Melatonin usage in children and young adults, a registry-based cohort study.

Sleep disorder is common in children and adolescents, particularly in those with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD). While non-pharmacological treatment is first line, occasionally an add-on of an oral drug is needed. The endogenous hormone melatonin is increasingly used for sleep disorders in children and adolescents. In this registry-based cohort study we follow dispensation of melatonin in young individuals, 0-25 years of age, in Stockholm, Sweden during 2016-2019. In all 9980 individuals, were dispensed melatonin in 2016 and followed for 3 years. Child psychiatrist was the most common prescribing specialty, 55% of all prescriptions. Only 20% had a recorded diagnosis of sleep disorder. The majority, 65% had a neuro psychiatric diagnose. Half of the individuals had at least 4 prescribed drugs dispensed during the follow-up. Almost half of our cohort were dispensed melatonin during the entire study period and doses and volumes of drug dispensed increased by 50 and 100%, respectively. Continuous medication was most common among children 6-12 years, where 7 out of 10 individuals were still adherent after three years. As long-term safety data is lacking, we find this concerning, and this illustrates the need of long-term follow-up of melatonin use in children and young individuals.

Resting EEG spectral slopes are associated with age-related differences in information processing speed.

BACKGROUND: Previous research has shown the slope of the EEG power spectrum differentiates between older and younger adults in various experimental cognitive tasks. We extend that work, assessing the relation between the EEG power spectrum and performance on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). METHODS: Twenty-one younger and twenty-three older adults completed the RBANS with EEG data collected at rest. Using spectral parameterization, we tested the mediating effect of the spectral slope on differences in subsequent cognitive task performance. RESULTS: Older adults performed reliably worse on the RBANS overall, and on the Attention and Delayed Memory domains specifically. However, evidence of mediation was only found for the Coding subtest. CONCLUSIONS: The slope of the resting EEG power spectrum mediated age-related differences in cognition, but only in a task requiring speeded processing. Mediation was not statistically significant for delayed memory, even though age-related differences were present.

Calcium channel blockers, survival and ischaemic stroke in patients with dementia: a Swedish registry study.

BACKGROUND: The effect of calcium channel blockers (CCB) on mortality and ischaemic stroke risk in dementia patients is understudied. OBJECTIVES: To calculate the risk of death and ischaemic stroke in dementia patients treated with CCBs, considering individual agents and dose response. METHODS: Longitudinal cohort study with 18 906 hypertensive dementia patients from the Swedish Dementia Registry (SveDem), 2008-2014. Other Swedish national registries contributed information on comorbidities, dispensed medication and outcomes. Individual CCB agents and cumulative defined daily doses (cDDD) were considered. RESULTS: In patients with hypertension and dementia, nifedipine was associated with increased mortality risk (aHR 1.32; CI 1.01-1.73; P < 0.05) compared to non-CCB users. Patients diagnosed with Alzheimer's dementia (AD) or dementia with Lewy bodies/Parkinson's disease dementia (DLB-PDD) taking amlodipine had lower mortality risk (aHR, 0.89; CI, 0.80-0.98; P < 0.05 and aHR 0.58; CI, 0.38-0.86; P < 0.01, respectively), than those taking other CCBs. Amlodipine was associated with lower stroke risk in patients with Alzheimer's dementia compared to other CCBs (aHR 0.63; CI, 0.44-0.89; P < 0.05). Sensitivity analyses with propensity score-matched cohorts repeated the results for nifedipine (aHR 1.35; 95% CI, 1.02-1.78; P < 0.05) and amlodipine in AD (aHR, 0.87; CI, 0.78-0.97; P < 0.05) and DLB-PDD (aHR, 0.56, 95%CI, 0.37-0.85; P < 0.05). CONCLUSION: Amlodipine was associated with reduced mortality risk in dementia patients diagnosed with AD and DLB-PDD. AD patients using amlodipine had a lower risk of ischaemic stroke compared to other CCB users.

Point-of-care versus central laboratory testing of INR in acute stroke.

OBJECTIVES: Effective anticoagulant therapy is a contraindication to thrombolysis, which is an effective treatment of ischemic stroke if given within 4.5 hours of symptom onset. INR above 1.7 is generally considered a contraindication for thrombolysis. Rapid measurement of INR in warfarin-treated patients is therefore of major importance in order to be able to decide on thrombolysis or not. We asked whether INR measured on a point-of-care instrument would be as good as a central laboratory instrument. MATERIAL AND METHODS: A total of 529 consecutive patients who arrived at the emergency department at a large urban teaching hospital with stroke symptoms were enrolled in the study. INR was measured with a CoaguChek and a Sysmex instrument. Basic clinical information such as age, sex, and diagnosis (if available) was recorded. INR from the instruments was compared using linear regression and Bland-Altman plot. RESULTS: Of 529 patients, 459 had INR results from both instruments. Among these, 3 patients were excluded as outliers. The rest (n = 456) showed good correlation between the methods (R2  = 0.97). In the current setting, CoaguChek was in median 63 minutes faster than Sysmex. CONCLUSION: Our results indicate that point-of-care testing is a safe mean to rapidly acquire a patient's INR value in acute clinical situations.

Sex differences in the presentation of stroke.

Stroke affects both men and women of all ages, although the condition is more common among the elderly. Stroke occurs at an older age among women than among men; although the incidence is lower among women than among men, as women have a longer life expectancy their lifetime risk is slightly higher. Ischemic stroke is the most common type of stroke; and reperfusion treatment is possible if the patient reaches hospital early enough. Thrombolysis and thrombectomy are time-sensitive treatments - the earlier they are initiated the better is the chance of a positive outcome. It is therefore important to identify a stroke as soon as possible. Medical personnel can readily identify typical stroke symptoms but the presentation of non-traditional stroke symptoms, such as impaired consciousness and altered mental status, is often associated with a significant delay in the identification of stroke and thus delay in or inability to provide treatment. Non-traditional stroke symptoms are reported to be more common in women, who are thereby at risk of delayed recognition of stroke and treatment delay.

Management of acute ischaemic stroke in patients with dementia.

An estimated 10% of stroke patients have an underlying dementia. As a consequence, health professionals often face the challenge of managing patients with dementia presenting with an acute stroke. Patients with dementia are less likely to receive thrombolysis (0.56-10% vs. 1-16% thrombolysis rates in the general population), be admitted to a stroke unit or receive some types of care. Anticoagulation for secondary stroke prevention is sometimes withheld, despite dementia not being listed as an exclusion criterion in current guidelines. Studies in this population are scarce, and results have been contradictory. Three observational studies have examined intravenous thrombolysis for treatment of acute ischaemic stroke in patients with dementia. In the two largest matched case-control studies, there were no significant differences between patients with and without dementia in the risks of intracerebral haemorrhage or mortality. The risk of intracerebral haemorrhage ranged between 14% and 19% for patients with dementia. Studies of other interventions for stroke are lacking for this population. Patients with dementia are less likely to be discharged home compared with controls (19% vs. 41%) and more likely to be disabled (64% vs. 59%) or die during hospitalization (22% vs. 11%). The aim of this review was to summarize current knowledge about the management of ischaemic stroke in patients with pre-existing dementia, including organizational aspects of stroke care, intravenous thrombolysis, access to stroke unit care and use of supportive treatment. Evidence to support anticoagulation for secondary prevention of stroke in patients with atrial fibrillation and antiplatelet therapy in nonembolic stroke will be discussed, as well as rehabilitation and how these factors influence patient outcomes. Finally, ethical issues, knowledge gaps and pathways for future research will be considered.

Repeated intratumoral administration of ONCOS-102 leads to systemic antitumor CD8+ T-cell response and robust cellular and transcriptional immune activation at tumor site in a patient with ovarian cancer.

Adenoviruses are excellent immunotherapeutic agents with a unique ability to prime and boost immune responses. Recombinant adenoviruses cause immunogenic cancer cell death and subsequent release of tumor antigens for antigen presenting cells, resulting in the priming of potent tumor-specific immunity. This effect may be further enhanced by immune-stimulating transgenes expressed by the virus. We report a case of a 38-year-old female with Stage 3 metastatic micropapillary serous carcinoma of the ovary. She was treated in a Phase I study with a granulocyte-macrophage colony stimulating factor (GMCSF)-expressing oncolytic adenovirus, Ad5/3-D24-GMCSF (ONCOS-102). The treatment resulted in progressive infiltration of CD8+ lymphocytes into the tumor and concomitant systemic induction of several tumor-specific CD8+ T-cell populations. The patient was alive at the latest follow up more than 20 months after initiation of the study.

Technical complications with implant-supported dental prostheses.

Studies are needed to determine the prognosis of different forms of dental prosthetic rehabilitation and the main complications involved. The purpose of the present study was to evaluate technical complications involving implant-supported prostheses. A retrospective one time snap-shot study was carried out with a total of 509 implants in 153 patients. Prosthetic conditions were determined by clinical and radiographic examination. The least frequent technical complication involved fracture (0.2%), loss (0.4%) and loosening (3.3%) of the screw. The most frequent complications were loss of resin covering the screw (23.8%), loss of overdenture retention (18.6%) and fractures of the resin (12.4%). A high frequency of misfit between the prosthesis and abutment (25.4%) was found, which was significantly associated (P < 0.05) with other variables, especially cemented prostheses (P < 0.001). To minimize the frequency of complications, protocols must be established from diagnosis to the completion of treatment and follow up of implant-supported prostheses, especially in terms of adequate technical steps and careful radiographic evaluation of the components.

Improved allometric models to estimate the aboveground biomass of tropical trees.

Terrestrial carbon stock mapping is important for the successful implementation of climate change mitigation policies. Its accuracy depends on the availability of reliable allometric models to infer oven-dry aboveground biomass of trees from census data. The degree of uncertainty associated with previously published pantropical aboveground biomass allometries is large. We analyzed a global database of directly harvested trees at 58 sites, spanning a wide range of climatic conditions and vegetation types (4004 trees ≥ 5 cm trunk diameter). When trunk diameter, total tree height, and wood specific gravity were included in the aboveground biomass model as covariates, a single model was found to hold across tropical vegetation types, with no detectable effect of region or environmental factors. The mean percent bias and variance of this model was only slightly higher than that of locally fitted models. Wood specific gravity was an important predictor of aboveground biomass, especially when including a much broader range of vegetation types than previous studies. The generic tree diameter-height relationship depended linearly on a bioclimatic stress variable E, which compounds indices of temperature variability, precipitation variability, and drought intensity. For cases in which total tree height is unavailable for aboveground biomass estimation, a pantropical model incorporating wood density, trunk diameter, and the variable E outperformed previously published models without height. However, to minimize bias, the development of locally derived diameter-height relationships is advised whenever possible. Both new allometric models should contribute to improve the accuracy of biomass assessment protocols in tropical vegetation types, and to advancing our understanding of architectural and evolutionary constraints on woody plant development.

Parâmetros utilizados para o diagnóstico periodontal em faculdades de odontologia brasileiras / Parameters used for Periodontal diagnosis in brazilian dental schools

A doença periodontal possui alta prevalência na população e o seu diagnóstico precoce é importante para o prognóstico do tratamento. Há uma extensa discussão acerca do método ideal para estabelecer o diagnóstico e a classificação das doenças periodontais. Este trabalho investigou os parâmetros clínicos utilizados em faculdades de Odontologia brasileiras para o diagnóstico das doenças periodontais. A metodologia consistiu no envio de um questionário, via e-mail, para um professor de Periodontia de cada instituição de ensino de Odontologia. Foram obtidas respostas de 30 faculdades brasileiras, as quais foram analisadas de forma descritiva. Foi observado que metade das faculdades brasileiras (50%) utiliza o PSR (registro periodontal simplificado) no exame inicial e 90% usam o periograma completo. A profundidade a sondagem foi o parâmetro mais utilizado para o diagnóstico (21%), enquanto que a perda de inserção utilizada para a classificação das doenças foi de 54%. Pôde-se concluir que existe uma uniformidade entre as faculdades em relação aos parâmetros clínicos utilizados para o diagnóstico e a classificação das doenças periodontais.

A nova inserção da periodontia nos currículos integrados de faculdades de odontologia brasileiras / Insertion of Periodontics in integrated curriculum at brazilian dental schools

A Periodontia tem sido incluída na base da estrutura de clínicas por complexidade crescente. Essa abordagem segue as Diretrizes Curriculares Nacionais propostas pelo Ministério da Educação e Cultura (MEC). De acordo com a evolução da Odontologia nos últimos anos e as mudanças ocorridas com relação às necessidades da população, este estudo propôs-se a investigar a inserção da Periodontia neste novo contexto e os parâmetros utilizados na avaliação periodontal e das estruturas peri-implantares. Um e-mail foi submetido para um professor de Periodontia de cada instituição de ensino brasileira. Neste havia um link que o professor deveria acessar, ler e concordar com o termo de consentimento para ter acesso ao questionário. As respostas enviadas por 30 faculdades brasileiras foram analisadas de forma descritiva. De acordo com as respostas dos questionários pôde-se verifcar que há uma tendência à renovação curricular pautada na integração clínica. Porém, uma readequação e/ou inclusão da avaliação de certos aspectos anatômicos relacionados ao periodonto, no que diz respeito à saúde e estética periodontal e peri-implantar, faz-se ainda necessária.

Clinical neurofunctional rehabilitation of a cat with spinal cord injury after hemilaminectomy and autologous stem cell transplantation.

Stem cell-based therapy has been investigated in a number of degenerative and traumatic diseases, including spinal cord injury. In the present study, we investigated the use of autologous mesenchymal stem cells in the functional rehabilitation of a domestic cat presenting a compressive L1-L5 fracture. Bone marrow cells collected by puncture of the iliac crest were cultured to obtain mesenchymal stem cells three weeks before surgery. Hemilaminectomy was performed, followed by injection of the mesenchymal stem cells in the injured area. Clinical evaluation of the animal prior to surgery showed absence of pain, muscular tonus, and panniculi reflexes. Seven days after surgery and cell transplantation the examination revealed a progressive recovery of the panniculus reflexes and of the responses to superficial and deep pain stimuli despite the low proprioceptive and hyperreflexic ataxic hind limbs. Physiotherapy protocols were applied for clinical rehabilitation after surgery. The cat's first steps, three-minute weight-bearing, and intestine and urinary bladder partial reestablishment were observed 75 days post-surgery. Our results indicate the therapeutic potential of mesenchymal stem cells in chronic spinal cord injuries.

Clinical Neurofunctional Rehabilitation of a Cat with Spinal Cord Injury after Hemilaminectomy and Autologous Stem Cell Transplantation

Stem cell-based therapy has been investigated in a number of degenerative and traumatic diseases, including spinal cord injury. In the present study, we investigated the use of autologous mesenchymal stem cells in the functional rehabilitation of a domestic cat presenting a compressive L1-L5 fracture. Bone marrow cells collected by puncture of the iliac crest were cultured to obtain mesenchymal stem cells three weeks before surgery. Hemilaminectomy was performed, followed by injection of the mesenchymal stem cells in the injured area. Clinical evaluation of the animal prior to surgery showed absence of pain, muscular tonus, and panniculi reflexes. Seven days after surgery and cell transplantation the examination revealed a progressive recovery of the panniculus reflexes and of the responses to superficial and deep pain stimuli despite the low proprioceptive and hyperreflexic ataxic hind limbs. Physiotherapy protocols were applied for clinical rehabilitation after surgery. The cat's first steps, three-minute weight-bearing, and intestine and urinary bladder partial reestablishment were observed 75 days post-surgery. Our results indicate the therapeutic potential of mesenchymal stem cells in chronic spinal cord injuries.

Investigator-initiated trials of targeted oncology agents: why independent research is at risk?

BACKGROUND: Drug development traditionally has relied upon the complementary contributions of clinicians and scientists at academic institutions and at pharmaceutical companies. Greater regulatory burdens, increased bureaucratic requirements, restricted reimbursement, and spiralling research and development costs are exerting pressure on the drug development pipeline. The result is a de-emphasis of exploratory research, particularly independent academic research, despite its proven value in identifying new drug targets and developing innovative cancer therapies. DESIGN: An expert panel assembled by the Biotherapy Development Association-a nonprofit international forum for academic and industry researchers, patients, and government regulatory and postregulatory agencies-examined the growing schism between academia and industry and identified several causes of declining academic research. RESULTS: The authors propose solutions to sustain investigator-initiated research and provide a new model whereby expert organisations provide a forum for academia and industry to plan studies within a regulatory framework to support licensure/authorisation and reimbursement for new molecularly targeted agents and biomarkers. CONCLUSIONS: Investigator-initiated trials have led to the discovery and development of innovative, safe, and effective cancer treatments. To ensure that such research continues, action will be required on the parts of legislative and regulatory bodies, industry, universities, patient advocacy organisations, and preclinical and clinical academic scientists.

Market and patient access to new oncology products in Europe: a current, multidisciplinary perspective.

To air challenging issues related to patient and market access to new anticancer agents, the Biotherapy Development Association--an international group focused on developing targeted cancer therapies using biological agents--convened a meeting on 29 November 2007 in Brussels, Belgium. The meeting provided a forum for representatives of pharmaceutical companies and academia to interact with European regulatory and postregulatory agencies. The goal was to increase all parties' understanding of their counterparts' roles in the development, licensure, and appraisal of new agents for cancer treatment, events guided by an understanding that cancer patients should have rapid and equitable access to life-prolonging treatments. Among the outcomes of the meeting were a greater understanding of the barriers facing drug developers in an evolving postregulatory world, clarity about what regulatory and postregulatory bodies expect to see in dossiers of new anticancer agents as they contemplate licensure and reimbursement, and several sets of recommendations to optimize patients' access to innovative, safe, effective, and fairly priced cancer treatments.

Synergistic apoptosis induction by proteasome and histone deacetylase inhibitors is dependent on protein synthesis.

Proteasome inhibitors are able to efficiently induce apoptosis in many tumor cells while leaving quiescent, untransformed cells largely unharmed. Here we investigated the further enhancement of proteasome inhibitor-mediated apoptosis induction in Bcr-Abl positive K562 CML cells by simultaneous treatment with different histone deacetylase inhibitors (HDIs). Combining proteasome and HDIs resulted in rapid hyperacetylation of histone H3 and accumulation of polyubiquitinated proteins and the synergistic induction of apoptosis. Apoptosis induction was associated with caspase 8, 3 and 9 activation, Bid processing, destruction of the mitochondrial membrane potential, cleavage of PARP and lamin B and extensive DNA fragmentation. The pan-caspase inhibitor Z-VAD-FMK and the caspase-8 inhibitor Z-IETD-FMK could inhibit K562 cell apoptosis. Apoptosis was also delayed by overexpression of Bcl-xL, as well as by crmA, a known inhibitor of caspases 1 and 8. Caspase 8 activity could still be detected in the presence of ectopic Bcl-xL, but not in crmA transfected cells. The most striking anti-apoptotic effect though was obtained by the translational inhibitor cycloheximide, which abolished caspase 8 processing, blocked Bid cleavage and maintained the mitochondrial transmembrane potential. Apoptosis by the combination treatment occurred independently from CD95/Fas receptor stimulation. These results demonstrated that transcriptional activation by HDIs combined with proteasome inhibitor mediated posttranslational stabilization of protein(s) results in significantly enhanced CML apoptosis which was striktly dependent on uninterrupted protein synthesis.

Spontaneous axonal regeneration in rodent spinal cord after ischemic injury.

Here we present evidence for spontaneous and long-lasting regeneration of CNS axons after spinal cord lesions in adult rats. The length of 200 kD neurofilament (NF)-immunolabeled axons was estimated after photochemically induced ischemic spinal cord lesions using a stereological tool. The total length of all NF-immunolabeled axons within the lesion cavities was increased 6- to 10-fold at 5, 10, and 15 wk post-lesion compared with 1 wk post-surgery. In ultrastructural studies we found the putatively regenerating axons within the lesion to be associated either with oligodendrocytes or Schwann cells, while other fibers were unmyelinated. Immunohistochemistry demonstrated that some of the regenerated fibers were tyrosine hydroxylase- or serotonin-immunoreactive, indicating a central origin. These findings suggest that there is a considerable amount of spontaneous regeneration after spinal cord lesions in rodents and that the fibers remain several months after injury. The findings of tyrosine hydroxylase- and serotonin-immunoreactivity in the axons suggest that descending central fibers contribute to this endogenous repair of ischemic spinal cord injury.