This is the first reported use of posaconazole for the treatment of feline disseminated histoplasmosis.
Approximately 1-year-old female spayed domestic longhair cat.
The cat presented to our ...institution with weight loss, lymphadenomegaly, hepatosplenomegaly, limb edema, abdominal fluid distension and ulcerated cutaneous nodules. The cat had been previously diagnosed with disseminated histoplasmosis at another institution approximately 6 months prior. Clinical signs had been refractory to treatment with fluconazole. Itraconazole had next been tried, and the cat's weight continued to decline, lesions failed to regress, and the cat formed abdominal fluid distension and marked pelvic limb edema.
The cat was prescribed posaconazole along with prednisolone. The cat's demeanor, body weight, and lesions all markedly improved. Histoplasma antigen was undetectable in urine samples while the cat was receiving posaconazole. However, posaconazole blood levels paired with markedly elevated ALT suggested potential toxicity and the drug was discontinued. Upon cessation of posaconazole, the cat's lesions returned with cytologic evidence of intralesional Histoplasma yeast. Itraconazole combine with terbinafine was prescribed. At last follow-up, the cat was clinically well, off all anti-fungal medication, and without detectable Histoplasma antigen in the urine.
Posaconazole therapy showed promise in this case. Had a safe and therapeutic dose been arrived at, we suspect that posaconazole would have cleared or maintained clinical remission of this cat's disease. This is the first report using posaconazole and the first successful report using combination itraconazole and terbinafine for the treatment of feline disseminated histoplasmosis. Generic drugs were used throughout this case report; the drug manufacturers are unknown to the authors.
During cerebral cortical development, neural precursor-precursor interactions in the ventricular zone neurogenic niche coordinate signaling pathways that regulate proliferation and differentiation. ...Previous studies with shRNA knockdown approaches indicated that N-cadherin adhesion between cortical precursors regulates β-catenin signaling, but the underlying mechanisms remained poorly understood.
Here, with conditional knockout approaches, we find further supporting evidence that N-cadherin maintains β-catenin signaling during cortical development. Using shRNA to N-cadherin and dominant negative N-cadherin overexpression in cell culture, we find that N-cadherin regulates Wnt-stimulated β-catenin signaling in a cell-autonomous fashion. Knockdown or inhibition of N-cadherin with function-blocking antibodies leads to reduced activation of the Wnt co-receptor LRP6. We also find that N-cadherin regulates β-catenin via AKT, as reduction of N-cadherin causes decreased AKT activation and reduced phosphorylation of AKT targets GSK3β and β-catenin. Inhibition of AKT signaling in neural precursors in vivo leads to reduced β-catenin-dependent transcriptional activation, increased migration from the ventricular zone, premature neuronal differentiation, and increased apoptotic cell death.
These results show that N-cadherin regulates β-catenin signaling through both Wnt and AKT, and suggest a previously unrecognized role for AKT in neuronal differentiation and cell survival during cortical development.
Background
Neutrophil extracellular traps (NETs), webs of DNA and citrullinated histones extruded from activated neutrophils cause transfusion‐related acute lung injury. Supernatants of stored red ...blood cell (RBC) units might promote NETosis in neutrophils from the units or from transfusion recipients.
Hypotheses
(1) NETs form during storage of canine RBC, (2) leukoreduction (LR) before storage of RBC reduces NETosis, and (3) supernatant from stored, nonleukoreduced (NLR) RBC units induces NETosis in healthy canine neutrophils modeling transfusion recipients.
Animals
Six healthy purpose‐bred research dogs were utilized for blood donation.
Methods
Prospective controlled study. RBC units were collected from each dog, aseptically divided into 2 equal subunits, 1 of which was leukoreduced, and stored for 42 days. Stored units were sampled biweekly for quantification of NET markers citrullinated histone H3 (Western blot) and cell‐free DNA (cfDNA) (DNA dye binding). Unit supernatants were applied ex vivo to canine neutrophils and extracellular DNA release representing NETosis was assessed.
Results
Markers of NETs increased during RBC storage (cfDNA P < .0001 and citrullinated H3 P = .0002) and were higher in NLR than LR units (day 42 LR cfDNA 0.34 ± 0.82 ng/mL vs day 42 NLR 1361.07 ± 741.00 ng/mL, P < .0001; day 42 LR citrullinated H3 0.19 ± 0.13 AU vs NLR 0.57 ± 0.34 AU, P = .007). Isolated neutrophils did not form NETs when exposed to stored canine RBC supernatant.
Conclusions and Clinical Importance
NETosis occurs in stored canine NLR RBC units, and is attenuated by LR before storage. NETs might be mediators of transfusion reactions.
Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates β-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces β-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates β-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number.
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► Cortical ventricular zone neural precursors exhibit β-catenin signaling ► N-cadherin maintains β-catenin signaling in cortical precursors ► N-cadherin regulates neuronal differentiation and cell cycle exit via β-catenin ► N-cadherin signals through Akt and phosphor-Ser552 of β-catenin
Background
Point‐of‐care (POC) portable blood glucose meters (PBGMs) are convenient and inexpensive tools for assessing patient blood glucose concentrations. They are often used to quickly diagnose ...hypoglycemia or collect serial glucose readings in diabetic patients. However, POC meters have been previously identified in human and veterinary literature to be inaccurate when utilized in patients with abnormal HCT. This problem may not be reflected in manufacturer guidelines referenced by practitioners in the POC setting.
Key Findings
A 1.5‐year‐old dog, previously diagnosed with multiple congenital cardiac malformations, right‐to‐left cardiac shunting and secondary erythrocytosis, presented to a veterinary emergency center minimally responsive and without detectable pulses. PBGM measurement identified hypoglycemia. Following stabilization of the dog, serial glucose assessments showed discordant results between PBGMs and the reference laboratory biochemistry analyzer. A pathological cause for hypoglycemia was not identified and PBGM readings were determined to be erroneously low due to the dog's abnormally high HCT.
Significance
This case demonstrates the limitations of using PBGMs to assess blood glucose in a dog with secondary erythrocytosis. The report emphasizes the need for judicious use of PBGMs in critically ill patients and that these glucometers may not be reliable in patients with abnormal HCT values.
SummaryA golden retriever dog was evaluated for cranial abdominal organomegaly. Clinical investigation found concurrent splenomegaly, anaemia, thrombocytopenia, hypoalbuminaemia and ...hypocholesterolaemia. Cytological evaluation of splenic aspirate samples identified a population of atypical, erythrophagocytic, mesenchymal cells. Due to the patient’s signalment, clinicopathological abnormalities and splenic cytological findings, the dog was suspected to have haemophagocytic histiocytic sarcoma. Splenectomy with splenic histopathology was performed to confirm the diagnosis. Histologically, granulomatous splenitis with erythrophagocytic macrophages was identified; a cause for splenitis was not identified. The dog was clinically diagnosed with reactive haemophagocytic syndrome secondary to splenitis. The patient clinically decompensated a month postsplenectomy and was euthanased.
Little is known about the architecture of cellular microenvironments that support stem and precursor cells during tissue development. Although adult stem cell niches are organized by specialized ...supporting cells, in the developing cerebral cortex, neural stem/precursor cells reside in a neurogenic niche lacking distinct supporting cells. Here, we find that neural precursors themselves comprise the niche and regulate their own development. Precursor-precursor contact regulates b-catenin signaling and cell fate. In vivo knockdown of N-cadherin reduces b-catenin signaling, migration from the niche, and neuronal differentiation in vivo. N-cadherin engagement activates b-catenin signaling via Akt, suggesting a mechanism through which cells in tissues can regulate their development. These results suggest that neural precursor cell interactions can generate a self-supportive niche to regulate their own number. Highlights - Cortical ventricular zone neural precursors exhibit b-catenin signaling N-cadherin maintains b-catenin signaling in cortical precursors N-cadherin regulates neuronal differentiation and cell cycle exit via b-catenin N-cadherin signals through Akt and phosphor-Ser552 of b-catenin
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