Targeting MYC-driven replication stress in medulloblastoma with AZD1775 and gemcitabine

Journal of Neuro-Oncology - MYC-driven medulloblastomas are highly aggressive childhood tumors with dismal outcomes and a lack of new treatment paradigms. We identified that targeting replication...     

The undesirable wink

Background:Marin-Amat syndrome is a rare acquired oculofacial synkinesis first reported in 1918. It manifests as involuntary eyelid closure on jaw opening or on lateral movement of the jaw following a peripheral facial nerve palsy. The increased orbicularis tone due to aberrant connections between the cranial nerve (CN) V and CN VII results in an undesirable wink with major psychosocial impact.Purpose:Most cases in literature were either observed or administered botulinum toxin injection to the orbicularis muscle. There are few sporadic reports of surgical interventions with successful outcomes.Hence there was a need to generate awareness regarding various modes of management of this rare entity.Synopsis:We present a video on the clinical presentation and management of six such patients, of whom one was bilateral. Five patients were females. Traumatic facial nerve paralysis and Bell’s palsy was previously diagnosed in one and five patients respectively. The mean age was 52 ± 9.48 years. The mean MRD (margin reflex distance) 1 and MRD 2 was 3.17 ± 0.60 and 5.33± 0.65 mm respectively. On smiling or on movement of the jaw the MRD 1 and 2 was reduced by 2. 50±0.40 and 1.50+/-0.40 mm respectively. Of the six patients four patients opted for nil intervention.Highlights:Botulinum toxin injection and preseptal orbicularis resection in the upper and lower eyelid along with blepharoplasty was performed in 1 patient each. Satisfactory reduction in the synkinetic movement was achieved in both. Marin-Amat syndrome is a rare often underdiagnosed synkinetic disorder following peripheral facial nerve palsy. Botulinum toxin injection and preseptal orbicularis resection are viable management options.Video link: https://youtu.be/YQbRecp449w     

Oral iron absorption in infantile protein-energy malnutrition.

The ability of infants with protein-energy malnutrition to absorb iron was assessed using the serum iron response to a dose of ferrous sulfate providing 3 mg elemental iron per kg body weight. Responses were grouped as flat (delta serum Fe less than 30 microgram/dl), intermediate (30 to 100 microgram/dl), and normal (greater the 100 microgram/dl). Of 25 consecutively admitted children studied, seven had a flat, five an intermediate, and 13 a normal curve (mean delta serum Fe: 10 microgram/dl, 66 microgram/dl, and 175 microgram/dl, respectively). There were no differences among the three groups in hematocrit, fasting serum iron or transferrin saturation, severity of malnutrition, or evidence of other malabsorption sufficient to explain these differences. Although hematocrits, fasting serum iron, and transferrin saturations did not change appreciably during nutritional rehabilitation, all children with initially abnormal responses subsequently had normal tests.     

Clinical and histopathological profile of primary caruncular lesions

Purpose:To provide a retrospective analysis of lesions of the caruncle which have been very rarely reported in the literature.Methods:A retrospective review of all the caruncular lesions between January 2000 and January 2020 was done at a single tertiary eye care hospital. The lesions were classified as benign and malignant lesions. Clinicopathological correlation was done for the excised lesions.Results:A total of 87 caruncular lesions were included in the study. Males (59%) were affected more than females (41%). The mean age at presentation was 44 ± 20 years. The mean duration of complaint was 36 ± 62 months. A total of 36 patients underwent surgical excision whereas the rest opted for conservative management. Recurrence was noted in five patients. Fifteen different types of lesions were identified histopathologically. Benign lesions (78%) were far more common than malignant ones (22%). Epithelial inclusion cyst was the most common benign lesion and sebaceous gland carcinoma was the most common malignant lesion. Correct clinicopathological correlation was seen in 52.7% of the cases. Caruncular tuberculosis, oncocytoma, and basosquamous cell carcinoma were some of the rare lesions.Conclusion:Caruncular lesions are uncommon and very diverse, which makes clinical diagnosis challenging. Epithelial inclusion cyst and sebaceous gland carcinoma were the most common benign and malignant lesions respectively. Correct clinicopathological correlation was seen in more than half of the cases.     

31P and 1H NMR spectroscopy to study the effects of gallopamil on brain ischemia

Studies were performed on 16 cats to evaluate the potential protective effects of Gallopamil on brain ischemia. Brain energy state was determined by 31P NMR and lactate concentration was determined by 1H NMR. Double-tuned surface coils (tuned to 35.8 and 88.4, respectively) were placed on the head after skin and muscle were removed from the calvarium. A 2.1-T, 25-cm-bore Oxford magnet interfaced to a Phosphoenergetics 250-80 spectrometer was used. The cats were bled to 50 mm Hg for 10 min with subsequent application of bilateral carotid occlusion for 10 min to produce ischemia. In all animals, brain energy state as measured by Pi/PCr and lactate concentrations were determined over 5-min intervals (before, during, and after the onset of ischemia). While Gallopamil did not prevent decreases in brain energy state or attenuate the rise in lactate concentration seen during ischemia, brain from animals treated with Gallopamil had a more rapid return of pHi to baseline during the recovery period. In Gallopamil-treated cats, higher levels of lactate were necessary to cause a similar decrease in pHi when compared to controls. The rate of lactate recovery to baseline levels was similar in both groups (control = -0.38 +/- 0.14 mM/min; Gallopamil = -0.44 +/- 0.32 mM/min). In conclusion, Gallopamil appears to lessen the acidosis caused by cerebral ischemia. In addition, we have demonstrated that multinuclear NMR spectroscopy is a powerful tool to study the effects of drugs on cerebral metabolism.     

The endogenous cannabinoid anandamide has effects on motivation and anxiety that are revealed by fatty acid amide hydrolase (FAAH) inhibition

Converging evidence suggests that the endocannabinoid system is an important constituent of neuronal substrates involved in brain reward processes and emotional responses to stress. Here, we evaluated motivational effects of intravenously administered anandamide, an endogenous ligand for cannabinoid CB1-receptors, in Sprague-Dawley rats, using a place-conditioning procedure in which drugs abused by humans generally produce conditioned place preferences (reward). Anandamide (0.03-3 mg/kg intravenous) produced neither conditioned place preferences nor aversions. However, when rats were pre-treated with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (cyclohexyl carbamic acid 3'-carbamoyl-3-yl ester; 0.3 mg/kg intraperitoneal), which blocks anandamide's metabolic degradation, anandamide produced dose-related conditioned place aversions. In contrast, URB597 alone showed no motivational effects. Like URB597 plus anandamide, the synthetic CB1-receptor ligand WIN 55,212-2 (50-300 microg/kg, intravenous) produced dose-related conditioned place aversions. When anxiety-related effects of anandamide and URB597 were evaluated in a light/dark box, both a low anandamide dose (0.3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) produced anxiolytic effects when given alone, but produced anxiogenic effects when combined. A higher dose of anandamide (3 mg/kg) produced anxiogenic effects and depressed locomotor activity when given alone and these effects were potentiated after URB597 treatment. Finally, anxiogenic effects of anandamide plus URB597 and development of place aversions with URB597 plus anandamide were prevented by the CB1-receptor antagonist AM251 (3 mg/kg intraperitoneal). Thus, additive interactions between the effects of anandamide on brain reward processes and on anxiety may account for its aversive effects when intravenously administered during FAAH inhibition with URB597.