anticipated. This finding also has implications for the psychiatric symptomatology classically associated with such illnesses as Addison's disease.

Rating depression in normals and depressives: observer versus self-rating scales.

Different methods of assessing depression and anxiety were tested in 20 patients suffering from a major depressive disorder with melancholia and 20 matched control subjects. Depressives were assessed before and after treatment with amitriptyline and normals were retested at the same interval. The scales used were: Paykel's Clinical Interview for Depression--which is an expanded version of the Hamilton Depression Rating Scale; the Brief Depression Rating Scale; and Symptom Questionnaire (SQ). All scales discriminated sensitively between patients and normals and the scores changed substantially with treatment. Except for the well-being subscales of the SQ, the scales showed an adequate test-retest reliability in normals. Although all scales were suitable for the measurement of depression, they differed in psychometric properties. For example, the Depression subscale of the SQ showed an unusually high test-retest reliability in normals, whereas the Contentment subscale was unreliable. Yet, the latter has been found to be highly sensitive in detecting differences between the effects of psychotropic drugs and placebo in drug trials, so it appears to measure sensitively a fleeting mood. The combined use of all three scales in patients with affective disorders yields information that might not be revealed if only one scale is used.

Hypochondriacal fears and beliefs in DSM-III melancholia. Changes with amitriptyline.

The authors administered the Illness Attitude Scales, which identify hypochondriacal patients, to 20 nonpsychotic inpatients with DSM-III diagnosis of melancholia before and after 4 weeks of treatment with amitriptyline, and to a matched group of normals. Before treatment characteristic hypochondriacal responses occurred in over one-third of melancholics whereas after treatment the number was the same as in normals. The findings are in accord with the clinical observation that melancholia is one of the causes of hypochondriacal fears and beliefs and these tend to remit with recovery from depression.