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Background: Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion., Methods and Results: A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production., Conclusions: These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection., (© 2014 American Heart Association, Inc.)

Objective: Preterm infants often show intolerance to the first enteral feeds, and the structural and functional basis of this intolerance remains unclear. We hypothesized that preterm and term neonates show similar gut trophic responses to feeding but different expression of intestinal functional proteins, thus helping to explain why preterm neonates are more susceptible to feeding-induced disorders such as necrotizing enterocolitis (NEC)., Methods: Incidence of feeding-induced NEC, intestinal mass, and brush border enzyme activities, and the intestinal proteome in preterm cesarean-delivered pigs were compared with the corresponding values in pigs delivered spontaneously at term., Results: For both preterm and term pigs, mucosal mass and maltase activity increased (50%-100%), whereas lactase decreased (-50%), relative to values at birth. Only preterm pigs were highly NEC sensitive (30% vs 0% in term pigs, P < 0.05). By gel-based proteomics, 36 identified proteins differed in expression, with most proteins showing downregulation in preterm pigs, including proteins related to intestinal structure and actin filaments, stress response, protein processing, and nutrient metabolism., Conclusions: Despite that enteral feeding induces rapid gut tropic response in both term and preterm neonates, the expression level of cellular proteins related to mucosal integrity, metabolism, and stress response differed markedly (including complement 3, prohibitin, ornithine carbamoyltransferase, and arginosuccinate synthetase). These proteins may play a role in the development of functional gut disorders and NEC in preterm neonates.

Background: Extensive bowel resection may lead to a state of inadequate nutrient absorption and malnutrition known as short bowel syndrome. Deficiencies in fat-soluble vitamins may occur from this condition, with sequelae such as a bleeding diathesis. Maternal vitamin deficiencies also have been associated with fetal anomalies., Case: A young gravid patient with a history of neonatal bowel resection presented with bleeding diathesis. She subsequently was found to have profound vitamin deficiencies and delivered a newborn with multiple anomalies., Conclusion: Preconceptional counseling, nutritional status evaluation, and concomitant management with a gastroenterologist are essential to optimize pregnancy outcome for patients with a history of extensive bowel resection.

The fear of developing Alzheimer disease (AD) is highly salient, particularly for biologic family members. The current study evaluated social/cognitive explanations for perceived AD threat beyond genetic relatedness, including personal experience with AD, belief in negative aging stereotypes, and performance on delayed memory tasks. Participants were 97 healthy older adults aged 50 to 85, self-referred for a free community memory screen. Results showed that, as expected, personal AD experience was related to perceived AD threat. Furthermore, consistent with expectations, AD experience moderated the relationship between perceived AD threat and other explanatory variables, including age, belief in negative aging stereotypes, and cognitive performance. In those with AD experience, whether genetic or not, younger age was associated with more perceived AD threat, but an inverse relationship was seen in those without AD experience. Those with genetic AD experience seem particularly vulnerable to the effects of negative age stereotype beliefs on perceived AD threat, and show an inverse relationship between their actual cognitive performance and their perception of personal AD threat. Results highlight the importance of considering personal experience with AD when assessing a person's self-reported concerns about AD or his/her own memory changes.

Gender differences in incidence of cardiac arrhythmias have been documented. It is generally believed that cardiac pathology provides an arrhythmogenic substrate but that a trigger such as sympathetic nervous system activation is required to initiate arrhythmias. This study was done to determine whether there is a sex difference in susceptibility to epinephrine-induced arrhythmias in healthy rats without preexisting pathology and to determine whether gonadal hormones play a role in development of arrhythmias. Untreated, sham-operated, and gonadectomized male and female rats were anesthetized and given IV boluses of epinephrine. ECG, heart rate, and blood pressure were measured continuously for 1 minute and intermittently over a period of 30 minutes. Male rat hearts have a higher occurrence and frequency of epinephrine-induced premature ventricular contractions, missed beats, and blocks than female rat hearts. Ovariectomy increases arrhythmias, thereby abolishing the female advantage. Castration has no effect on occurrence and frequency of premature ventricular contractions but attenuates missed beats and blocks. Sex differences and effect of gonadectomy on epinephrine-induced alterations in heart rate and blood pressure implicate baroreceptor reflex in the dimorphic arrhythmogenic response. Male rat hearts are more susceptible than female hearts to epinephrine-induced arrhythmias, and gonadal hormones play a role in this disparity.

Objective: To describe how an animal model system can be used to explore basic questions about the nature of loss and the effects of early loss on later vulnerability to disease., Method: The physiological and behavioral responses of infant rats to separation from their mothers are first described and then analyzed experimentally into component mechanisms., Results: These studies have revealed an extensive layer of processes underlying the psychological constructs generally used to understand the response to loss. Hidden within the observable interactions of parent and offspring, we found a number of discrete sensorimotor, thermal, and nutrient-based events that have unexpected long-term regulatory effects on specific components of infant physiology and behavior. Release from all of these inhibitory and excitatory regulators together during maternal separation constitutes a novel mechanism by which the experience of loss can be translated into a complex patterned response. Evidence for early regulatory processes has also been found in monkey and human mother-infant interactions. Here they may well constitute the building blocks from which attachment and object representations develop. We and others have found long-term effects of loss, and of selective replacement of regulators, on behavioral development and on later vulnerability to disease., Conclusions: The results give us a new understanding of early attachment as a developmental force and of human grief as a risk to health.

Objective: Research on the relationship between physiological responses to stressful stimulation and the onset of psychosomatic illnesses has been an area of intense interest for many years. Studies using animal models have contributed significantly to this field of inquiry by taking several complementary approaches., Method: Three specific research strategies taken in our laboratory will be highlighted here. Each involves studies in conscious, freely behaving animals., Results: Genetically selected animals have been exposed to acute stressors to unmask neuroendocrine and autonomic abnormalities related to disease susceptibility. In addition, studies of aged animals suggest that exaggerated physiological responses to acute stress may underlie some age-related pathologies. Finally, a series of studies has revealed that exposure of laboratory animals to stressful stimulation may exert long-lasting influences on the ways in which these subjects respond in the future to the same or novel stressors., Conclusions: These findings illustrate how studies with laboratory animals have the potential for refining the questions that are posed in research with clinical populations and for providing insight into the underlying physiological mechanisms of individual variability in disease susceptibility and the development of appropriate therapeutic interventions.

Patients with neoplastic diseases are predisposed to develop invasive fungal infections as the result of impairments of host defense mechanisms due principally to pharmacologic immunosuppression resulting from intensive cytotoxic chemotherapy, ablative radiation therapy, and corticosteroids. Candida species, Aspergillus species, and emerging opportunistic fungal pathogens comprise the principal etiologic agents of opportunistic mycoses in cancer patients. This paper reviews the recent progress, particularly during the year of 1991, in management of invasive fungal infections and the current problems of invasive mycosis, which confront patients with neoplastic diseases.

The effect of fused segments in the cervical spine has been documented to cause chronic changes in adjacent levels. This article reports an association between the presence of fused cervical segments and the predisposition to acute, traumatic instability at adjacent levels. Patients with cervical fractures were reviewed during a 12-year period. Fifteen patients were identified who sustained cervical fractures in the presence of previously fused segments. The presence of fusion was reviewed for its effect of neurologic injury, delay in diagnosis, and patterns of fractures. The diagnostic studies used to document instability were reviewed. We found that preexisting cervical fusions often result in a delay of diagnosis because of altered anatomy and atypical fracture patterns. The fractures occurred within one or two levels from the fused segment. There are different fracture patterns associated with fusions in the upper cervical spine and those fusions in the lower cervical spine. The presence of fusions significantly affected treatment choices in this group of patients.