Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis

Journal of Neurology - Neurofilament light chain protein (NfL) is currently the most accurate cerebrospinal fluid (CSF) biomarker in amyotrophic lateral sclerosis (ALS) in terms of both diagnostic...     

Treatment pathway analysis of newly diagnosed dementia patients in four electronic health record databases in Europe

Purpose

Real-world studies to describe the use of first, second and third line therapies for the management and symptomatic treatment of dementia are lacking. This retrospective cohort study describes the first-, second- and third-line therapies used for the management and symptomatic treatment of dementia, and in particular Alzheimer’s Disease.

Methods

Medical records of patients with newly diagnosed dementia between 1997 and 2017 were collected using four databases from the UK, Denmark, Italy and the Netherlands.

Results

We identified 191,933 newly diagnosed dementia patients in the four databases between 1997 and 2017 with 39,836 (IPCI (NL): 3281, HSD (IT): 1601, AUH (DK): 4474, THIN (UK): 30,480) fulfilling the inclusion criteria, and of these, 21,131 had received a specific diagnosis of Alzheimer’s disease. The most common first line therapy initiated within a year (± 365 days) of diagnosis were Acetylcholinesterase inhibitors, namely rivastigmine in IPCI, donepezil in HSD and the THIN and the N-methyl-d-aspartate blocker memantine in AUH.

Conclusion

We provide a real-world insight into the heterogeneous management and treatment pathways of newly diagnosed dementia patients and a subset of Alzheimer’s Disease patients from across Europe.

     

COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches

GeroScience - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface ACE2 receptors, thereby leading to coronavirus disease 2019...     

Quantitative detection of human immunodeficiency virus type 1 (HIV-1) proviral DNA in peripheral blood mononuclear cells by SYBR green real-time PCR technique.

BACKGROUND: The persistence of proviral human immunodeficiency virus type 1 (HIV-1) DNA reservoir represents one of the major drawbacks to the total eradication of HIV-1. The quantitative determination of proviral HIV-1 DNA load offers significant therapeutic information, especially when the HIV-1 RNA levels drop below the detectable limits during the highly active retroviral therapy (HAART) treatment. Moreover, the detection of HIV-1 proviral DNA is an important diagnostic marker in the evaluation of HIV-1 infection of newborns of HIV-1 seropositive women. OBJECTIVE: We evaluated a real-time PCR based on LightCycler technology revealed through SYBR green fluorochrome (SYBR green real-time PCR) to quantify the HIV-1 proviral DNA load in peripheral blood mononuclear cells (PBMC) of HIV-1 seropositive patients. STUDY DESIGN: Firstly, we assessed the SYBR green real-time quantitative PCR for HIV-1 proviral DNA load detection determining the specificity and sensitivity of the assay using the LightCycler system. Secondly, we tested the performance of our SYBR green real-time PCR on 50 HIV-1 seropositive patients under HAART and 20 blood donors. RESULTS/CONCLUSIONS: The results of this study showed that our SYBR green real-time PCR is able to detect five copies of the HIV-1 genome. Moreover, our method revealed HIV-1 proviral DNA in all the 50 HIV-1 seropositive patients ( 627 +/- 1068 HIV-1 proviral DNA copies per 10(6) PBMC, with a range of 30-6300 copies), whereas no positive signal was observed in any PBMC blood donors. Our SYBR green real-time PCR represents a sensitive and useful approach that could be applied both in HIV-1 proviral DNA reservoir determination and in HAART monitoring, particularly when the HIV-1 plasmatic RNA is undetectable.     

Inhibition of herpes simplex virus types 1 and 2 in vitro infection by sulfated derivatives of Escherichia coli K5 polysaccharide

Herpes simplex virus type 1 (HSV-1) and HSV-2 are neurotropic viruses and common human pathogens causing major public health problems such as genital herpes, a sexually transmitted disease also correlated with increased transmission and replication of human immunodeficiency virus type 1 (HIV-1). Therefore, compounds capable of blocking HIV-1, HSV-1, and HSV-2 transmission represent candidate microbicides with a potential added value over that of molecules acting selectively against either infection. We report here that sulfated derivatives of the Escherichia coli K5 polysaccharide, structurally highly similar to heparin and previously shown to inhibit HIV-1 entry and replication in vitro, also exert suppressive activities against both HSV-1 and HSV-2 infections. In particular, the N,O-sulfated [K5-N,OS(H)] and O-sulfated epimerized [Epi-K5-OS(H)] forms inhibited the infection of Vero cells by HSV-1 and -2, with 50% inhibitory concentrations (IC₅₀) between 3 ± 0.05 and 48 ± 27 nM, and were not toxic to the cells at concentrations as high as 5 μM. These compounds impaired the early steps of HSV-1 and HSV-2 virion attachment and entry into host cells and reduced the cell-to-cell spread of HSV-2. Since K5-N,OS(H) and Epi-K5-OS(H) also inhibit HIV-1 infection, they may represent valid candidates for development as topical microbicides preventing sexual transmission of HIV-1, HSV-1, and HSV-2.     

Prediction of attack frequency in migraine treatment

Usually limited information about the frequency of migraine episodes is derived from acute migraine trials. However, the design of some studies is such that they also provide relevant information about the attack frequency without the bias associated with patient expectations of treatment effect between attacks during prophylaxis trials. Using clinical data from repeated migraine attacks treated with placebo, naratriptan 2.5 mg or sumatriptan 100 mg, we show that attack and interictal periods can be described by a random probability distribution. Based on a gamma distribution, the mean interval between attacks was estimated to be 24 (17–34) days for placebo, 23 (18–29) days for naratriptan 2.5 mg and 22 (17–28) for sumatriptan 100 mg. These findings suggest that the interictal interval is not affected by abortive treatment with triptans. Interpretation of these results may be limited by the study type, yet the method represents a new tool for the evaluation of disease dynamics and treatment effect in the prophylaxis of migraine.     

Use of 6-min and 12-min walking test for assessing the efficacy of formoterol in COPD

Exercise tolerance is an important outcome measure in patients with COPD, mostly because there is evidence that exercise testing is superior to other functional measurements obtained at rest in demonstrating the positive effect of a specific intervention. We assessed the effect of a 5-day treatment with formoterol 12mug twice daily on lung function, exercise capacity and dyspnea in 22 stable COPD patients, and compared 6-MWT with 12-MWT in evaluating formoterol efficacy. All subjects entered a crossover design. They underwent 6-MWT or 12-MWT in a randomised order and soon after started the 5-day treatment. After a 3-day washout, patients who had first performed 6-MWT, underwent 12-MWT, and the contrary. Formoterol induced a progressively significant increase in pre-drug FEV1 and IC and also significant changes in these parameters 2h after its inhalation at each test day. Moreover, it increased the walked distance by 53.6m at the end of 6-MWT and 59.9m at the end of 12-MWT. Formoterol also induced a significant change in Borg score for dyspnea caused by the 6-MWT when compared with the pre-treatment values, whereas it significantly changed dyspnea induced by 12-MWT only after the first dose. Our study not only strengthens the importance of walking tests as a useful tool for evaluating the impact of a bronchodilator on some COPD patient-centred outcomes, but also indicates that 6-MWT seems to be a more appropriate instrument than 12-MWT for assessing the exercise response to a bronchodilator in COPD.     

Effects of a walking aid in COPD patients receiving oxygen therapy

STUDY OBJECTIVES: To elucidate whether a simple walking aid may improve physical performance in COPD patients with chronic respiratory insufficiency who usually carry their own heavy oxygen canister. DESIGN: Randomized crossover trial. SETTING: Physiopathology laboratory of three rehabilitation centers. PATIENTS AND INTERVENTIONS: We studied 60 stable COPD patients (mean age, 70.6 +/- 7.9 years; FEV(1), 44.8 +/- 14.3% of predicted [+/- SD]) with chronic respiratory insufficiency who randomly performed, on 2 consecutive days, a standardized 6-min walking test using two different modalities: a full-weight oxygen canister transported using a small wheeled cart and pulled by the patient (Aid modality) or full-weight oxygen canister carried on the patient's shoulder (No-Aid modality). MEASUREMENTS AND RESULTS: The distance walked, peak effort dyspnea, and leg fatigue scores as primary outcomes, and other cardiorespiratory parameters as secondary outcomes were recorded during both tests. A significant difference (p < 0.05) between the two tests occurred for all the measured outcomes in favor of the Aid modality. Most importantly, significant changes for distance (+ 43 m, p < 0.001), peak effort dyspnea (- 2.0 points, p < 0.001), leg fatigue (- 1.4 points, p < 0.001), as well as for mean and nadir oxygen saturation and heart rate with the Aid modality (but not with the No-Aid modality) were recorded in the subgroup of patients walking < 300 m at baseline. CONCLUSIONS: This study suggests that a simple walking aid may be helpful in COPD patients receiving long-term oxygen therapy, particularly in those with lower residual exercise capacity.     

Massive cerebellar infarct complicated by hydrocephalus

We report a case of massive cerebellar infarction in which CT and MRI led to the diagnosis of acute hydrocephalus. All the neurological symptoms cleared after CSF shunting.

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Sommario Viene riportato il caso di una paziente, colpita da infarto cerebellare massivo, nel quale la TAC cerebrale ha permesso di diagnosticare un idrocefalo acuto, regredito dopo derivazione liquorale.

     

Relevance of Absorption Rate and Lag Time to the Onset of Action in Migraine

OBJECTIVE: The objective of this analysis was to simulate the performance of oral triptan formulations with varying absorption characteristics and their impact on the onset and magnitude of the antimigraine effect using a Markov model for migraine attacks. ANALYSIS: Sumatriptan pharmacokinetic data were obtained from clinical pharmacology studies in which marketed solid formulations were administered. Based on a population pharmacokinetic model, mean concentration-time profiles were generated by varying the absorption rate constant and lag time. Subsequently, the simulated profiles were evaluated in a disease model of migraine to predict the onset and duration of the effect (the pain-free, pain-relief response). RESULTS: Based on a therapeutic dose of 50 mg of sumatriptan, a maximum gain in the pain-free response of 12% was achieved with an increased absorption rate. This gain in the response was reached approximately 0.5 hours after administration. A decrease only in the lag time with respect to the currently available formulations (i.e. 0.24 hours) resulted in a maximum gain of 5% in the pain-free response, which in contrast may not be interpreted as clinically relevant. CONCLUSION: Model-based predictions suggest that increases in the absorption rate of the currently marketed oral formulation of sumatriptan result in a gain in the pain-free response that is both clinically and statistically relevant.