Measures of Suicidal Thoughts and Behaviors in Children and Adolescents: A Systematic Review and Recommendations for Use in Clinical and Research Settings.

Empirically supported measures of suicidal thoughts and behaviors (STBs) are needed to serve as reference outcomes for suicide risk screening tools and to monitor severity and treatment progress in children and adolescents with STBs. The present paper systematically reviewed existing measures of STBs in youth and studies evaluating their psychometric properties and clinical utility. Measures were then evaluated on reliability, validity, and clinical utility. Sixteen articles (20 independent samples) were found with psychometric data with youth samples for eight measures. Interview-based measures were found to have the strongest psychometric support and clinical utility. Significant limitations exist for all self-report measures due to inherent characteristics of these measures that cannot be remedied through additional psychometric study. There is an urgent need for the development and validation of new self-report measures of STBs, particularly for preadolescent children, sexual and gender minority youth, and racial/ethnic minority youth.

Seventy years of pheochromocytomas and paragangliomas in Argentina. The FRENAR database.

Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors characterized by the excessive production of catecholamines. This study aims to describe the clinical characteristics of PPGL cases in Argentina over recent decades. A multicenter retrospective cross-sectional analysis was carried out using a database comprising both pediatric and adult patients with confirmed PPGL diagnoses based on pathological reports. A cohort of 486 patients with PPGL was recruited. Women represent 58.4% of the patients, with a mean age of 38.3 years old at the time of diagnosis and 15.2% of the patients were under the age of 18. Hypertension, as well as classic signs and symptoms, were present in 80.9% of the patients. The adrenal incidentaloma, as a mode of presentation, increased in the last two decades rising from 3.9% (1953-2000) to 21.8% (2001-2022), p<0.001. Most tumors were located within the adrenal glands, accounting 83.0% of the cases, with bilateral occurrences noted in 20.0%. The median tumor size was 4.8cm. Local recurrence and metastases were observed in 10.9% and 12.2%. Out of 412 patients, 87.0% exhibited urinary excretion elevation of catecholamines and/or their metabolites. Furthermore, 148 patients, representing 30.4% of the study population, displayed a distinct genetic profile indicative of hereditary syndromes. The distribution of hereditary syndromes revealed that MEN2, VHL, and PGL4 constituted the most prevalent syndromes. This population-based study, spanning seven decades, offers valuable insights into the demographic and clinical characteristics of PPGL patients in Argentina.

Understanding limb necrotizing infections: A comprehensive approach.

INTRODUCTION: Necrotizing soft tissue infections (NSTI) are increasing, posing a significant risk of morbidity and mortality. Due to nonspecific symptoms, a high index of suspicion is crucial. Treatment involves a multidisciplinary approach, with broad-spectrum antibiotics, early surgical debridement, and life support. This study analyzes the characteristics, demographics, complications, and treatment of NSTI in a hospital in Madrid, Spain. METHODS: A retrospective observational study was conducted, including all surgically treated NSTI patients at our center from January 2016 to December 2022, examining epidemiological and clinical data. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) was prospectively calculated for all patients. RESULTS: Twenty-two patients (16 men, 6 women, mean age 54.8) were included. Median time from symptom onset to emergency room visit was 3.5 days. All reported severe treatment-resistant pain; sixteen had fever exceeding 37.8°C (72.7%). Skin lesions occurred in twelve (54.5%), and thirteen had hypotension and tachycardia (59.1%). Treatment involved resuscitative support, antibiotherapy, and radical debridement. Median time to surgery was 8.25h. Intraoperative cultures were positive in twenty patients: twelve Streptococcus pyogenes, four Staphylococcus aureus, one Escherichia coli, and four polymicrobial infection. In-hospital mortality rate was 22.73%. CONCLUSIONS: We examined the correlation between our results, amputation rates and mortality with LRINEC score and time to surgery. However, we found no significant relationship unlike some other studies. Nevertheless, a multidisciplinary approach with radical debridement and antibiotic therapy remains the treatment cornerstone. Our hospital stays, outcomes and mortality rates align with our literature review, confirming high morbimortality despite early and appropriate intervention.

Vitamin A Status Modulates Epithelial Mesenchymal Transition in the Lung: The Role of Furin.

Vitamin A deficiency (VAD) induced TGF-ß hyperactivation and reduced expression of cell adhesion proteins in the lung, suggesting that the disruption of retinoic acid (RA) signaling leads to epithelial-mesenchymal transition (EMT). To elucidate the role of lung vitamin A status in EMT, several EMT markers and the expression of the proprotein convertase furin, which activates TGF-ß, were analyzed in two experimental models. Our in vivo model included control rats, VAD rats, and both control rats and VAD rats, treated with RA. For the in vitro studies, human bronchoalveolar epithelial cells treated with RA were used. Our data show that EMT and furin are induced in VAD rats. Furthermore, furin expression continues to increase much more markedly after treatment of VAD rats with RA. In control rats and cell lines, an acute RA treatment induced a significant increase in furin expression, concomitant with changes in EMT markers. A ChIP assay demonstrated that RA directly regulates furin transcription. These results emphasize the importance of maintaining vitamin A levels within the physiological range since both levels below and above this range can cause adverse effects that, paradoxically, could be similar. The role of furin in EMT is discussed.

Current level of evidence for improvement of antidepressant efficacy and tolerability by pharmacogenomic-guided treatment: A Systematic review and meta-analysis of randomized controlled clinical trials.

The aim of the study was to assess the clinical utility of currently available pharmacogenomic (PGx) tools compared with treatment as usual (TAU), using a meta-analysis of dichotomous and continuous antidepressant efficacy and tolerability data from previously published clinical trials. MEDLINE, clinicaltrial.gov, EU Clinical Trials Register, WHO ICTRP and CENTRAL were systematically searched; of the 962 results originally reviewed, 15 trials were included. Antidepressant efficacy was quantified by relative and absolute changes in symptom severity after eight weeks of treatment and by response and remission rates, while tolerability was estimated by the rate of study discontinuation for any reason. In the PGx-guided patients, symptom severity reduced by an average of 31.0% after eight weeks of treatment, compared to an average reduction of 26.8% in the TAU group. Accordingly, PGx-guided patients experienced a greater reduction in symptom severity of 3.4% (95%CI: 1.6-5.3%), which corresponded to a reduction in the Hamilton Depression score of 0.75 (0.30-1.21), a 37% (15-63%) higher remission rate, and an 18% (5-33%) higher response rate compared with TAU patients, while no difference was observed in discontinuation rate between groups. Notably, the majority of associations lost statistical significance when restricting the dataset to low risk of bias studies, while certain funnel plots suggested a potential publication bias favoring the reporting of statistically significant results. In summary, PGx tools marginally enhance antidepressant efficacy, but not antidepressant tolerability; thus, additional research and advancement of PGx tools are needed to improve integration of PGx in clinical pharmacotherapy of depression.

Chronic inflammation is associated with worsening working memory performance: Preliminary evidence from a diverse, longitudinal cohort of adolescents and young adults.

Many depressed individuals experience cognitive difficulties that persist when depression is in remission. Inflammation is hypothesized to play a role in cognitive dysfunction in depression; however, many aspects of this relationship are not well characterized. The current study examined whether inflammation is associated with specific cognitive deficits in individuals with a history of depression and with progressively worsening working memory over time. Adolescents who participated in a prospective, longitudinal study of adolescent-onset depression were recruited to complete a follow-up cognitive assessment. The sample was comprised of 82 participants (52.4% female; 37.8% white; 42.7% low socioeconomic status) who were aged 22.61 years (SD = 1.50) at the time of the follow-up cognitive assessment. Prior to the follow-up cognitive assessment, they had completed an average of 6.24 (SD = 1.80) prior annual assessments over 6.24 years (SD = 2.08) as part of the parent longitudinal study in which C-reactive protein (CRP), depressive symptoms, and working memory were assessed repeatedly. First, using linear regression, we tested whether individuals exhibiting inflammation (CRP ≥3 mg/L) at multiple timepoints and a history of likely depression (Children's Depression Inventory ≥19) exhibited differentially worse executive functioning, episodic memory, or psychomotor speed. Second, using hierarchical linear modeling, we tested whether the combination of inflammation and likely past depression was associated with poorer working memory over time. Chronic inflammation was associated with worsening working memory over time, but no significant associations were observed in cross-sectional analyses. These preliminary data indicate that chronic inflammation may lead to progressive decline in working memory over time.

[Prevalence, knowledge and control of arterial hypertension in vulnerable neighborhoods of Argentina: A Cross-sectional Study]. / Estudio de prevalencia, conocimiento y control de la hipertensión arterial en barrios vulnerables de Argentina.

INTRODUCTION: Hypertension (HTN) represents the primary individual risk factor, contributing significantly to the global burden of cardiovascular diseases (CVD). In our country, epidemiological research has highlighted substantial variations in the prevalence of these risk factors across different populations. However, there is a lack of epidemiological studies assessing exclusive cardiovascular risk factors within vulnerable neighborhoods characterized by extremely limited economic resources, sociocultural challenges, and inadequate healthcare access. METHODS: A multicenter cross-sectional observational study was conducted among individuals residing in economically deprived and marginalized communities, including informal settlements and underprivileged neighborhoods. Simple random sampling of households was employed. Blood pressure measurements, anthropometric assessments, and epidemiological, economic, and sociocultural questionnaires were administered. Results encompass prevalence rates, awareness levels, and blood pressure control across diverse regions. Logistic regression was utilized to identify independent variables influencing primary outcomes. RESULTS: A total of 989 participants were analyzed. The overall prevalence of hypertension was 48.2%. About 82% had a body mass index (BMI) >25. Approximately 45.3% had less than 6 years of formal education. Independent association was established between education levels below 6 years and higher hypertension prevalence. Among hypertensive individuals, 44% were unaware of their condition, with only 17.2% achieving control, correlated with having health insurance and a higher educational background. Merely 24% were receiving combined therapy. CONCLUSION: The prevalence of hypertension within vulnerable neighborhoods is alarmingly high, surpassing rates in other social strata. Knowledge, treatment, and control levels of hypertension are suboptimal, comparable to other populations. Inadequate use of combination therapy was observed. This study underscores the urgent need for targeted interventions addressing cardiovascular risk factors in poor areas to mitigate the burden of CVD.

Orbital myositis in a patient with Crohn's disease: A case report of two episodes.

PURPOSE: To describe a case report of a 34 years-old patient with Crohn's Disease and two episodes of Ocular Myositis. METHODS: The research methodology employed in this study consisted of a retrospective review of the patient's complete medical history. RESULTS: Crohn's Disease is a chronic inflammatory bowel disorder known to be associated with a wide range of extraintestinal manifestations. Ocular abnormalities, such as episcleritis and uveitis, are commonly observed. However, orbital myositis is an extremely rare ocular extraintestinal manifestations characterized by acute ocular pain that worsens with eye movements and is often accompanied by diplopia. In this case report, we present the case of a 34-year-old woman with a confirmed diagnosis of Crohn's Disease, who experienced two episodes of acute orbital pain exacerbated by ocular movements and diplopia. The diagnosis was established through clinical evaluation and radiologic imaging, with confirmation after a good response to systemic corticosteroids. She responded favorably to systemic corticosteroid therapy on both episodes, and no additional treatment was required. As of now, she remains stable without any ocular sequelae. CONCLUSION: It is important to note that orbital myositis is an uncommon ocular manifestation associated with Crohn's Disease, and prompt recognition and management are crucial to achieve successful outcomes.

Clinical results of total hip arthroplasty assisted by robotic arm in Spain: Preliminary study. / Resultados clínicos de artroplastia total de cadera asistida por brazo robótico en España: estudio preliminar.

OBJECTIVES: Clinical, radiological and functional results of the first Spanish series of patients undergoing total hip arthroplasty assisted by Mako® (Stryker) robotic arm at the Hospital Clínico San Carlos (HCSC) in Madrid. MATERIAL AND METHODS: Prospective and descriptive study analyzing the first 25 patients who underwent robotic-assisted THA at the HCSC, with a minimum follow-up of 4months. Demographics, imaging studies (Mako® processing, Rx and CT), clinical parameters, functionality (modified Harris) and associated complications were evaluated. RESULTS: Average age was 67.2years (min 47, max 88), being 56% male population sample. 88% involves primary coxarthrosis, 4% post-traumatic coxarthrosis, 4% secondary avascular necrosis and 4% secondary femoroacetabular impingement. Average surgery time was 116.9min (min 92, max 150). The average time of the first five surgeries was 122.6min, and, regarding the last five interventions, it was 108.2min. Found medical intraoperative complications were four intraoperative markers loss. Average admission time was 4.4days (min 3, max 7), with an average postoperative hemoglobin decrease of 3.08±1.08g/dL, requiring a transfusion in 12% of the cases. Three medical complications have been registered in the meantime of the admission, with a relevant case of a confusional syndrome and a fall, which resulted in a non-displaced AG1 periprosthetic fracture. The analysis of the positioning of registered implants with Mako® system shows 40.55±1.53 acetabular inclination degrees and 12.2±3.6 acetabular anteversion degrees. The postoperative image study carried out on patients, are consistent with Mako® s results, as it shows an acetabular inclination of 41.2±1.7 in Rx, as well as acetabular anteversion of 16±4.6 in CT. Hip length variance ranges depending on preoperative values of 3.91mm (SD: 3.9; min -12, max 3) to 1.29mm (SD: 1.96) after surgery registered with Mako®, with an increase of an average hip length of 5.64mm (SD: 3.35). Rx simple study results show a postoperative difference between both hips of 0.5±3.08mm, which is consistent with Mako® results. Native femoral offset was stable after surgery with a showing difference both pre and post operative of the intervened hip of 0.1mm (SD: 3.7), registered with Mako®. Preoperatory modified Harris punctuation was 41.6±13.3, improving to postoperative values of 74.6±9.7 after four months since the surgery. No complications were registered in immediate postoperative (4month). CONCLUSIONS: Total hip arthroplasty robot-assisted achieves an adequate precision and repeatability of the implant positioning and the postoperative hip dysmetry without showing an increase of associated complications to the technique applied. Surgery time, complications and functional results in a short-time period are similar to conventional techniques applied to great series previously published.

[Translated article] Clinical results of total hip arthroplasty assisted by robotic arm in Spain: Preliminary study.

OBJECTIVES: Clinical, radiological and functional results of the first Spanish series of patients undergoing total hip arthroplasty assisted by Mako® (Stryker) robotic arm at the Hospital Clínico San Carlos (HCSC) in Madrid. MATERIAL AND METHODS: Prospective and descriptive study analyzing the first 25 patients who underwent robotic-assisted THA at the HCSC, with a minimum follow-up of 4 months. Demographics, imaging studies (Mako® processing, Rx and CT), clinical parameters, functionality (modified Harris) and associated complications were evaluated. RESULTS: Average age was 67.2 years (min 47, max 88), being 56% male population sample. 88% involves primary coxarthrosis, 4% post-traumatic coxarthrosis, 4% secondary avascular necrosis and 4% secondary femoroacetabular impingement. Average surgery time was 116.9min (min 92, max 150). The average time of the first five surgeries was 122.6min, and, regarding the last five interventions, it was 108.2min. Found medical intraoperative complications were four intraoperative markers loss. Average admission time was 4.4days (min 3, max 7), with an average postoperative haemoglobin decrease of 3.08±1.08g/dl, requiring a transfusion in 12% of the cases. Three medical complications have been registered in the meantime of the admission, with a relevant case of a confusional syndrome and a fall, which resulted in a non-displaced AG1 periprosthetic fracture. The analysis of the positioning of registered implants with Mako® system shows 40.55±1.53 acetabular inclination degrees and 12.2±3.6 acetabular anteversion degrees. The postoperative image study carried out on patients, are consistent with Mako® results, as it shows an acetabular inclination of 41.2±1.7 in Rx, as well as acetabular anteversion of 16±4.6 in CT. Hip length variance ranges depending on preoperative values of 3.91mm (SD: 3.9; min -12, max 3) to 1.29mm (SD: 1.96) after surgery registered with Mako®, with an increase of an average hip length of 5.64mm (SD: 3.35). Rx simple study results show a postoperative difference between both hips of 0.5±3.08mm, which is consistent with Mako® results. Native femoral offset was stable after surgery with a showing difference both pre and post operative of the intervened hip of 0.1mm (SD: 3.7), registered with Mako®. Preoperatory modified Harris punctuation was 41.6±13.3, improving to postoperative values of 74.6±9.7 after four months since the surgery. No complications were registered in immediate postoperative (4 months). CONCLUSIONS: Total hip arthroplasty robot-assisted achieves an adequate precision and repeatability of the implant positioning and the postoperative hip dysmetry without showing an increase of associated complications to the technique applied. Surgery time, complications and functional results in a short-time period are similar to conventional techniques applied to great series previously published.

A Weight of Evidence approach to support the assessment of the quality of Manila clam farming sites in a coastal lagoon.

Aquaculture productivity in coastal lagoons is endangered by a complex interplay of anthropogenic and environmental factors, amplified by the effects of climate change in these sensitive areas. To reach a more comprehensive assessment of farming sites quality, a quantitative Weight of Evidence approach (QWoE) is applied for the first time to data collected at four Manila clam (R. philippinarum) farming sites in the Venice lagoon (Italy). This included sediment quality, chemical bioaccumulation, and biological responses. Results revealed a greater hazard for sites closer to the open sea. In these areas, the combination of sediment characteristics and a higher frequency of salinity and temperature stress could explain the alterations measured at a transcriptional and biomarker level. The findings demonstrate that a QWoE approach that integrates multiple sources of evidence should also include physicochemical conditions in order to better understand the impacts of human activities and other stressors on clam aquaculture productivity.

Endothelial ILK induces cardioprotection by preventing coronary microvascular dysfunction and endothelial-to-mesenchymal transition.

Endothelial dysfunction is an early event in coronary microvascular disease. Integrin-linked kinase (ILK) prevents endothelial nitric oxide synthase (eNOS) uncoupling and, thus, endothelial dysfunction. However, the specific role of endothelial ILK in cardiac function remains to be fully elucidated. We hypothesised that endothelial ILK plays a crucial role in maintaining coronary microvascular function and contractile performance in the heart. We generated an endothelial cell-specific ILK conditional knock-out mouse (ecILK cKO) and investigated cardiovascular function. Coronary endothelial ILK deletion significantly impaired cardiac function: ejection fraction, fractional shortening and cardiac output decreased, whilst left ventricle diastolic internal diameter decreased and E/A and E/E' ratios increased, indicating not only systolic but also diastolic dysfunction. The functional data correlated with extensive extracellular matrix remodelling and perivascular fibrosis, indicative of adverse cardiac remodelling. Mice with endothelial ILK deletion suffered early ischaemic-like events with ST elevation and transient increases in cardiac troponins, which correlated with fibrotic remodelling. In addition, ecILK cKO mice exhibited many features of coronary microvascular disease: reduced cardiac perfusion, impaired coronary flow reserve and arterial remodelling with patent epicardial coronary arteries. Moreover, endothelial ILK deletion induced a moderate increase in blood pressure, but the antihypertensive drug Losartan did not affect microvascular remodelling whilst only partially ameliorated fibrotic remodelling. The plasma miRNA profile reveals endothelial-to-mesenchymal transition (endMT) as an upregulated pathway in endothelial ILK conditional KO mice. Our results show that endothelial cells in the microvasculature in endothelial ILK conditional KO mice underwent endMT. Moreover, endothelial cells isolated from these mice and ILK-silenced human microvascular endothelial cells underwent endMT, indicating that decreased endothelial ILK contributes directly to this endothelial phenotype shift. Our results identify ILK as a crucial regulator of microvascular endothelial homeostasis. Endothelial ILK prevents microvascular dysfunction and cardiac remodelling, contributing to the maintenance of the endothelial cell phenotype.

The theory of thermoelasticity with a memory-dependent dynamic response for a thermo-piezoelectric functionally graded rotating rod.

By laminating piezoelectric and flexible materials during the manufacturing process, we can improve the performance of electronic devices. In smart structure design, it is also important to understand how the functionally graded piezoelectric (FGP) structure changes over time when thermoelasticity is assumed. This is because these structures are often exposed to both moving and still heat sources during many manufacturing processes. Therefore, it is necessary to conduct theoretical and experimental studies of the electrical and mechanical characteristics of multilayer piezoelectric materials when they are subjected to electromechanical loads and heat sources. Since the infinite speed of heat wave propagation is a challenge that classical thermoelasticity cannot address, other models based on extended thermoelasticity have been introduced. For this reason, the effects of an axial heat supply on the thermomechanical behavior of an FGP rod using a modified Lord-Shulman model with the concept of a memory-dependent derivative (MDD) will be explored in this study. The exponential change of physical properties in the direction of the axis of the flexible rod will be taken into account. It was also assumed that there is no electric potential between the two ends of the rod while it is fixed at both ends and thermally isolated. Applying the Laplace transform method, the distributions of the physical fields under investigation were calculated. The obtained results were compared to those in the corresponding literature with varying heterogeneity values, kernel functions, delay times, and heat supply speeds. It was discovered that the studied physical fields and the dynamic behavior of the electric potential are weakened by increasing the inhomogeneity index.

Characterization of the C6D7-RBD Human Monoclonal Antibody Specific to the SARS-CoV-2 S Protein Receptor-Binding Domain.

The new coronavirus infection COVID-19 is an acute viral disease that affects primarily the upper respiratory tract. The etiological agent of COVID-19 is the SARS-CoV-2 RNA virus (Coronaviridae family, Betacoronavirus genus, Sarbecovirus subgenus). We have developed a high-affinity human monoclonal antibody, called C6D7-RBD, which is specific to the S protein receptor-binding domain (RBD) from the SARS-CoV-2 Wuhan-Hu-1 strain and exhibits virus-neutralizing activity in a test with recombinant antigens: angiotensin-converting enzyme 2 (ACE2) and RBD.

Case report: Gastroenterological management in a case of cardio-facio-cutaneous syndrome.

Background: cardio-facio-cutaneous syndrome is a rare genetic disorder affecting less than 900 people in the world. It is mainly characterized by craniofacial, dermatologic and cardiac defects, but also gastroenterological symptoms may be present, ranging from feeding difficulties to gastroesophageal reflux and constipation.In this report we describe a case of this syndrome characterized by severe feeding and growth difficulties, with a particular focus on the management of gastroenterological complications. Case presentation: the patient was a caucasian male affected by Cardio-Facio-Cutaneous syndrome who presented feeding difficulties already a few hours after birth. These symptoms worsened in the following months and lead to a complete growth arrest and malnutrition. He was first treated with a nasogastric tube placement. Subsequently, a laparoscopic Nissen fundoplication and a laparoscopic Stamm gastrostomy were performed. The child was fed with nocturnal enteral nutrition and diurnal oral and enteral nutrition. Eventually the patient resumed feeding validly and regained adequate growth. Conclusion: this paper aims to bring to light a complex rare syndrome that infrequently comes to the attention of the pediatricians and whose diagnosis is not always straightforward. We also highlight the possible complications under a gastroenterologic point of view. Our contribution can be helpful to the pediatrician in the first diagnostic suspect of this syndrome. In particular, it is worth highlighting that -in an infant with Noonan-like features- symptoms like suction or swallowing problems, vomiting and feeding difficulties should orient towards the diagnosis of a Cardio-facio-cutaneous syndrome. It is also important to stress that its related gastroenterological issues may lead to severe growth failure and therefore the role of the gastroenterologist is key to manage supplemental feeding and to establish whether a nasogastric or gastrostomic tube placement is necessary.

Microscopic lesions and modulation of gene expression in cervical medulla during BoAHV-1and BoAHV-5 infection: A mini-review.

Bovine herpesvirus (BoAHV) types 1 and 5 are closely-related neurotropic alpha-herpesviruses. BoAHV-1 generally causes respiratory and genital disease but can occasionally cause encephalitis. BoAHV-5 is the causative agent of non suppurative meningoencephalitis in calves. During neuroinvasion, both viruses reach the central and peripheral nervous system. While brain alterations are well-described, the changes that occur in the medulla have not been fully detailed. In this work, we integrated and analyzed the virological findings, the microscopic lesions and the changes that occur in the expression of genes related to the innate immunity, cell cycle and apoptosis in the cervical medulla of calves experimentally-infected with BoAHV-1 and BoAHV-5. This will contribute to the understanding of the differential neuropathogenesis of these alpha-herpesviruses of cattle.

The Impact of Early and Recent Life Stress on Trajectories of Inflammatory Biomarkers in a Diverse Sample of Adolescents.

Elevated inflammatory activity is one possible pathway through which exposure to childhood adversity engenders risk for physical and psychiatric illnesses. Limited research has investigated the compounding effects of childhood and adolescent stress exposure on changes in circulating levels of inflammatory biomarkers. This study assessed whether childhood adversity interacted with chronic or acute stress during adolescence to affect the temporal trajectories of five inflammatory biomarkers across at least three blood draws in a diverse sample of adolescents (N = 134; observations = 462). Using multilevel modeling, the interaction of childhood adversity, time, and within-person variance of acute stressors significantly predicted trajectories of higher interleukin-10 levels, controlling for demographics, medication use, and body mass index. Adolescents with high levels of childhood adversity who were exposed to a higher frequency of acute stressors compared to their own average rate of stress exposure consistently had higher levels of IL-10 as they got older, but those with average and below frequency of acute stressors had decreasing trajectories of log IL-10 as they matured. The results demonstrate how events early in life shape biological responses to the adolescent environment. This study also highlights the importance of developmental timing on the body's enhanced reactivity to acute and sustained stressors following childhood adversity.

The humanised CYP2C19 transgenic mouse exhibits cerebellar atrophy and movement impairment reminiscent of ataxia.

AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.

Impact of NFIB and CYP1A variants on clozapine serum concentration-A retrospective naturalistic cohort study on 526 patients with known smoking habits.

Clinical response of clozapine is closely associated with serum concentration. Although tobacco smoking is the key environmental factor underlying interindividual variability in clozapine metabolism, recent genome-wide studies suggest that CYP1A and NFIB genetic variants may also be of significant importance, but their quantitative impact is unclear. We investigated the effects of the rs2472297 C>T (CYP1A) and rs28379954 T>C (NFIB) polymorphisms on serum concentrations in smokers and nonsmokers. The study retrospectively included 526 patients with known smoking habits (63.7% smokers) from a therapeutic drug monitoring service in Norway. Clozapine dose-adjusted concentrations (C/D) and patient proportions with subtherapeutic levels (<1070 nmol/L) were compared between CYP1A/NFIB variant allele carriers and homozygous wild-type carriers (noncarriers), in both smokers and nonsmokers. Clozapine C/D was reduced in patients carrying CYP1A-T and NFIB-C variants versus noncarriers, both among smokers (-48%; p < 0.0001) and nonsmokers (-35%; p = 0.028). Patients who smoke carrying CYP1A-T and NFIB-C variants had a 66% reduction in clozapine C/D versus nonsmoking noncarriers (p < 0.0001). The patient proportion with subtherapeutic levels was 2.9-fold higher in patients who smoke carrying NFIB-C and CYP1A-T variants versus nonsmoking noncarriers (p < 0.0001). In conclusion, CYP1A and NFIB variants have significant and additive impact on clozapine dose requirements for reaching target serum concentrations. Patients who smoke carrying the studied CYP1A and NFIB variants, comprising 2.5% of the study population, may need threefold higher doses to prevent risk of clozapine undertreatment. The results suggest that pre-emptive genotyping of NFIB and CYP1A may be utilized to guide clozapine dosing and improve clinical outcomes in patients with treatment-resistant schizophrenia.

Regulatory and metabolic adaptations in the nitrogen assimilation of marine picocyanobacteria.

Prochlorococcus and Synechococcus are the two most abundant photosynthetic organisms on Earth, with a strong influence on the biogeochemical carbon and nitrogen cycles. Early reports demonstrated the streamlining of regulatory mechanisms in nitrogen metabolism and the removal of genes not strictly essential. The availability of a large series of genomes, and the utilization of latest generation molecular techniques have allowed elucidating the main mechanisms developed by marine picocyanobacteria to adapt to the environments where they thrive, with a particular interest in the strains inhabiting oligotrophic oceans. Given that nitrogen is often limited in those environments, a series of studies have explored the strategies utilized by Prochlorococcus and Synechococcus to exploit the low concentrations of nitrogen-containing molecules available in large areas of the oceans. These strategies include the reduction in the GC and the cellular protein contents; the utilization of truncated proteins; a reduced average amount of N in the proteome; the development of metabolic mechanisms to perceive and utilize nanomolar nitrate concentrations; and the reduced responsiveness of key molecular regulatory systems such as NtcA to 2-oxoglutarate. These findings are in sharp contrast with the large body of knowledge obtained in freshwater cyanobacteria. We will outline the main discoveries, stressing their relevance to the ecological success of these important microorganisms.