Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons

The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4–2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1^−/− with Ndfip1^+/+ mice exposed to Fe reveals that Ndfip1^−/− brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.     

Does attachment avoidance help people cope with loss? the moderating effects of relationship quality

Previous research has been inconsistent about the role of attachment avoidance in coping with loss. The present study sought to resolve this issue by examining the potential moderating role of relationship quality with the deceased. The authors used longitudinal data on bereaved spouses (N=50) collected at 4 and 18 months postloss. Three‐way effects emerged among attachment avoidance, attachment anxiety, and marital quality in the prediction of complicated grief (CG) symptoms at 18 months, controlling for 4‐month symptoms. Findings indicated that, in the context of high but not low marital quality, persons with a dismissingly avoidant attachment style (high avoidance, low anxiety) experienced marked reductions in CG symptoms from 4 to 18 months. Findings clarify the role of attachment avoidance in coping with loss and underscore that relationship quality is a critical factor in the attachment‐grief relationship. © 2009 Wiley Periodicals, Inc. J Clin Psychol 65:1–10, 2009.     

Anxiety,depression, and quality of life in Parkinson’s disease: the implications of multidisciplinary treatment

Anxiety and depression in Parkinson’s disease (PD) reduce well-being of the patients. Emotional alterations influence motor skills and cognitive performance; moreover, they contribute significantly and independently to worsen rehabilitative treatment response. We investigated anxiety, depression, and quality of life in PD patients subjected to multidisciplinary rehabilitative training. The self-controlled study included 100 PD patients (49 males and 51 females with the mean age of 64.66 years) admitted to 60 days hospitalization rehabilitative program, between January 2017 and December 2018. Motor, cognitive, linguistic abilities, and functional independence were evaluated at admission (T0 baseline visit) and 60 days after (T1) the multidisciplinary rehabilitation including motor exercises, speech therapies, and cognitive intervention. The multidisciplinary rehabilitation improved functional status in PD patients and exerted its positive effects on mood, motor abilities, autonomy in the activities of daily life, perception of quality of life, cognitive performance and speech skills. Non-motor symptoms may worsen severe disability and reduce quality of life. They are often poorly recognized and inadequately treated. Nonetheless, multidisciplinary rehabilitative training represents an optimal strategy to improve disease management. The study was approved by Istituito di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi “Bonino-Pulejo” Ethical Committee (approval No. 6/2016) in June 2016.     

Divalproex sodium in the treatment of migraine and cluster headaches

The discovery of a new class of effective migraine-abortive medications, the triptans, has sparked a new interest in the study of vascular headache. Over the past few years, the Food and Drug Administration (FDA) has approved six new abortive pharmacologic therapies, with several others in various stages of clinical trials. Unfortunately, concurrent pharmacologic changes in headache prophylaxis have not kept pace with their abortive counterparts. However, divalproex sodium (Depakote), which is approved by the FDA as a migraine prophylactic agent, is the first in the anticonvulsant class of medication for migraine headache and has expanded the options in headache treatment. The objective of this retrospective multicenter study of 284 patients with migraine or cluster headaches was to examine the clinical efficacy and safety of divalproex sodium as prophylaxis in monotherapy and in polytherapy. Sixty-one percent of migraineurs and 73% of cluster patients noted a decrease in pain with divalproex sodium and continued that therapy for more than 3 months. Reported negative side effects included weight gain, nausea, somnolence, tremor, alopecia, dysequilibrium, and rash. However, only 14% of subjects discontinued therapy due to these side effects. Overall, divalproex sodium was found to be an effective and generally well-tolerated prophylactic treatment option as monotherapy or in polytherapy for migraine and cluster headache.     

Lysosomal Ca(2+) stores in bovine corneal endothelium

PURPOSE: Acidic organelles, including Golgi bodies and lysosomes, are known to operate as Ca(2+) storage sites in many cell types. This study demonstrates the presence of Ca(2+) stores in lysosomes of bovine corneal endothelial cells (BCECs) and examines their interaction with Ins(1,4,5)P(3)-sensitive Ca(2+) stores. METHODS: Glycyl-L-phenylalanine-beta-naphthylamide (GPN) was used to release Ca(2+) from lysosomes by inducing their selective osmotic swelling. Ca(2+) released into the cytoplasm was measured with fura-2 or fura-PE3 fluorescent dyes. Fluorescence of acridine orange (AO), which selectively sequesters into acidic organelles, was used to establish swelling of lysosomes in response to GPN. RESULTS: Exposure to GPN (100-200 microM) in cultured BCECs produced an increase in free cytosolic Ca(2+) ([Ca(2+)](i)) equivalent to approximately 79% of the peak response to uridine triphosphate (UTP), a P2Y agonist (n = 19). The endothelium of the freshly isolated cornea also produced [Ca(2+)](i) transients similar to those in cultured BCECs; however, the peak [Ca(2+)](i) increase was smaller ( approximately 43% of the peak response to UTP; n = 13). In cultured BCECs, the response to UTP was unaffected by pretreatment with GPN with extracellular calcium ([Ca(2+)](o)) at 0 and 1.2 mM (n = 10). Neither pretreatment with thapsigargin (5 microM) nor with U73122 (a phospholipase C inhibitor; 10 microM) blocked the peak GPN response (n = 6). Exposure to 20 microM monensin produced a [Ca(2+)](i) increase with [Ca(2+)](o) at 0 and 1.2 mM and also reduced the subsequent peak response to GPN (n = 6). CONCLUSIONS: GPN-sensitive lysosomal Ca(2+) stores, distinct from Ins(1,4,5)P(3)-sensitive Ca(2+) stores, are found in both cultured cells and fresh tissue. These stores are susceptible to depletion by the loss of the pH gradient across lysosomes and P2 agonists. The latter occurs through mechanisms independent of phospholipase C (PLC) activation or Ins(1,4,5)P(3). The GPN stores also induce [Ca(2+)](o) influx in response to their depletion.     

Pitfalls in surgical resuscitation

Timing of diagnosis and intervention, together with understanding of physiology and knowledge of anatomy, are essential for success in the practice of surgery in general, and emergency surgery in particular. Either excess of treatment, for example fluid overload in tamponated haemorrhage such as a ruptured retroperitoneal Abdominal Aortic Aneurysm, or defect of treatment such as delayed arrest of life threatening bleeding from a transected Superficial Femoral Artery above the knee, can both lead to disastrous outcome or death. Proximal control of damaged arteries is an obligatory step before repair and in emergency situations must be effected rapidly: the femoral artery can be easily aggressed at the groin under local anaesthesia; the abdominal aorta can be rapidly controlled with digital compression at the hiatus through the avascular area of the gastrohepatic ligament.     

Diagnostic value of troponin T for alterations in left ventricular mass and function in dialysis patients

BACKGROUND: Cardiac troponin T (cTnT) is related to left ventricular (LV) mass in patients with end-stage renal disease (ESRD). Furthermore, cTnT reflects the severity of systolic dysfunction in patients with heart diseases. We tested the diagnostic value of cTnT for left ventricular hypertrophy (LVH) and LV systolic dysfunction in a large group of clinically stable hemodialysis patients without heart failure. RESULTS: CTnT was significantly (P < 0.001) higher in patients with LVH than in those with normal LV mass. In a multiple logistic regression model, adjusting for potential confounders (including cardiac ischemia), systolic pressure and cTnT (both P = 0.003) were the strongest correlates of LVH. Similarly, cTnT was significantly higher (P = 0.005) in patients with systolic dysfunction than in those with normal LV function and in a multiple logistic regression model cTnT ranked as the second independent correlate of this alteration after male sex. Serum cTnT had a high positive prediction value for the diagnosis of LVH (87%) but its negative prediction value was relatively low (44%). The positive predictive value of cTnT for LV dysfunction was low (25%) while its negative predictive value was high (93%). A combined analysis including systolic pressure (for the diagnosis of LVH) and sex (for the diagnosis of LV systolic dysfunction) augmented the diagnostic estimates to an important extent (95% positive prediction value for LVH and 98% negative prediction value for LV systolic dysfunction). CONCLUSIONS: CTnT has a fairly good diagnostic potential for the identification of LVH and for the exclusion of LV systolic dysfunction in patients with ESRD without heart failure. This marker may be useful for the screening of alterations in LV mass and function in clinically stable hemodialysis patients.