Current antifungal agents cover a majority of opportunistic fungal pathogens; however, breakthrough invasive fungal infections continue to occur and increasingly involve relatively uncommon yeasts ...and molds, which often exhibit decreased susceptibility. APX001A (manogepix) is a first-in-class small-molecule inhibitor of the conserved fungal Gwt1 protein. This enzyme is required for acylation of inositol during glycosylphosphatidylinositol anchor biosynthesis. APX001A is active against the major fungal pathogens, i.e.,
(except
),
, and hard-to-treat molds, including
and
In this study, we tested APX001A and comparators against 1,706 contemporary clinical fungal isolates collected in 2017 from 68 medical centers in North America (37.3%), Europe (43.4%), the Asia-Pacific region (12.7%), or Latin America (6.6%). Among the isolates tested, 78.5% were
spp., 3.9% were non-
yeasts, including 30 (1.8%)
var.
isolates, 14.7% were
spp., and 2.9% were other molds. All isolates were tested by CLSI reference broth microdilution. APX001A (MIC
, 0.008 μg/ml; MIC
, 0.06 μg/ml) was the most active agent tested against
sp. isolates; corresponding anidulafungin, micafungin, and fluconazole MIC
values were 16- to 64-fold higher. Similarly, APX001A (MIC
, 0.25 μg/ml; MIC
, 0.5 μg/ml) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against
var.
Against
spp., AXP001A (50% minimal effective concentration MEC
, 0.015 μg/ml; MEC
, 0.03 μg/ml) was comparable in activity to anidulafungin and micafungin.
isolates (>98%) exhibited a wild-type phenotype for the mold-active triazoles (itraconazole, posaconazole, and voriconazole). APX001A was highly active against uncommon species of
, non-
yeasts, and rare molds, including 11 isolates of
spp. (MEC values, 0.015 to 0.06 μg/ml). APX001A demonstrated potent
activity against recent fungal isolates, including echinocandin- and fluconazole-resistant strains. The extended spectrum of APX001A was also notable for its potency against many less common but antifungal-resistant strains. Further studies are in progress to evaluate the clinical utility of the methyl phosphate prodrug, APX001, in difficult-to-treat resistant fungal infections.
We evaluated the
activity of manogepix and comparator agents against 1,435 contemporary fungal isolates collected worldwide from 73 medical centers in North America, Europe, the Asia-Pacific region, ...and Latin America during 2020. Of the isolates tested, 74.7% were
spp.; 3.7% were non-
yeasts, including 27 Cryptococcus neoformans var.
(1.9%); 17.1% were Aspergillus spp.; and 4.5% were other molds. All fungal isolates were tested by reference broth microdilution according to CLSI methods. Based on MIC
values, manogepix (MIC
/MIC
, 0.008/0.06 mg/liter) was 16- to 64-fold more active than anidulafungin, micafungin, and fluconazole against
spp. isolates and the most active agent tested. Similarly, manogepix (MIC
/MIC
, 0.5/1 mg/liter) was ≥8-fold more active than anidulafungin, micafungin, and fluconazole against C. neoformans var.
. Based on minimum effective concentration for 90% of the isolates tested (MEC
) and MIC
values, manogepix (MEC
, 0.03 mg/liter) was 16- to 64-fold more potent than itraconazole, posaconazole, and voriconazole (MIC
s, 0.5 to 2 mg/liter) against 246 Aspergillus spp. isolates. Aspergillus fumigatus isolates exhibited a wild-type (WT) phenotype for the mold-active triazoles, including itraconazole (87.0% WT) and voriconazole (96.4% WT). Manogepix was highly active against uncommon species of
, non-
yeasts, and rare molds, including 11 isolates of Candida auris (MIC
/MIC
, 0.004/0.015 mg/liter) and 12 isolates of
spp. (MEC
/MEC
, 0.06/0.12 mg/liter). Additional studies are in progress to evaluate the clinical utility of the manogepix prodrug fosmanogepix in difficult-to-treat resistant fungal infections.
Synthetic ligands of androgen receptor (AR) are a standard in the treatment of androgen deficiency. One of the effects of androgen deficiency is the disturbance in the homeostasis of lipid ...metabolism. Till date, there are no effective compounds developed to treat androgen deficiency without having any side effects. Nonsteroidal selective androgen receptor modulators (SARMs) are a promising solution for various clinical indications. In this study, we investigated the effect of ostarine (enobosarm), a nonsteroidal SARM, on the rat adipocyte metabolism using in vitro techniques. Isolated rat adipocytes were incubated in the presence of different concentrations of ostarine. Control incubation with testosterone as the natural ligand for AR was performed. AR inhibitors were used to investigate the genomic activity of ostarine. Changes in the intensity of lipolysis, lipogenesis, and the secretion of leptin and adiponectin were measured. Moreover, the gene expression of leptin and adiponectin was assessed. For the first time, we have shown that ostarine has a significant effect on the intensity of lipid metabolism. Ostarine downregulates the expression of leptin and adiponectin mRNAs, as well as decreases their release from rat adipocytes. According to our results, ostarine acts via AR with a similar effect as testosterone in the regulation of lipid metabolism and endocrine function of mature rat adipocytes in vitro. Our results indicate the need for further studies on the effects of SARM on the whole organism.
Orbital cavernomas are low-flow vascular malformations that are the most common benign neoplasms of the orbit in adults, typically becoming symptomatic in the middle age.
The medical records of six ...patients with clinically suspected orbital cavernomas receiving elective surgical excision were analysed concerning symptoms, physical findings, treatment results and visual outcome. The pathologic slides were evaluated, and additional immunohistochemical stains were done if necessary to obtain diagnosis.
Histologic evaluation revealed three of six cases not being cavernomas, although the clinical and macroscopic findings were consistent with orbital cavernomas. Two of them were haemorrhagic lymphangiomas, and one was a solitary fibrous tumour.
Haemorrhagic lymphangiomas and other vascular tumours may mimic orbital cavernomas regarding anamnesis, radiologic and intraoperative findings and gross examination. Therefore, exact histologic evaluation is necessary to get the correct diagnosis.
We present the case of a 24-year-old man with a painful ring finger following minimal trauma during a handball game. The X-ray showed a pathological fracture of the proximal phalanx due to an ...enchondroma. Conservative treatment was initiated, consisting of cast immobilisation for 6 weeks. After 8 months of follow-up, the X-ray revealed that the bone marrow cavity was almost completely filled with bone tissue.
We report on eight children who suffered from cerebrovascular ischemia or stroke at the age of 2 or up to 11 years. Antiphospholipid antibodies (APLA) were detected in two cases during the ischemic ...event and in six cases during follow-up examinations (after six weeks or within a span of six years). In two patients multiple stenoses of basal cerebral arteries were found; one of them suffered from moyamoya syndrome. The acute hemiplegia in one patient was linked to an asymptomatic mycoplasmal infection and APLA. In three cases, one of the parents was also APLA-positive. Seven patients were treated with acetylsalicylic acid, and in four cases immunoglobulin infusions were given. Transient ischemic attacks subsided after the child with the moyamoya syndrome received immunoglobulins. No effect of medication could be established in the other children. The concept of the antiphospholipid syndrome is still evolving. As none of the common risk factors pertaining to strokes in adults apply to children, pediatric research may offer a suitable platform for specific investigations on the causal, pathogenetic role of APLA. We propose that all children suffering from stroke or transient ischemic attacks should be tested for APLA.
Objective
To examine region‐ and substrate‐specific autoradiographic and in vitro binding patterns of positron emission tomography tracer F‐18‐AV‐1451 (previously known as T807), tailored to allow in ...vivo detection of paired helical filament‐tau–containing lesions, and to determine whether there is off‐target binding to other amyloid/non‐amyloid proteins.
Methods
We applied F‐18‐AV‐1451 phosphor screen autoradiography, F‐18‐AV‐1451 nuclear emulsion autoradiography, and H‐3‐AV‐1451 in vitro binding assays to the study of postmortem samples from patients with a definite pathological diagnosis of Alzheimer disease, frontotemporal lobar degeneration–tau, frontotemporal lobar degeneration–transactive response DNA binding protein 43 (TDP‐43), progressive supranuclear palsy, corticobasal degeneration, dementia with Lewy bodies, multiple system atrophy, cerebral amyloid angiopathy and elderly controls free of pathology.
Results
Our data suggest that F‐18‐AV‐1451 strongly binds to tau lesions primarily made of paired helical filaments in Alzheimer brains (eg, intraneuronal and extraneuronal tangles and dystrophic neurites), but does not seem to bind to a significant extent to neuronal and glial inclusions mainly composed of straight tau filaments in non‐Alzheimer tauopathy brains or to lesions containing β‐amyloid, α‐synuclein, or TDP‐43. F‐18‐AV‐1451 off‐target binding to neuromelanin‐ and melanin‐containing cells and, to a lesser extent, to brain hemorrhagic lesions was identified.
Interpretation
Our data suggest that F‐18‐AV‐1451 holds promise as a surrogate marker for the detection of brain tau pathology in the form of tangles and paired helical filament‐tau–containing neurites in Alzheimer brains but also point to its relatively lower affinity for lesions primarily made of straight tau filaments in non‐Alzheimer tauopathy cases and to the existence of some F‐18‐AV‐1451 off‐target binding. These findings provide important insights for interpreting in vivo patterns of F‐18‐AV‐1451 retention. Ann Neurol 2015 Ann Neurol 2015;78:Ann Neurol 2015;78:679–696
Objective
Antibodies to glutamic acid decarboxylase (GAD) have been described in a few patients with temporal lobe epilepsies consistent with limbic encephalitis (LE). We studied a cohort of patients ...with recent‐onset temporal lobe epilepsy caused by LE to test for GAD antibody positivity and response to immunotherapies.
Methods
Over a period of 3.75 years, 138 patients aged ≥18 years investigated at the Department of Epileptology, University of Bonn, for recent‐onset epilepsy were prospectively collected and studied for cliniconeuroradiological features of LE, autoantibodies, and treatment responses.
Results
Fifty‐three adult patients fulfilled the criteria for LE: (1) limbic signs and symptoms for ≤5 years and (2) brain MRI revealing mediotemporal encephalitis (T2/fluid attenuated inversion recovery hyperintensity without atrophy). Nine had high‐titer GAD antibodies; 10 had voltage‐gated potassium channel (VGKC) antibodies. Patients with GAD antibodies were younger (median age, 23 years; range, 17‐66 years) (p = 0.003) and presented with seizures only, whereas polymorphic limbic features were more common in the VGKC antibody‐positive group (p < 0.001). None had tumors. Patients with GAD antibodies more frequently had cerebrospinal fluid oligoclonal bands (p = 0.009) and intrathecal secretion of the specific antibody (p = 0.01). Following monthly intravenous methylprednisolone pulses, GAD antibodies remained highly elevated in 6/6 patients, whereas VGKC antibodies normalized in 6/9 patients (p = 0.03). Despite more intense anticonvulsive treatment in the GAD antibody‐positive group (p = 0.01), none of these patients became seizure free, unlike all of the patients with VGKC antibodies (p < 0.001).
Interpretation
High‐titer GAD antibodies define a form of nonparaneoplastic LE. This is a chronic, nonremitting disorder and should be included in the differential diagnosis of patients with TLE and mediotemporal encephalitis. Therapeutic trials of other immunotherapies should be undertaken. ANN NEUROL 2010;67:470–478
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