Clinical and MRI Predictors of Conversion From Mild Behavioural Impairment to Dementia.

OBJECTIVE: As an analogy with mild cognitive impairment (MCI), the mild behavioral impairment (MBI) construct has been proposed as a diagnostic label for those presenting late-onset behavioral symptoms. To date, however, the clinical, cognitive, and structural imaging features associated with an increased risk of conversion from MBI to dementia are poorly understood. METHODS: We retrospectively analyzed the cognitive performance and structural brain MRI of 113 subjects, with a clinical follow-up of at least 4 years available. Subjects were randomly assigned to a Group A (56 subjects; age: 65.4 ± 7.9 years, 15 females, MMSE score: 28.4 ± 2.3)) or to a Group B (57 subjects, age: 66.6 ± 6.4, 17 females, MMSE score: 28.0 ± 1.4). In the Group A, cognitive and structural variables were compared between converters (at 4 years) and nonconverters and then verified in the Group B group. RESULTS: In the Group A, 14 patients converted to behavioral-variant of frontotemporal dementia (bv-FTD) and 4 to Alzheimer's Disease (AD). Converters presented at baseline lower executive function scores and total Theory of Mind (ToM scores), as well as more severe focal frontal atrophy. In the Group B, 13 subjects converted to bv-FTD and none to AD. The combination of the variables identified in the Group A significantly (p <0.001) discriminated between converters and nonconverters in the Group B with a sensitivity of 0.615 and a specificity of 1 (total accuracy 91.22%). CONCLUSION: The combined presence of executive deficit, impaired ToM, and presence of isolated frontal atrophy was associated with risk of progression from MBI to a clinically evident neurodegenerative condition, mainly bv-FTD, over a 4-year period.

Checking rounds for isolation precautions in the control of multidrug-resistant organisms: reduction achieved.

The objective of this investigation was to analyze the effectiveness of a quality improvement initiative in limiting the spread of multidrug-resistant organisms (MDROs) in the hospital setting. During the period 2011-2013, a multimodal intervention was activated at a tertiary care center in Italy. The intervention included: laboratory-based surveillance, interdisciplinary training sessions, monitoring the adoption of isolation precautions and daily supervision provided by infection control nurses, and a monthly feedback. Time series analysis was used to evaluate the trends and correlations between the MDROs rate, intensity of checking rounds, and hospital-wide data (i.e., transfer of patients, patients' days, site of isolation, etc.). A total of 149,251 patients were included in the study. The proportion of patients undergoing transmission-based isolation precautions within 24 h from a positive laboratory finding increased from 83% in 2011 to 99% in 2013 (p < 0.05). The wards appropriately adopting the correct isolation precaution increased from 83% in 2011 to 97.6% in 2013 (p < 0.05). The frequency of controls was significantly reduced after the observation of compliance in the appropriate wards (p < 0.05). After three years, the incidence rate changed from 5.8/1000 days of stay [95% confidence interval (CI) 5.6-6.1] in 2011 to 4.7 (95% CI 4.4-4.9) in 2013 (p < 0.0001). Moreover, microorganisms isolated from different types of specimens showed variable potential for transmission (i.e., skin as the most potential and urine the least). The results demonstrate the efficacy of the multimodal intervention, with sustained reduction of MDROs rate, besides check reduction, and highlight the long-term efficacy of checking rounds in changing professionals' behaviors.

The use of CEUS in the diagnosis of retinal/choroidal detachment and associated intraocular masses - preliminary investigation in patients with equivocal findings at conventional ultrasound.

PURPOSE: To investigate whether contrast-enhanced ultrasound (CEUS) may help to diagnose retinal/choroidal detachment and may help to differentiate intraocular lumps in cases with equivocal features on conventional grayscale and Doppler modes. MATERIALS AND METHODS: The institutional review board approved this retrospective study. The need for informed consent was waived. A computerized data search was performed in the database of our institution for patients with vitreous hemorrhage who underwent CEUS of the eye to assess retinal/choroidal detachment and/or associated masses. This process yielded a total of 31 patients (18 men, 13 women, age range: 39 - 88 years) in whom CEUS was performed because the findings on conventional grayscale and Doppler modes were equivocal. CEUS was performed using low acoustic power contrast-specific modes. A 2.4 - 4.8  mL bolus of SonoVue was injected, followed by a saline flush. All examinations were digitally recorded for retrospective analysis. Confirmation of CEUS findings was obtained at surgery (n = 20) or with binocular indirect fundoscopy performed after clearance of the ocular media (n = 11). Two readers with different levels of ultrasound experience independently reviewed the imaging features. A five-degree scale ranging from definitely absent (score 1) to definitely present (score 5) was used to assess the presence or absence of retinal/choroidal detachment on conventional ultrasound modes alone and with the addition of CEUS. ROC curve analysis was performed to assess the diagnostic accuracy of both methods. The inter-reader agreement was also evaluated. In patients with associated intraocular lumps, conventional Doppler modes and CEUS were used to differentiate non-tumor masses from tumor masses. RESULTS: According to the reference standard, 13 patients had retinal detachment, 4 had choroidal detachment, and 3 had both retinal and choroidal detachment. There were 8 associated intraocular lumps (4 subretinal hemorrhages, 3 malignant melanomas, 1 metastasis). The inter-reader agreement was good (K = 0.644) and very good (K = 0.833) for conventional modes and CEUS, respectively. The diagnostic performance of CEUS was high for both readers (area ± standard error under the ROC curve: 0.966 ±â€Š0.031 and 0.900 ±â€Š0.055 for readers 1 and 2, respectively). There were 2 false-positive results and 1 false-negative result in patients with proliferative diabetic retinopathy. CEUS was effective in differentiating subretinal hemorrhage from hypovascular tumors. CONCLUSION: CEUS can be used as a problem-solving technique when conventional ultrasound modes are not diagnostic for retinal/choroidal detachment and when intraocular lumps cannot be characterized as tumor or non-tumor masses on conventional modes. The evaluation of patients with proliferative diabetic retinopathy, however, may be problematic.

Insomnia as a predictor of high-lethality suicide attempts.

INTRODUCTION: Research has demonstrated that patients with insomnia are at an increased risk of experiencing suicidal ideation and/or making a suicide attempt. OBJECTIVES: To evaluate the relation between insomnia and suicidal behaviour. AIMS: To examine factors associated with a diagnosis of insomnia in patients admitted to an Emergency Department (ED) and assessed by the psychiatrist in charge. METHODS: Participants were 843 patients consecutively admitted to the ED of Sant'Andrea Hospital in Rome, between January 2010 and December 2011. All patients admitted were referred to a psychiatrist. A clinical interview based on the Mini International Neuropsychiatric Interview (MINI) and a semi-structured interview was conducted. Patients were asked about 'ongoing' suicidal ideation or plans for suicide. RESULTS: Forty-eight percent of patients received a diagnosis of bipolar disorder (BD), major depressive disorder (MDD) or an anxiety disorder; whereas, 17.1% were diagnosed with Schizophrenia or other non-affective psychosis. Patients with insomnia (compared to patients without insomnia) more frequently had a diagnosis of BD (23.9% vs. 12.4%) or MDD (13.3% vs. 9.5%; p < 0.001). Moreover, patients with insomnia less frequently had attempted suicide in the past 24 h (5.3% vs. 9.5%; p < 0.05) as compared with other patients, but those patients with insomnia who attempted suicide more frequently used a violent method (64.3% vs. 23.6%; p < 0.01) compared to other suicide attempters. CONCLUSIONS: Our results do not support an association between insomnia and suicidal behaviour. However, suicide attempters with insomnia more frequently used violent methods, and this phenomenon should be taken into serious consideration by clinicians.

Effects of transcranial magnetic stimulation on cocaine addiction: A systematic review of randomized controlled trials.

OBJECTIVE: While pharmacological strategies appear to be ineffective in treating long-term addiction, repetitive transcranial magnetic stimulation (rTMS) is emerging as a promising new tool for the attenuation of craving among multiple substance dependent populations. METHOD: A systematic review of randomized controlled trials (RCTs) was conducted on the efficacy and tolerability of rTMS in treating cocaine use disorder (CUD). Relevant papers published in English through November 30th 2022 were identified, searching the electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Library. RESULTS: Eight studies matched inclusion criteria. The best findings were reported by the RCTs conducted at high-frequency (≥5 Hz) multiple sessions of rTMS delivered over the left dorsolateral prefrontal cortex (DLPFC): a significant decrease in self-reported cue-induced cocaine craving and lower cocaine craving scores and a considerable amelioration in the tendency to act rashly under extreme negative emotions (impulsivity) were found in the active group compared to controls. CONCLUSION: Although still scant and heterogeneous, the strongest evidence so far on the use of rTMS on individuals with CUD support the high frequency stimulation over the left DLPFC as a well tolerated treatment of cocaine craving and impulsivity.

Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation.

BACKGROUND: Risk factors for suicide are at least partially heritable and functional polymorphisms of targeted genes have been suggested to be implicated in the pathogenesis of this phenomenon. However, other studies examining the association between specific gene variants and suicide revealed inconsistent findings. We aims to evaluate the possible association between MAO-A3, CYP1A2*1F and GNB3 gene variants, hopelessness and suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. METHODS: 56 women were genotyped for MAO-A3, CYP1A2*1F and GNB3 gene variants. Participants were also assessed using Beck Hopelessness Scale (BHS), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A), and the Suicidal History Self-Rating Screening Scale (SHSS). RESULTS: Patients with higher total scores on affective dysregulated temperaments are more likely to have higher BHS (11.27+/=5.54 vs. 5.73+/=3.81; t19.20 = -3.57; p < 0.01) and higher SHSS total scores (4.79+/=3.31 vs. 1.05±2.31; t17.74 = -3.90; p < 0.001) than those with lower total scores. 67% of patients in the dysregulated group has BHS total scores >= 9 indicating high levels of hopelessness. No association was found between MAO-A3, CYP1A2*1F and GNB3 gene variants and suicidal risk as assessed by BHS and SHSS. CONCLUSIONS: This study did not sustain the association between MAO-A3, CYP1A2*1F and GNB3 gene variants and increased suicidal risk in patients with chronic migraine and affective temperamental dysregulation. Further studies investigating the gene-environment interaction or focusing on other genetic risk factors involved in suicidal behaviour are needed.  

Hyper/neuroinflammation in COVID-19 and suicide etiopathogenesis: Hypothesis for a nefarious collision?

Accumulating scientific and clinical evidence highlighted pathological hyperinflammation as a cardinal feature of SARS-CoV-2 infection and acute COVID-19 disease. With the emergence of long COVID-19 syndrome, several chronic health consequences, including neuropsychiatric sequelae, have gained attention from the public and medical communities. Since inflammatory mediators have also been accredited as putative biomarkers of suicidal ideations and behaviors, hyper- and neuroinflammation might share some colliding points, overlapping and being interconnected in the context of COVID-19. This review aims to provide a summary of current knowledge on the molecular and cellular mechanisms of COVID-19-associated hyper/neuroinflammation with focus on their relevance to the inflammatory hypothesis of suicide development. Subsequently, strategies to alleviate COVID-19 hyper/neuroinflammation by immunomodulatory agents (many of which at experimental stages) as well as psychopharmacologic/psychotherapeutic approaches are also mentioned. While suicide risk in COVID-19 survivors - until now little known - needs further analysis through longitudinal studies, current observations and mechanistic postulates warrant additional attention to this possibly emerging mental health concern.

Affective temperaments are associated with higher hopelessness and perceived disability in patients with open-angle glaucoma.

AIM: The aims of the study were to study: (i) affective temperaments in open-angle glaucoma (OAG) patients with some degree of functional visual impairment; (ii) psychological well-being and perceived disability, and their associations with affective temperaments; and (iii) associations between visual impairment, affective temperaments and psychological well-being. METHOD: Participants were 91 outpatients (39 women, and 52 men) with open-angle glaucoma (OAG) who were assessed for Visual Field Index, Mean Defect and Pattern Standard Deviation. Patients were also administered the Beck Hopelessness Scale, the TEMPS-A (Rome), the Gotland Male Depression Scale, the Emotional Well-being Scale, the Perceived Disability Questionnaire and the Suicidal History Self-Rating Screening Scale. RESULTS: Open-angle glaucoma patients (compared with a non-clinical sample of university students) had higher scores on the TEMP-A dysthimic and hyperthimic traits and lower scores on cyclothimic, irritability and anxiety traits. Such temperament variability was not linked to differences in severity of glaucoma. We did not find strong evidence supporting the fact that measures of visual impairment were linked to emotional well-being and depression. However, logistic regression analysis revealed that patients may have different patterns related to their illness according to specific temperaments. CONCLUSION: Patients with OAG may have different temperament profiles than non-clinical individuals. Such categorisation may be useful for predicting how they face the illness, for providing better care as well as for early recognition of mood disorders symptoms.

Prospective, open study of long-acting injected risperidone versus oral antipsychotics in 88 chronically psychotic patients.

INTRODUCTION: A long-acting, injected, carbohydrate-microsphere preparation of risperidone (RLAI; Risperdal Consta ((R))) is reported to be safe and effective in chronic psychotic illnesses but, as its long-term and comparative efficacy remain unclear, this study compared clinical status during oral antipsychotic treatment versus conversion to RLAI. METHODS: Psychotic patients (n=88; initial BPRS=93+/-5) were treated for 6 months with clinically chosen oral medication and then converted to biweekly RLAI for the first 6 months (6-6 months matched mirror comparison) and then for another 18 months. Clinical status in the two treatment periods and in the 18 months of follow-up was compared with measures including BPRS improvement (primary outcome), CGI variants and SF-36 ratings. RESULTS: RLAI (at a mean dose of 47 mg/2 weeks at six and up to 23.1+/-3.3 months) was associated with major improvements in all outcome measures (p<0.001). Initial BPRS scores fell by an average of 50% within six months; hospitalizations declined from 19.8% to 0%, and rates of adverse events were reduced by 2.5- to 7.4-fold. Such benefits were sustained during 18 months of follow-up with RLAI-treatment. CONCLUSIONS: The findings are limited by the lack of a parallel control treatment, such as with oral risperidone or another antipsychotic, lack of blinded assessments, and a moderate number of subjects. Nevertheless, the findings add to indications that RLAI can be an effective and well-tolerated treatment-option for chronically psychotic patients.

Expression and characterization of the periplasmic cobalamin-binding protein of Photobacterium damselae subsp. piscicida.

Abstract Cobalamin (vitamin B(12)) is an essential cofactor in a variety of enzymatic reactions and most prokaryotes contain transport systems to import vitamin B(12). A gene coding for a periplasmic cobalamin-binding protein of Photobacterium damselae subsp. piscicida was identified by in silico analysis of sequences from a genomic library. The open reading frame was composed of 834 bp encoding a protein of 277 amino acids. The protein showed 61% identity with the vitamin B(12)-binding protein precursor of P. profundum, 53% identity with the corresponding protein of Vibrio parahaemolyticus and 43% identity with the periplasmic binding protein BtuF of Escherichia coli. The expression of the native protein was investigated in P. damselae subsp. piscicida, but BtuF was weakly expressed under normal conditions. To characterize the BtuF of P. damselae subsp. piscicida, the recombinant protein was expressed with a C-terminal His(6)-tag and purified; the molecular weight was estimated to be approximately 30 kDa. The protein does not contain any free thiol group, consistent with the view that the two cysteine residues are involved in a disulphide bond. The purified BtuF binds cyanocobalamin with an affinity constant of 6 +/- 2 microm.

Conceptualizations of suicide through time and socio-economic factors: a historical mini-review.

OBJECTIVES: Suicide is a complex phenomenon determined by the interplay of an articulated network of factors including socio-economic factors which have a decisive role. This paper investigates the development of the modern conceptualization of suicide in Europe, its sociological understandings and its intertwinement with economic cycles throughout time. METHODS: MEDLINE, SCHOLAR, EMBASE using the keywords 'socioeconomic factors AND suicide'; 'economic cycles AND suicide'; 'history AND suicide' without timeframe limitations. Moreover, journal-by-journal search in journals of related areas was performed. RESULTS: In total, 51 historical studies focusing on the subjects in European countries were included. Three main areas arose: (a) development of the conceptualization of suicide over time; (b) sociological understandings of suicide according to the structure of society and its economy of power; (c) economic theories explaining the intertwinement of economic cycles and suicides. CONCLUSIONS: Suicide is a deeply human phenomenon inescapably linked to and grounded in society and economic cycles. Understandings from the past show the importance of accurate analysis of socio-economic contexts that shape societies together with man's own sense of self in order to organize multi-layered tangible and intangible support strategies to better understand and prevent suicide in this day and age.

Betalains increase vitexin-2-O-xyloside cytotoxicity in CaCo-2 cancer cells.

Vitexin-2-O-xyloside (XVX) from Beta vulgaris var. cicla L. (BVc) seeds, betaxanthin (R1) and betacyanin (R2) fractions from Beta vulgaris var. rubra L. (BVr) roots were combined and tested for cytotoxicity in CaCo-2 colon cancer cells. XVX was the most cytotoxic molecule, but the combination of XVX with R1 and R2 significantly prolonged its cytotoxicity. Cytotoxicity was mediated by the intrinsic apoptotic pathway, as shown by an increase in Bcl2-like protein 4, cleaved Poly ADP-Ribosyl Polymerase 1 and cleaved Caspase 3 levels with a parallel decrease in anti-apoptotic protein B-cell leukemia/lymphoma 2 levels. R1 and R2, used alone or in combination, reduced oxidative stress triggered by H2O2 in CaCo-2 cells. Betalains dampened cyclooxygenase-2 and interleukin-8 mRNA expression after lipopolysaccharide induction in CaCo-2, showing an anti-inflammatory action. Our results support the use of a cocktail of R1, R2 and XVX as a chemopreventive tool against colon cancer.

Binding of non-catalytic ATP to human hexokinase I highlights the structural components for enzyme-membrane association control.

BACKGROUND: Hexokinase I sets the pace of glycolysis in the brain, catalyzing the ATP-dependent phosphorylation of glucose. The catalytic properties of hexokinase I are dependent on product inhibition as well as on the action of phosphate. In vivo, a large fraction of hexokinase I is bound to the mitochondrial outer membrane, where the enzyme adopts a tetrameric assembly. The mitochondrion-bound hexokinase I is believed to optimize the ATP/ADP exchange between glucose phosphorylation and the mitochondrial oxidative phosphorylation reactions. RESULTS: The crystal structure of human hexokinase I has been determined at 2.25 A resolution. The overall structure of the enzyme is in keeping with the closed conformation previously observed in yeast hexokinase. One molecule of the ATP analogue AMP-PNP is bound to each N-terminal domain of the dimeric enzyme in a surface cleft, showing specific interactions with the nucleotide, and localized positive electrostatic potential. The molecular symmetry brings the two bound AMP-PNP molecules, at the centre of two extended surface regions, to a common side of the dimeric hexokinase I molecule. CONCLUSIONS: The binding of AMP-PNP to a protein site separated from the catalytic centre of human hexokinase I can be related to the role played by some nucleotides in dissociating the enzyme from the mitochondrial membrane, and helps in defining the molecular regions of hexokinase I that are expected to be in contact with the mitochondrion. The structural information presented here is in keeping with monoclonal antibody mapping of the free and mitochondrion-bound forms of the enzyme, and with sequence analysis of hexokinases that differ in their mitochondria binding properties.

The interaction of phosphorylated sugars with human hexokinase I.

Glucose 6-phosphate as well as several other hexose mono- and diphosphates were found by kinetic studies to be competitive inhibitors of human hexokinase I (ATP:D-hexose 6-phosphotransferase, EC 2.7.1.1) versus MgATP. Limited proteolysis by trypsin does not destroy the hexokinase activity but produces as well-defined peptide map when the digested enzyme is electrophoresed in the presence of sodium dodecyl sulfate. MgATP at subsaturating concentration protects hexokinase from trypsin digestion, while phosphorylated sugars, Mg2+, glucose and inorganic phosphate have no effect. Addition of glucose 6-phosphate to the MgATP-hexokinase complex at a concentration 100-times higher than its Ki was not able to reverse the MgATP-induced conformation of hexokinase, suggesting that the binding of glucose 6-phosphate and MgATP are not mutually exclusive. Similar evidence was also obtained by studies of the induced modifications of ultraviolet spectra of hexokinase by the binding of MgATP, glucose 6-phosphate and both compounds. Among a library of monoclonal antibodies produced against rat brain hexokinase I and that recognize human placenta hexokinase I, one (4A6) was found to be able to modify the Ki of glucose 6-phosphate (from 25 to 140 microM) for human hexokinase I. The same antibody also weakens the inhibition by all the other hexoses phosphate studied without affecting the apparent Km for MgATP (from 0.6 to 0.75 mM) or for glucose. These data support the view for the binding of glucose 6-phosphate at a regulatory site on the enzyme.

Molecular bases of hexokinase deficiency.

Hexokinase (ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1; HK) deficiency is a rare disease where the predominant clinical effect is nonspherocytic hemolytic anemia. We have previously shown that the only patient for which hexokinase deficiency has been so far investigated at molecular level is a double heterozygote carrying a T1667 --> C substitution on one HK type I allele and a 96 bp deletion (concerning nucleotides 577 to 672 in the HK cDNA sequence) in the other allele. To investigate whether these mutations found in the patient with the hexokinase variant referred to as 'HK-Melzo' could be associated with hexokinase deficiency, we have expressed in E. coli the wild-type human hexokinase type I and two different mutants carrying the T --> C nucleotide substitution at position 1667 and the nt 577-672 deletion, respectively. Wild-type human recombinant hexokinase is expressed in bacterial cells as a soluble catalytically active enzyme that, upon purification to homogeneity, exhibited the same kinetic properties of human placenta hexokinase type I. Both mutant hexokinases were also expressed as soluble recombinant proteins under the same conditions, but they showed an impaired catalytic activity with respect to the wild-type enzyme. In particular, the T1667 --> C substitution, causing the amino acid change from Leu529 to Ser, is responsible for the complete loss of the hexokinase catalytic activity, while the 96 bp deletion causes a drastic reduction of the hexokinase activity. Taken together, both mutations explain the hexokinase deficiency found in the patient with the 'HK-Melzo' variant.

The soluble but not mitochondrially bound hexokinase is a substrate for the ATP- and ubiquitin-dependent proteolytic system.

Intracellular protein degradation is highly selective, however, the mechanism(s) underlying this selectivity are not fully understood. We have previously shown that purified rabbit hexokinase type I, an enzyme present in mammalian brain both in soluble and mitochondrial bound form, is conjugate to ubiquitin and then degraded by a rabbit reticulocyte fraction II. In the present study we report that the mitochondrial bound hexokinase is stable for several hours in the same proteolytic system both in the presence or absence of ATP. E1, E2 and E3, the enzymes of the ubiquitin conjugating system, are able to incorporate 125I- or biotin-labelled ubiquitin in an ATP-dependent manner in soluble hexokinase as well as in a number of mitochondrial proteins. Furthermore, the mitochondria by themselves have a pronounced ATP-dependent ability to conjugate 125I-ubiquitin. However, Western blotting experiments, using a specific antibody against hexokinase, or against ubiquitin, showed that the mitochondrial bound enzyme is neither ubiquitinated nor degraded. This result has been confirmed by purification of bound hexokinase from the brain mitochondrial fraction or following the incubation of intact mitochondria with ATP, 125I-ubiquitin and E1, E2 and E3. Thus, mitochondrial bound hexokinase is not recognized by the ubiquitin conjugating system while the soluble enzyme is conjugate to ubiquitin and then degraded. Furthermore, the soluble hexokinase from rabbit brain was isolated by immunoaffinity chromatography and shown to be recognized by an anti-ubiquitin antibody. These results suggest that the intracellular distribution of protein is an important feature of a protein which determines its susceptibility to ubiquitin-dependent degradation.