Clofazimine for Treatment of Cryptosporidiosis in Human Immunodeficiency Virus Infected Adults: An Experimental Medicine, Randomized, Double-blind, Placebo-controlled Phase 2a Trial.

BACKGROUND: We evaluated the efficacy, pharmacokinetics (PK), and safety of clofazimine (CFZ) in patients living with human immunodeficiency virus (HIV) with cryptosporidiosis. METHODS: We performed a randomized, double-blind, placebo-controlled study. Primary outcomes in part A were reduction in Cryptosporidium shedding, safety, and PK. Primary analysis was according to protocol (ATP). Part B of the study compared CFZ PK in matched individuals living with HIV without cryptosporidiosis. RESULTS: Twenty part A and 10 part B participants completed the study ATP. Almost all part A participants had high viral loads and low CD4 counts, consistent with failure of antiretroviral (ARV) therapy. At study entry, the part A CFZ group had higher Cryptosporidium shedding, total stool weight, and more diarrheal episodes compared with the placebo group. Over the inpatient period, compared with those who received placebo, the CFZ group Cryptosporidium shedding increased by 2.17 log2 Cryptosporidium per gram stool (95% upper confidence limit, 3.82), total stool weight decreased by 45.3 g (P = .37), and number of diarrheal episodes increased by 2.32 (P = .87). The most frequent solicited adverse effects were diarrhea, abdominal pain, and malaise. One placebo and 3 CFZ participants died during the study. Plasma levels of CFZ in participants with cryptosporidiosis were 2-fold lower than in part B controls. CONCLUSIONS: Our findings do not support the efficacy of CFZ for the treatment of cryptosporidiosis in a severely immunocompromised HIV population. However, this trial demonstrates a pathway to assess the therapeutic potential of drugs for cryptosporidiosis treatment. Screening persons living with HIV for diarrhea, and especially Cryptosporidium infection, may identify those failing ARV therapy. CLINICAL TRIALS REGISTRATION: NCT03341767.

Extracellular Vesicles Derived from Neural Progenitor Cells--a Preclinical Evaluation for Stroke Treatment in Mice.

Stem cells such as mesenchymal stem cells (MSCs) enhance neurological recovery in preclinical stroke models by secreting extracellular vesicles (EVs). Since previous reports have focused on the application of MSC-EVs only, the role of the most suitable host cell for EV enrichment and preclinical stroke treatment remains elusive. The present study aimed to evaluate the therapeutic potential of EVs derived from neural progenitor cells (NPCs) following experimental stroke. Using the PEG technique, EVs were enriched and characterized by electron microscopy, proteomics, rt-PCR, nanosight tracking analysis, and Western blotting. Different dosages of NPC-EVs displaying a characteristic profile in size, shape, cargo protein, and non-coding RNA contents were incubated in the presence of cerebral organoids exposed to oxygen-glucose deprivation (OGD), significantly reducing cell injury when compared with control organoids. Systemic administration of NPC-EVs in male C57BL6 mice following experimental ischemia enhanced neurological recovery and neuroregeneration for as long as 3 months. Interestingly, the therapeutic impact of such NPC-EVs was found to be not inferior to MSC-EVs. Flow cytometric analyses of blood and brain samples 7 days post-stroke demonstrated increased blood concentrations of B and T lymphocytes after NPC-EV delivery, without affecting cerebral cell counts. Likewise, a biodistribution analysis after systemic delivery of NPC-EVs revealed the majority of NPC-EVs to be found in extracranial organs such as the liver and the lung. This proof-of-concept study supports the idea of EVs being a general concept of stem cell-induced neuroprotection under stroke conditions, where EVs contribute to reverting the peripheral post-stroke immunosuppression.

Interaction between behavioral inhibition and neural alcohol cue-reactivity in ADHD and alcohol use disorder.

RATIONALE: Compared to the general population, adult Attention-Deficit / Hyperactivity Disorder (ADHD) is more prevalent in patients with Alcohol Use Disorder (AUD). Impaired behavioral inhibition is a common characteristic in both ADHD and AUD. Relapse risk is increased in patients with AUD and comorbid, untreated ADHD and in AUD patients with increased neural cue-reactivity. OBJECTIVES: In this study, we examined the interaction between neural correlates of behavioral inhibition and alcohol cue-reactivity with a hybrid imaging task. METHODS: Out of 69 adult study participants, we included n = 49 in our final analyses: Individuals had a diagnosis of either AUD (n = 13), ADHD (n = 14) or both (n = 5), or were healthy controls (HC; n = 17). The functional magnetic resonance imaging paradigm aimed to examine the combined effects of both an interference-inhibition task ("Simon-task") and an alcohol cue-reactivity task. Instead of segregating by diagnostic group, we pursued a dimensional approach in which we compared measures of AUD and ADHD severity, as well as the interaction of both, using multiple regression analyses. RESULTS: The four groups did not differ on the behavioral level on either the inhibition task or the alcohol cue-reactivity task. However, brain activation in frontal control and reward-related regions during completion of the combined tasks were related to ADHD and AUD severity (symptom load). During presentation of both alcohol cues and the inhibition task, participants with higher AUD and ADHD symptom load exhibited greater BOLD (blood oxygen level dependent) responses in subcortical reward-related regions. CONCLUSIONS: Our findings support the hypothesis that ADHD additionally diminishes inhibition ability in individuals with AUD. This may increase relapse risk when confronted with alcohol cues. Further, it is crucial for patients with comorbid AUD and ADHD to take into account not only reduced cognitive control over behavioral inhibition but also simultaneously heightened alcohol cue-reactivity.

Extraocular muscle enlargement in retinoencephalofacial angiomatosis.

A 22-year-old female presented for evaluation of five years of progressive left exophthalmos and intermittent blurred vision. She had previously received laser treatment for peripheral retinal neovascularization and had undergone lip reconstruction for a left-sided congenital vascular facial malformation. Magnetic resonance imaging demonstrated diffuse enlargement of the left extraocular and temporalis muscles, with prominent vessels in the temporalis muscle and intraconal fat. Left fundoscopic examination revealed grossly enlarged, tortuous retinal vessels extending from the optic disc to the peripheral retina and an abnormal network of capillaries. On the basis of these findings, a diagnosis of retinoencephalofacial angiomatosis was established. Retinoencephalofacial angiomatosis is a rare, non-hereditary disorder associated with ipsilateral retinal, brain, and facial arteriovenous malformations. This is the first report, to the authors' knowledge, of retinoencephalofacial angiomatosis presenting with exophthalmos secondary to extraocular muscle enlargement.

Case Report: Management of Corneal Clouding from Lecithin: Cholesterol Acyltransferase Deficiency.

SIGNIFICANCE: Given that there are few reported cases of lecithin:cholesterol acyltransferase (LCAT) deficiency, recognition of the condition with proper management is notable. Long-term follow-up and contact lens fitting after penetrating keratoplasty provide best possible outcomes. PURPOSE: The purpose of this study was to report a case of LCAT deficiency successfully treated with penetrating keratoplasty and longer-term follow-up with contact lens fitting. CASE REPORT: A 43-year-old white woman of Italian descent presented with corneal clouding and trouble with night vision. The patient had a history of LCAT deficiency, irritable bowel syndrome, gastroesophageal reflux disease, osteoporosis, and hemolytic anemia. Slit-lamp examination demonstrated corneal haze throughout the corneal layers. The corneas had normal pachymetry. Given the opacity of each cornea (right greater than left) and decreased night vision, penetrating keratoplasty was performed on the right eye. At post-operative month 16, the corneal graft remained clear. The patient was able to achieve a best-corrected visual acuity of 20/30+ with a scleral lens. CONCLUSIONS: Penetrating keratoplasty may be necessary to provide better quality of vision in LCAT deficiency patients, specifically to enhance one's contrast sensitivity, despite relatively good Snellen visual acuity.

System level design of the ITER bolometer port plug cameras.

The ITER bolometer diagnostic is planned to have 550 lines of sight (LOS) distributed all over the vessel. 240 channels are provided by cameras mounted in two upper ports and in one equatorial port. This paper describes the current status of the system level design of the port cameras and the solutions proposed on how to implement all required camera components while meeting a multitude of competing requirements. Sensor holders, support structures, and different apertures depending on the camera type (pinhole or collimator), cable connectors, ceramic track plates, and many mineral insulated cables have to be integrated within a restricted space envelope to guarantee functionality. The design of the internal electrical interfaces and the external mechanical mountings will be described as well. Using the example of an upper port camera with 60 LOS, the assembly of the camera components is explained and two currently discussed architecture options for the remote handling maintenance scheme in the hot cell are compared.

Biochemical markers in vascular cognitive impairment associated with subcortical small vessel disease - A consensus report.

BACKGROUND: Vascular cognitive impairment (VCI) is a heterogeneous entity with multiple aetiologies, all linked to underlying vascular disease. Among these, VCI related to subcortical small vessel disease (SSVD) is emerging as a major homogeneous subtype. Its progressive course raises the need for biomarker identification and/or development for adequate therapeutic interventions to be tested. In order to shed light in the current status on biochemical markers for VCI-SSVD, experts in field reviewed the recent evidence and literature data. METHOD: The group conducted a comprehensive search on Medline, PubMed and Embase databases for studies published until 15.01.2017. The proposal on current status of biochemical markers in VCI-SSVD was reviewed by all co-authors and the draft was repeatedly circulated and discussed before it was finalized. RESULTS: This review identifies a large number of biochemical markers derived from CSF and blood. There is a considerable overlap of VCI-SSVD clinical symptoms with those of Alzheimer's disease (AD). Although most of the published studies are small and their findings remain to be replicated in larger cohorts, several biomarkers have shown promise in separating VCI-SSVD from AD. These promising biomarkers are closely linked to underlying SSVD pathophysiology, namely disruption of blood-CSF and blood-brain barriers (BCB-BBB) and breakdown of white matter myelinated fibres and extracellular matrix, as well as blood and brain inflammation. The leading biomarker candidates are: elevated CSF/blood albumin ratio, which reflects BCB/BBB disruption; altered CSF matrix metalloproteinases, reflecting extracellular matrix breakdown; CSF neurofilment as a marker of axonal damage, and possibly blood inflammatory cytokines and adhesion molecules. The suggested SSVD biomarker deviations contrasts the characteristic CSF profile in AD, i.e. depletion of amyloid beta peptide and increased phosphorylated and total tau. CONCLUSIONS: Combining SSVD and AD biomarkers may provide a powerful tool to identify with greater precision appropriate patients for clinical trials of more homogeneous dementia populations. Thereby, biomarkers might promote therapeutic progress not only in VCI-SSVD, but also in AD.

Cellular prion protein promotes post-ischemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition.

Although cellular prion protein (PrP(c)) has been suggested to have physiological roles in neurogenesis and angiogenesis, the pathophysiological relevance of both processes remain unknown. To elucidate the role of PrP(c) in post-ischemic brain remodeling, we herein exposed PrP(c) wild type (WT), PrP(c) knockout (PrP-/-) and PrP(c) overexpressing (PrP+/+) mice to focal cerebral ischemia followed by up to 28 days reperfusion. Improved neurological recovery and sustained neuroprotection lasting over the observation period of 4 weeks were observed in ischemic PrP+/+ mice compared with WT mice. This observation was associated with increased neurogenesis and angiogenesis, whereas increased neurological deficits and brain injury were noted in ischemic PrP-/- mice. Proteasome activity and oxidative stress were increased in ischemic brain tissue of PrP-/- mice. Pharmacological proteasome inhibition reversed the exacerbation of brain injury induced by PrP-/-, indicating that proteasome inhibition mediates the neuroprotective effects of PrP(c). Notably, reduced proteasome activity and oxidative stress in ischemic brain tissue of PrP+/+ mice were associated with an increased abundance of hypoxia-inducible factor 1α and PACAP-38, which are known stimulants of neural progenitor cell (NPC) migration and trafficking. To elucidate effects of PrP(c) on intracerebral NPC homing, we intravenously infused GFP(+) NPCs in ischemic WT, PrP-/- and PrP+/+ mice, showing that brain accumulation of GFP(+) NPCs was greatly reduced in PrP-/- mice, but increased in PrP+/+ animals. Our results suggest that PrP(c) induces post-ischemic long-term neuroprotection, neurogenesis and angiogenesis in the ischemic brain by inhibiting proteasome activity.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

Development of a Multicompartment Permeability-Limited Lung PBPK Model and Its Application in Predicting Pulmonary Pharmacokinetics of Antituberculosis Drugs.

Achieving sufficient concentrations of antituberculosis (TB) drugs in pulmonary tissue at the optimum time is still a challenge in developing therapeutic regimens for TB. A physiologically based pharmacokinetic model incorporating a multicompartment permeability-limited lung model was developed and used to simulate plasma and pulmonary concentrations of seven drugs. Passive permeability of drugs within the lung was predicted using an in vitro-in vivo extrapolation approach. Simulated epithelial lining fluid (ELF):plasma concentration ratios showed reasonable agreement with observed clinical data for rifampicin, isoniazid, ethambutol, and erythromycin. For clarithromycin, itraconazole and pyrazinamide the observed ELF:plasma ratios were significantly underpredicted. Sensitivity analyses showed that changing ELF pH or introducing efflux transporter activity between lung tissue and ELF can alter the ELF:plasma concentration ratios. The described model has shown utility in predicting the lung pharmacokinetics of anti-TB drugs and provides a framework for predicting pulmonary concentrations of novel anti-TB drugs.

A comparison of region-of-interest measures for extracting whole brain data using survival analysis in alcoholism as an example.

BACKGROUND: Aggregation of functional magnetic resonance imaging (fMRI) data in regions-of-interest (ROIs) is required for complex statistical analyses not implemented in standard fMRI software. Different data-aggregation measures assess various aspects of neural activation, including spatial extent and intensity. NEW METHOD: In this study, conducted within the framework of the PREDICT study, we compared different aggregation measures for voxel-wise fMRI activations to be used as prognostic factors for relapse in 49 abstinent alcohol-dependent individuals in an outpatient setting using a cue-reactivity task. We compared the importance of the data-aggregation measures as prognostic factors for treatment outcomes by calculating the proportion of explained variation. RESULTS AND COMPARISON WITH EXISTING METHOD(S): Relapse risk was associated with cue-induced brain activation during abstinence in the ventral striatum (VS) and in the orbitofrontal cortex (OFC). While various ROI measures proved appropriate for using fMRI cue-reactivity to predict relapse, on the descriptive level the most "important" prognostic factor was a measure defined as the sum of t-values exceeding an individually defined threshold. Data collected in the VS was superior to that from other regions. CONCLUSIONS: In conclusion, it seems that fMRI cue-reactivity, especially in the VS, can be used as prognostic factor for relapse in abstinent alcohol-dependent patients. Our findings suggest that data-aggregation measures that take both spatial extent and intensity of cue-induced brain activation into account make better biomarkers for predicting relapse than measures that consider an activation's spatial extent or intensity alone.

Supporting dementia patients in hospital environments: health-related risks, needs and dedicated structures for patient care.

The diagnostics and treatment of dementia are progressively gaining importance for European neurologists. Our hospital structures are poorly prepared for patients suffering from dementia. As a consequence of cognitive and physical deficits, dementia patients have an increased risk for serious complications and poor outcomes in hospital environments. In this review, the specific needs of dementia patients are outlined, describing how geriatricians, neurologists and psychiatrists may contribute to better patient care, e.g. with consultation or liaison services, geriatric wards, dedicated dementia wards or memory clinics in interaction with nurses, occupational therapists, physiotherapists, speech therapists, psychologists and social workers. Due to their multifaceted needs, dementia patients can most successfully be supported in clinical environments that closely integrate specialized inpatient, outpatient and primary care offers.

Supporting dementia patients and their caregivers in daily life challenges: review of physical, cognitive and psychosocial intervention studies.

BACKGROUND AND PURPOSE: Dementia is associated with multiple daily life challenges that have a major impact for health outcome, affecting both the patients and their caregivers. In this review, the efficacy of physical, cognitive and psychosocial interventions in the treatment of dementia patients is evaluated, and how caregiver education and support may contribute to patient care is analysed. RESULTS AND CONCLUSIONS: Due to the complex nature of cognitive and psychosocial interventions, their efficacy depends strongly on local settings. Thus, active components of these interventions are not always obvious, even in controlled randomized trials. Successful patient management includes (i) the safekeeping of basic support, (ii) the provision of a stable external milieu that is adjusted to the patients' cognitive resources and (iii) the provision of multimodal therapeutic concepts that are closely adapted to the practical needs of the patients and caregivers.

Effects of acute versus post-acute systemic delivery of neural progenitor cells on neurological recovery and brain remodeling after focal cerebral ischemia in mice.

Intravenous transplantation of neural progenitor cells (NPCs) induces functional recovery after stroke, albeit grafted cells are not integrated into residing neural networks. However, a systematic analysis of intravenous NPC delivery at acute and post-acute time points and their long-term consequences does not exist. Male C57BL6 mice were exposed to cerebral ischemia, and NPCs were intravenously grafted on day 0, on day 1 or on day 28. Animals were allowed to survive for up to 84 days. Mice and tissues were used for immunohistochemical analysis, flow cytometry, ELISA and behavioral tests. Density of grafted NPCs within the ischemic hemisphere was increased when cells were transplanted on day 28 as compared with transplantation on days 0 or 1. Likewise, transplantation on day 28 yielded enhanced neuronal differentiation rates of grafted cells. Post-ischemic brain injury, however, was only reduced when NPCs were grafted at acute time points. On the contrary, reduced post-ischemic functional deficits due to NPC delivery were independent of transplantation paradigms. NPC-induced neuroprotection after acute cell delivery was due to stabilization of the blood-brain barrier (BBB), reduction in microglial activation and modulation of both peripheral and central immune responses. On the other hand, post-acute NPC transplantation stimulated post-ischemic regeneration via enhanced angioneurogenesis and increased axonal plasticity. Acute NPC delivery yields long-term neuroprotection via enhanced BBB integrity and modulation of post-ischemic immune responses, whereas post-acute NPC delivery increases post-ischemic angioneurogenesis and axonal plasticity. Post-ischemic functional recovery, however, is independent of NPC delivery timing, which offers a broad therapeutic time window for stroke treatment.

B-type natriuretic peptide predicts stroke of presumable cardioembolic origin in addition to coronary artery calcification.

BACKGROUND AND PURPOSE: B-type natriuretric peptide (BNP) is a marker of cardiac dysfunction that is released from myocytes in response to ventricular wall stress. Previous studies suggested that BNP predicts stroke events in addition to classical risk factors. It was suggested that the BNP-associated risk results from coronary atherosclerosis or atrial fibrillation. METHODS: Three thousand six hundred and seventy five subjects from the population-based Heinz Nixdorf Recall study (45-75 years; 47.6% men) without previous stroke, coronary heart disease, myocardial infarcts, open cardiac valve surgery, pacemakers and defibrillators were followed up over 110.1 ± 23.1 months. Cox proportional hazards regressions were used to examine BNP as a stroke predictor in addition to vascular risk factors (age, gender, systolic blood pressure, low-density lipoprotein, high-density lipoprotein, diabetes, smoking), renal insufficiency, atrial fibrillation/known heart failure and coronary artery calcification. RESULTS: Eighty-nine incident strokes occurred (80 ischaemic, 9 hemorrhagic). Subjects suffering stroke had significantly higher BNP values at baseline than the remaining subjects [26.3 (Q1; Q3 = 12.9; 51.0) vs. 17.4 (9.4; 31.4); P < 0.001]. In a multivariable regression, log10 BNP was an independent stroke predictor [hazard ratio 1.96, 95% confidence interval (CI) 1.13-3.41; P = 0.017] in addition to age (1.24 per 5 years, CI 1.04-1.49; P = 0.016), systolic blood pressure (1.25 per 10 mmHg, CI 1.14-1.38; P < 0.001), smoking (2.05, CI 1.24-3.39; P = 0.005), atrial fibrillation/heart failure (2.25, CI 1.05-4.83; P = 0.037) and computed-tomography-based log10 (coronary artery calcification + 1) (1.47, CI 1.15-1.88; P = 0.002). Log10 BNP predicted stroke in men but not women, both in subjects ≤65 and >65 years. In subsequent analyses, BNP discriminated the incidence of cardioembolic stroke (P for trend = 0.001), but not stroke of macroangiopathic (P = 0.555), microangiopathic (P = 0.809) or unknown (P = 0.367) origin. CONCLUSIONS: BNP predicts presumable cardioembolic stroke independent of coronary calcification.