Aβ neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors

N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aβ(1-42) (10 nM-5 μM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aβ(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aβ(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor.     

Evaluation of the three-dimensional soft tissue changes after anterior segmental maxillary osteotomy

The aim of this study was to assess the three-dimensional soft tissue changes following anterior segmental maxillary osteotomy, in terms of magnitude and direction in correlation to hard tissue changes, using cone beam computed tomography (CBCT). The study included 6 patients (age range 17-35 years) suffering from dental maxillary protrusion that required surgical correction by anterior segmental maxillary osteotomy. For each patient, preoperative and postoperative CBCT, photographs, and orthodontic casts were taken before and 6 months after operation to analyse soft tissue changes, in terms of magnitude and direction in correlation to hard tissue changes, using linear and angular measurements. Hard and soft tissue changes were only observed in the maxillary region, upper lip area and nasal tip. Soft tissue mean change included 53% backward displacement of the labrale superius in relation to bone displacement and 18.7% mean increase in the naso-labial angle. The highest correlation coefficient was obtained between the hard and soft tissue changes in the upper lip region. Anterior segmental maxillary osteotomy might be recommended as the treatment modality of choice in patients with maxillary or dento-alveolar protrusion, the technique is simple, safe, and postoperative complications are minimal.     

Pregnancy among residents enrolled in general surgery: a nationwide survey of attitudes and experiences

Background

Medical student interest in general surgery has declined, and the lack of adequate accommodation for pregnancy and parenting during residency training may be a deterrent. We explored resident and program director experiences with these issues in general surgery programs across Canada.

Methods

Using a web-based tool, residents and program directors from 16 Canadian general surgery programs were surveyed regarding their attitudes toward and experiences with pregnancy during residency.

Results

One hundred seventy-six of 600 residents and 8 of 16 program directors completed the survey (30% and 50% response rate, respectively). Multiple issues pertaining to pregnancy during surgical residency were reported including the lack of adequate policies for maternity/parenting, the major obstacles to breast-feeding, and the increased workload for fellow resident colleagues. All program directors reported the lack of a program-specific maternity/parenting policy.

Conclusions

General surgery programs lack program-specific maternity/parenting policies. Several issues have been highlighted in this study emphasizing the importance of creating and implementing such a policy.     

Bilateral stress fractures of femoral neck in non-athletes: a report of four cases

Femoral neck stress fractures (FNSFs) are rare,constituting only 5％ of all stress fractures in young adults.These fractures are usually seen in athletes,military recruits and patients with underlying m...     

Maternal–fetal transport kinetics of manganese in perfused human placental lobule in vitro

Objective: There have been no detailed reports relating to maternal–fetal transport kinetics of manganese, an essential trace element in the human pregnancies, and hence we have attempted to study the transport kinetics of this trace element in the human placenta in vitro.

Methods: Human placentae from normal uncomplicated pregnancies were collected postpartum. Manganese chloride solution (GFS Chem Inc., Columbus, OH), 10 times the physiological concentrations, along with antipyrine (Sigma Chem Co., St. Louis, MO) as reference marker were then injected as a single bolus (100?µl) into the maternal arterial circulation of perfused placental lobules and perfusate samples collected from maternal and fetal circulations over a period of five minutes. National Culture and Tissue Collection medium, diluted with Earle’s buffered salt solution was used as the perfusate and serial perfusate samples from fetal venous perfusate collected for a period of 30?min. Concentration of manganese in perfusate samples was assessed by atomic absorption spectrophotometry, while that of antipyrine was assessed by spectrophotometry. Transport kinetics of substances studied were computed using established permeation parameters.

Results: Differential transport rates of manganese and antipyrine in 12 perfusions differed significantly for 25.75, 90% efflux fractions (ANOVA test, p?<?0.05), while those of 10 and 50% efflux fractions were not significantly different between the study and reference substances. Transport fraction (TF) of manganese averaged 54.9% of bolus dose in 12 perfusions, whereas that of antipyrine averaged 89% of bolus dose, representing 61.80% of reference marker TF. The difference observed in TF values of manganese and antipyrine was statistically significant (Student’s t-test, p?<?0.05). Pharmacokinetic parameters such as area under the curve, clearance, absorption rate, elimination rate of manganese compared to reference marker were significantly different (ANOVA test, p?<?0.05) between the study and reference substances.

Conclusions: Our studies show for the first time maternal–fetal transport kinetics of manganese in human placenta in vitro. Considering the restricted transfer of this essential trace element despite its small molecular weight, we hypothesize possibility of active transport of manganese across the human placental membrane. Further studies relating to manganese placental transport in “diabetic model” placental perfusions are in progress.     

Syntheses,Cholinesterases Inhibition,and Molecular Docking Studies of Pyrido[2,3‐b]pyrazine Derivatives

Cholinesterases, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), have a role in cholinergic deficit which evidently leads to Alzheimer's disease (AD). Inhibition of cholinesterases with small molecules is an attractive strategy in AD therapy. This study demonstrates synthesis of pyrido[2,3‐b]pyrazines ( 6a ‐ 6q ) series, their inhibitory activities against both cholinesterases, AChE and BChE, and molecular docking studies. The bioactivities data of pyrido[2,3‐b]pyrazines showed 3‐(3′‐nitrophenyl)pyrido[2,3‐b]pyrazine 6n a potent dual inhibitor among the series against both AChE and BChE with IC₅₀ values of 0.466 ± 0.121 and 1.89 ± 0.05 μm , respectively. The analogues 3‐(3′‐methylphenyl)pyrido[2,3‐b]pyrazine 6c and 3‐(3′‐fluorophenyl)pyrido[2,3‐b]pyrazine 6f were found to be selective inhibition for BChE with IC₅₀ values of 0.583 ± 0.052 μm and AChE with IC₅₀ value of 0.899 ± 0.10 μm , respectively. Molecular docking studies of the active compounds suggested the putative binding modes with cholinesterases. The potent compounds among the series could potentially serves as good leads for the development of new cholinesterase inhibitors.