The opposite effects of stress on dendritic spines in male vs. female rats are NMDA receptor-dependent

Dendritic spines in the hippocampus are sources of synaptic contact that may be involved in processes of learning and memory [Moser (1999) Cell. Mol. Life Sci., 55, 593-600]. These structures are sensitive to sex differences as females in proestrus possess a greater density than males and females in other stages of the estrous cycle [Woolley et al. (1990) J. Neurosci., 10, 4035-4039]. Moreover, exposure to an acute stressful event increases spine density in the male hippocampus but decreases spine density in the female hippocampus [Shors et al. (2001) J. Neurosci., 21, 6292-6297]. Here we demonstrate that antagonism of N-methyl-d-aspartate (NMDA) receptors prevents the increase in spine density as females transition from diestrus 2 to proestrus, when estrogen levels are rising. Antagonism of NMDA receptors during exposure to the stressful event also prevented the changes in spine density in males and females, despite differences in the direction of these effects. Thus, the stress-induced increase in spine density was prevented in the male hippocampus as was the stress-induced decrease in spine density in the female hippocampus. NMDA receptor antagonism during exposure to the stressful event did not alter corticosterone levels or the corticosterone response to stress. These data suggest that both increases and decreases in spine density can be dependent on NMDA receptor activation.     

Transcoronary ablation of septal hypertrophy (TASH): a new treatment option for hypertrophic obstructive cardiomyopathy

Summary In 1991, our group started to develop a catheter interventional therapy for hypertrophic obstructive cardiomyopathy (HOCM). The new concept was proposed in 1994. It is based on the conventional PTCA technique with the aim of inducing an artificial myocardial infarction by instillation of 96% ethanol into the most proximally situated septal branch of the left anterior descending coronary artery. This leads to a subaortic contraction disorder with subsequent decrease of the intraventricular pressure gradient, shrinkage of the hypertrophied septal bulge and widening of the outflow tract ("therapeutic remodeling"). The subaortic defect is small and well demarcated as assessed by left ventricular angiography, transesophageal echocardiography and 18 F-glucose positron emission tomography. The term transcoronary ablation of septum hypertrophy (TASH) was suggested. Our patient cohort that now comprises 215 therapeutic procedures in 187 patients underwent a large variety of prospective studies (maximum follow-up 4.5 years) including invasive controls at regular intervals, investigation of hemodynamics at rest and at exercise, transesophageal and transthoracic echocardiography. Doppler echocardiography during bicycle exercise, electrophysiologic testing, Holter monitoring and measurement of myocardial metabolism and perfusion, assessment of microembolic events by transcranial Doppler sonography and histological examinations. This article gives an overview and reports our increasing experience in applying TASH. The following post-TASH findings were obtained: significant hemodynamic and clinical improvement at rest and at exercise, decrease of septum thickness, increase of outflow tract area and decrease of induced ventricular tachycardia. There were well-demarcated, histologically atypical subaortic myocardial defects, no microembolic events, abnormal early peak of infarct related enzymes, and no change of baroreflex sensitivity. Pre-/post-TASH evaluations of the patients should be based in particular on clinical symptoms correlated to the intraventricular gradient measured by bicycle exercise Doppler echocardiography and to outflow tract area as assessed by transesophageal echocardiography. Since 1994, as a roughly estimate, worldwide 1000 patients in 20 countries have been treated. According to published articles, abstract presentations and workshops, TASH consistently leads to a pronounced clinical and hemodynamic benefit for patients with HOCM. TASH has become an established technique. At least in centers with a high level of expertise, it is no longer experimental but a routinely performed alternative to surgical treatment for HOCM, i.e., the previous gold standard of therapy. Of course, patient outcome needs further careful clinical and prognostic evaluation. With respect to complications, TASH appears to be superior to surgery (transaortic septal myectomy) for HOCM. Like surgical treatment, TASH is currently indicated in critically ill patients with typical HOCM (subaortic form), who exhibit with drug refractory symptoms, including patients, who preferred DDD pacemaker therapy as a first therapeutic step but in whom this produced no subsequent clinical benefit.     

A proposed framework for differentiating the 21 Pew competencies by level of nursing education

Now nearly a decade old, the original Pew Health Professions Commission Competencies have stood up well to the test of time. The competencies were designed to provide all health professionals, from physicians to physical therapists, with a general guide to the values, skills, and knowledge they would need to be successful in the health care system that was beginning to emerge in the late 1980s. They have been used across the range of health professions and in many practice settings to create a framework for curricular change, work redesign, and assessment of professional competence. The interpretation of the competencies offered here should prove to be a useful tool to nurses and health system leaders as they carry on the hard work of adapting the current model of nursing practice to the demands and realties of the contemporary and continually evolving health care environment. This work is important for two reasons. First, many of the skills and attributes of the professional nurse are not adequately used or valued by the health care system because the profession is both fragmented and poorly differentiated and articulated. Without markers that define and promote collaborative practice within nursing, the full potential of nurses at all levels of preparation will continue to be inadequately and inappropriately deployed. This model exacerbates the current nursing shortage because it fails to use nurses in appropriate, well-delineated, and challenging roles. Without this kind of differentiation, one that can be owned and supported by all nurses, there will continue to be suboptimal use of the nursing workforce in the United States. The framework of differentiated Pew competencies and the companion teaching-learning strategies proposed here offer one approach to rationalizing both nursing education and practice, with the potential for improving the quality of care, and reducing fragmentation, cost, and public confusion.     

Mitochondrial dysfunction: the first domino in brain aging and Alzheimer's disease?

With the increasing average life span of humans and with decreasing cognitive function in elderly individuals, age-related cognitive disorders including dementia have become a major health problem in society. Aging-related mitochondrial dysfunction underlies many common neurodegenerative disorders diseases, including Alzheimer's disease (AD). AD is characterized by two major histopathological hallmarks, initially intracellular and with the progression of the disease extracellular accumulation of oligomeric and fibrillar beta-amyloid (Abeta) peptides and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein. In this review, the authors focus on the latest findings in AD animal models indicating that these histopathological alterations induce deficits in the function of the complexes of the respiratory chain and therefore consecutively result in mitochondrial dysfunction. This parameter is intrinsically tied to oxidative stress. Both are early events in aging and especially in the pathogenesis of aging-related severe neurodegeneration. Ginkgo biloba extract seems to be of therapeutic benefit in the treatment of mild to moderate dementia of different etiology, although the data are quite heterogeneous. Herein, the authors suggest that mitochondrial protection and subsequent reduction of oxidative stress are important components of the neuroprotective activity of Ginkgo biloba extract.     

Effects of the standardized Ginkgo biloba extract EGb 761® on neuroplasticity

Neuroplasticity, the ability of synapses to undergo structural adaptations in response to functional demand or dysfunctions is increasingly impaired in aging and Alzheimer's disease. EGb761? has been shown in several preclinical reports to increase nearly all aspects of impaired neuroplasticity (long-term potentiation, spine density, neuritogenesis, neurogenesis). While all three fractions of constituents (ginkgolides, flavonoids, bilobalide) seem to be active, the flavonoids and specifically the aglycone isorhamnetin seem to be most relevant.     

The complexity of the dopaminergic synapses and their modulation by antipsychotics

Since the mid of the 1960s, striking similarities between the psychosis seen in subjects taking high doses of amphetamines and the symptoms of patients with paranoid schizophrenia have been noted and placed in the context of increased catecholaminergic neurotransmission as a fundamental cause underlying major symptoms of the disease. Subsequent studies emphasized the contribution of central dopaminergic mechanisms for at least several psychotic symptoms of schizophrenia. The most compelling pharmacological data to support the developing "dopamine hypothesis of schizophrenia" originated from the clear relationship between antipsychotic drug efficacy and affinity for D2-like dopamine receptors strongly indicating D2-antagonism as major if not exclusive mechanism of antipsychotic drug action. Accordingly, in this review we focus on the neuropharmacology of the dopaminergic system in our brain with special emphasis on the dopaminergic synapse.     

Gestational stress induces persistent depressive‐like behavior and structural modifications within the postpartum nucleus accumbens

Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Pregnancy stress enhances vulnerability to PPD and has also been shown to increase depressive‐like behavior in postpartum rats. Thus, gestational stress may be an important translational risk factor that can be used to investigate the neurobiological mechanisms underlying PPD. Here we examined the effects of gestational stress on depressive‐like behavior during the early/mid and late postpartum periods and evaluated whether this was accompanied by altered structural plasticity in the nucleus accumbens (NAc), a brain region that has been linked to PPD. We show that early/mid (postpartum day 8) postpartum female rats exhibited more depressive‐like behavior in the forced swim test as compared with late postpartum females (postpartum day 22). However, 2 weeks of restraint stress during pregnancy increased depressive‐like behavior regardless of postpartum timepoint. In addition, dendritic length, branching and spine density on medium spiny neurons in the NAc shell were diminished in postpartum rats that experienced gestational stress although stress‐induced reductions in spine density were evident only in early/mid postpartum females. In the NAc core, structural plasticity was not affected by gestational stress but late postpartum females exhibited lower spine density and reduced dendritic length. Overall, these data not only demonstrate structural changes in the NAc across the postpartum period, they also show that postpartum depressive‐like behavior following exposure to gestational stress is associated with compromised structural plasticity in the NAc and thus may provide insight into the neural changes that could contribute to PPD.     

Hyperforin modulates dendritic spine morphology in hippocampal pyramidal neurons by activating Ca2+‐permeable TRPC6 channels

The standardized extract of the St. John's wort plant (Hypericum perforatum ) is commonly used to treat mild to moderate depression. Its active constituent is hyperforin, a phloroglucinol derivative that reduces the reuptake of serotonin and norepinephrine by increasing intracellular Na⁺ concentration through the activation of nonselective cationic TRPC6 channels. TRPC6 channels are also Ca²⁺‐permeable, resulting in intracellular Ca²⁺ elevations. Indeed, hyperforin activates TRPC6‐mediated currents and Ca²⁺ transients in rat PC12 cells, which induce their differentiation, mimicking the neurotrophic effect of nerve growth factor. Here, we show that hyperforin modulates dendritic spine morphology in CA1 and CA3 pyramidal neurons of hippocampal slice cultures through the activation of TRPC6 channels. Hyperforin also evoked intracellular Ca²⁺ transients and depolarizing inward currents sensitive to the TRPC channel blocker La³⁺, thus resembling the actions of the neurotrophin brain‐derived neurotrophic factor (BDNF) in hippocampal pyramidal neurons. These results suggest that the antidepressant actions of St. John's wort are mediated by a mechanism similar to that engaged by BDNF. © 2012 Wiley Periodicals, Inc.