INAUGURAL ARTICLE by a Recently Elected Academy Member:Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.In the brain, iron is needed for mitochondrial respiration and synthesis of myelin, neurotransmitters, and monoamine oxidases (1, 2). Transferrin receptor 1 (TFR1) is known to be required for iron uptake by some, but not all, cell types (3–7). Its ligand, transferrin (TF), carries extracellular iron. Fe₂-TF/TFR1 is internalized by receptor-mediated endocytosis and trafficked to endosomes, where low pH liberates iron from TF, allowing it to leave the endosome through transmembrane transport. This transport is mediated by divalent metal transporter 1 (DMT1/SLC11A2) in erythroblasts and possibly other cell types (8). Imported iron is used directly, incorporated into heme or Fe-S clusters, or stored in ferritin. It has been widely assumed that neuronal iron uptake depends on TFR1-mediated endocytosis of Fe₂-TF (9), but in vivo evidence is scant. Expression of a dominant negative form of Tfr1 was shown to decrease iron uptake by hippocampal CA1 pyramidal neurons (10). However, others noted that iron distribution does not correlate with Tfr1 expression in the brain and suggested that Tfr1 may have roles unrelated to iron uptake (11).There is only one known mechanism for cellular iron release, involving the transmembrane transporter ferroportin (FPN). FPN exports iron, in collaboration with ceruloplasmin or a related ferroxidase, to be loaded onto TF (8). Intracellular iron homeostasis is controlled by iron-regulatory proteins (IRPs), which recognize iron regulatory elements (IREs) in the untranslated portions of mRNAs encoding proteins important for iron transport or storage (12). In iron deficiency, IRPs bind IREs to block ribosomal entry onto ferritin mRNAs, precluding translation of this iron storage protein, and IRPs stabilize mRNAs encoding TFR1 and SLC11A2, facilitating iron uptake. In iron surfeit, ferritin mRNAs are actively translated to store excess iron and iron import-related mRNAs are degraded. This well-studied homeostatic mechanism allows cells to regulate their iron content and offers a very sensitive approach to detect cellular iron deficiency and surfeit (12).Iron homeostasis is altered locally, in the affected part of the brain, in most human neurodegenerative disorders (13). Iron accumulates in the substantia nigra (SN) in Parkinson’s disease (PD) (14–16), although it is unsettled whether increased iron is in neuropil (17) or dopaminergic (DA) neurons (18), or both. Excess DA neuron iron has been proposed to contribute to disease pathogenesis (19). Conversely, several reports suggest that systemic iron deficiency, rather than iron overload, may predispose to PD. PD has been associated with a history of anemia years before the onset of motor symptoms (20), with multiple blood donations that deplete iron stores (21), and with low serum iron (22). Genetic predisposition to iron overload appears to be protective (23–25). Thus, iron deposition in the SN may or may not be in DA neurons themselves, and iron overload, iron deficiency, or both might be deleterious to DA neurons.We used conditional KO mice to study how perturbations of iron transport affect DA neuron survival and function. Others previously suggested that inactivation of FPN results in iron accumulation in DA neurons, causing PD (19). However, it was not clear why DA neurons would require active iron export or why compensatory changes in cellular iron import or storage would not maintain iron homeostasis. Accordingly, we found that mice lacking Fpn in DA neurons had no apparent abnormalities in neuronal iron homeostasis and no evidence of neurodegeneration or DA neuron dysfunction. However, mice lacking Tfr1 in DA neurons developed a severe phenotype characterized by DA neuron iron insufficiency, progressive degeneration of neurons in the SN, decreased motor activity, and early death. We conclude that Tfr1 is important for iron homeostasis in DA neurons of the SN and that Fpn is dispensable.     

A comparative study of the pharmacokinetics of traditional and automated dosing/blood sampling systems using gabapentin

Objective:

The present study was undertaken to investigate the pharmacokinetics (PKs) of gabapentin as determined by traditional manual blood sampling and by using an automated dosing/blood sampling technique in awake and freely moving rats using combined liquid chromatography tandem mass-spectrometry (LC-MS/MS).

Materials and Methods:

PK comparisons were conducted by allocating rats into two groups; an automated dosing/blood sampling (ADI/ABS) group (IV study, n = 6 and intragastric study, n = 6) and a manual group (IV study, n = 6 and oral study, n = 6). A series of blood samples from carotid artery were taken at specified times and analyzed using a validated LC-MS/MS method. Various PK parameters like area under curve (AUC_inf), maximum concentration, time to reach maximum concentration, terminal half life, distribution volume at the steady state, and total clearance were calculated and the two study groups were compared with respect to these parameters.

Results:

Significant differences in PK parameters were observed between the manual group and the ADI/ABS group and respective bioavailability were measured (46.82 ± 19.45% and 61.54 ± 21.23%, respectively) which is 1.31-fold difference (P = 0.0051, P<0.05).

Conclusion:

The described ADI/ABS method was found to be a useful drug development tool for accelerating the pace of preclinical in vivo studies and for obtaining reliable and accurate PK parameters even from single animals as it minimized interanimal and physiological variations.     

Guillain‐Barré syndrome associated with Coronavirus disease 2019: A case from Nepal

Coronavirus disease 2019 (COVID‐19) has now spread widely after the outbreak since December 31, 2019. Guillain‐Barré syndrome is an immunological postinfectious neuropathy, which has been reported to be a rare but possible complication COVID‐19. We report a case of Guillain‐Barré syndrome associated with COVID‐19 in Nepal.     

Deep venous sinus thrombosis with right thalamic infarction in a young patient after COVID-19 vaccination

Cerebral venous thrombosis is a rare illness, it compromises 0.5% of cases of cerebrovascular diseases globally. The condition can be treated if discovered and treated properly and quickly. With many known risk factors and in recent times with invent of the COVID-19 vaccine, there have been reported incidences of vaccination being implicated in cerebral venous sinus thrombosis. We report an unusual case of an adolescent female with imaging findings of deep cerebral venous sinus thrombosis and right thalamic infarction after recent vaccination against COVID-19. Laboratory results revealed microcytic hypochromic anemia. Further imaging was done which included a non-contrast CT head, magnetic resonance imaging, and magnetic resonance venography leading to a diagnosis of thrombosis of deep venous (galenic) system with vasogenic edema in bilateral thalami and left caudate nucleus with areas of infarction in the right thalamus. She was treated with subcutaneous low molecular weight heparin (Enoxaparin) and discharged on the third day under oral dabigatran and oral iron.Key words: Cerebral venous sinus thrombosis (CVST), Cerebral venous thrombosis (CVT), Thalamic infarct     

Diagnostic dilemma in diagnosing rare cause of protein losing enteropathy: Waldmann's disease

Waldmann''s disease, or primary intestinal lymphangiectasia, is an unusual cause of protein‐losing enteropathy primarily characterized by lymphopenia, hypoalbuminemia, and hypogammaglobulinemia. However, variable clinical presentations result dilemmas in diagnosis and effective management. We present a toddler diagnosed with Waldmann''s disease managed with a high‐protein diet and medium‐chain triglyceride supplementation.     

No relationship between socioeconomic status,education level and development and progression of diabetic retinopathy in type 2 diabetes: a FIELD trial substudy

In 6002 Australian adults with type 2 diabetes and a median 5-year follow-up in the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, baseline socioeconomic status (SES) and self-reported education level were not related to development of on-trial sight-threatening diabetic retinopathy. Similarly, in a retinal photography substudy (n = 549), two-step diabetic retinopathy progression was not related to SES or education.     

Invasive ductal carcinoma of breast with neuroendocrine differentiation: A case report

Primary invasive breast carcinoma with neuroendocrine differentiation is an uncommon presentation. We hereby report a case diagnosed as invasive ductal carcinoma with neuroendocrine differentiation in a 52‐year‐old female patient who presented with a painless right breast lump.