Caribbean mesophotic coral ecosystems are unlikely climate change refugia.

Deeper coral reefs experience reduced temperatures and light and are often shielded from localized anthropogenic stressors such as pollution and fishing. The deep reef refugia hypothesis posits that light-dependent stony coral species at deeper depths are buffered from thermal stress and will avoid bleaching-related mass mortalities caused by increasing sea surface temperatures under climate change. This hypothesis has not been tested because data collection on deeper coral reefs is difficult. Here we show that deeper (mesophotic) reefs, 30-75 m depth, in the Caribbean are not refugia because they have lower bleaching threshold temperatures than shallow reefs. Over two thermal stress events, mesophotic reef bleaching was driven by a bleaching threshold that declines 0.26 °C every +10 m depth. Thus, the main premise of the deep reef refugia hypothesis that cooler environments are protective is incorrect; any increase in temperatures above the local mean warmest conditions can lead to thermal stress and bleaching. Thus, relatively cooler temperatures can no longer be considered a de facto refugium for corals and it is likely that many deeper coral reefs are as vulnerable to climate change as shallow water reefs.

Antagonism of purinergic signalling improves recovery from traumatic brain injury.

The recent public awareness of the incidence and possible long-term consequences of traumatic brain injury only heightens the need to develop effective approaches for treating this neurological disease. In this report, we identify a new therapeutic target for traumatic brain injury by studying the role of astrocytes, rather than neurons, after neurotrauma. We use in vivo multiphoton imaging and show that mechanical forces during trauma trigger intercellular calcium waves throughout the astrocytes, and these waves are mediated by purinergic signalling. Subsequent in vitro screening shows that astrocyte signalling through the 'mechanical penumbra' affects the activity of neural circuits distant from the injury epicentre, and a reduction in the intercellular calcium waves within astrocytes restores neural activity after injury. In turn, the targeting of different purinergic receptor populations leads to a reduction in hippocampal cell death in mechanically injured organotypic slice cultures. Finally, the most promising therapeutic candidate from our in vitro screen (MRS 2179, a P2Y1 receptor antagonist) also improves histological and cognitive outcomes in a preclinical model of traumatic brain injury. This work shows the potential of studying astrocyte signalling after trauma to yield new and effective therapeutic targets for treating traumatic brain injury.

Pyruvate modulation of redox potential controls mouse sperm motility.

Sperm gain fertilization competence in the female reproductive tract through a series of biochemical changes and a requisite switch from linear progressive to hyperactive motility. Despite being essential for fertilization, regulation of sperm energy transduction is poorly understood. This knowledge gap confounds interpretation of interspecies variation and limits progress in optimizing sperm selection for assisted reproduction. Here, we developed a model of mouse sperm bioenergetics using metabolic phenotyping data, quantitative microscopy, and spectral flow cytometry. The results define a mechanism of motility regulation by microenvironmental pyruvate. Rather than being consumed as a mitochondrial fuel source, pyruvate stimulates hyperactivation by repressing lactate oxidation and activating glycolysis in the flagellum through provision of nicotinamide adenine dinucleotide (NAD)+. These findings provide evidence that the transitions in motility requisite for sperm competence are governed by changes in the metabolic microenvironment, highlighting the unexplored potential of using catabolite combination to optimize sperm selection for fertilization.

Linking impact to cellular and molecular sequelae of CNS injury: modeling in vivo complexity with in vitro simplicity.

Traumatic brain injury (TBI) represents one of most common disorders to the central nervous system (CNS). Despite significant efforts, though, an effective clinical treatment for TBI is not yet available. The complexity of human TBI is modeled with a broad group of experimental models, with each model matching some aspect of the human condition. In the past 15 years, these in vivo models were complemented with a group of in vitro models, with these in vitro models allowing investigators to more precisely identify the mechanism(s) of TBI, the different intracellular events that occur in acute period following injury, and the possible treatment of this injury in vitro. In this paper, we review the available in vitro models to study TBI, discuss their biomechanical basis for human TBI, and review the findings from these in vitro models. Finally, we synthesize the current knowledge and point out possible future directions for this group of models, especially in the effort toward developing new therapies for the traumatically brain injured patient.

Relationship of diabetes with cardiovascular disease-related hospitalization rates, length of stay, and charges: analysis by race/ethnicity, age, and sex.

OBJECTIVE: Determine relationship of diabetes with risk of cardiovascular disease hospitalizations and the effect on hospital length of stay and charges. DESIGN: A cross-sectional analysis of Georgia hospital discharge data for 1998 through 2001. PATIENTS: Patients hospitalized principally with one of six cardiovascular disease (CVD) conditions (myocardial infarction, ischemic heart disease, cardiac dysrhythmia, heart failure, cerebrovascular events, peripheral vascular disease) were identified in the hospital discharge data. MAIN OUTCOME MEASURES: Aggregated CVD-related hospitalization rates, length of stay, and charges were compared by presence of diabetes. Analyses were adjusted for age, sex, and race/ethnicity. RESULTS: A total of 3,900,337 discharges were recorded between 1998 to 2001. Of these, 468,957 discharges (12%) had one of the six selected CVD diagnoses (average age 67 years, average length of stay 4.7 days, average total charge $15,702, 48% women, 76% non-Hispanic Whites, 22% non-Hispanic Blacks, and 1% Hispanics). Diabetes was a concurrent diagnosis in 30% of these CVD-related discharges. CVD hospitalization rates were significantly higher and length of stay and total charges were significantly greater among non-Hispanic Whites and Blacks-but not in Hispanics-with diabetes compared to persons without diabetes. Diabetes had a similar effect on CVD hospitalizations among men and women, but the effect of diabetes was lessened with increasing age. CONCLUSION: These data suggests that aggressive outpatient modification of metabolic abnormalities in diabetes patients should be attempted to decrease risk of CVD-related hospitalization and lower the economic impact of these combined conditions.

Common reasons for hospitalization among adult patients with diabetes.

OBJECTIVE: To determine reasons for hospitalization among adult patients with diabetes. METHODS: A cross-sectional analysis was conducted of hospital discharges in the state of Georgia for the years 1998 through 2001 that contained either a primary or a coexisting diagnosis of diabetes. With use of the Clinical Classification Software of the Agency for Healthcare Research and Quality, the principal diagnoses among diabetes-related hospital discharges were organized into diagnostic categories. RESULTS: Diabetes was listed as a diagnosis in 14% of all Georgia hospital discharges of adult patients during our study period (57% women; 62% non-Hispanic white; mean age, 64 years; mean length of stay, 5.7 days; and mean hospital charge, 13,540 dollars). Among patients with a diagnosis of diabetes, the 3 most common categories of discharges were "diseases of the circulatory system" (33%), "endocrine, nutritional, and metabolic; immunity disorders" (13%), and "diseases of the respiratory system: (11%). When infections were identified and aggregated, however, these conditions became the second most frequent discharge category (14% of all hospital discharges among patients with diabetes). "Congestive heart failure," "coronary atherosclerosis," and "acute myocardial infarction" were the first, second, and fifth most frequently found unique diagnoses, respectively, among patients with diabetes. CONCLUSION: In this study, diseases of the circulatory system were the most common diagnoses in hospital discharge data for adult patients with diabetes in Georgia. Hospitals should be cognizant of the increased burden placed on them by diabetes, and outpatient treatment of diabetes should focus on prevention of cardiovascular diseases to avoid hospitalizations.

Potentially modifiable metabolic factors and the risk of cardiovascular disease hospitalizations in urban African Americans with diabetes.

OBJECTIVE: Diabetes and cardiovascular disease (CVD) are frequent causes of hospitalization in African Americans but have rarely been studied as coexisting diagnoses. We analyzed data from an urban African American diabetes patient population to identify variables associated with CVD hospitalizations. DESIGN: Demographic, disease, and metabolic characteristics of patients seen from 1991 to 1997 were extracted from an electronic patient tracking system. Data were linked to a statewide hospital discharge dataset to establish who was hospitalized between 1998 and 2001. Patients with a CVD hospitalization were compared to patients without a CVD hospitalization. RESULTS: 3397 diabetes patients (average age, 56 years; 65% women; 92% African American) were included in the analysis; 24% had hospitalizations primarily due to CVD. Persons with CVD hospitalizations were older and had diabetes longer, and fewer were women. Mean systolic blood pressure (SBP), low-density lipoprotein (LDL) cholesterol, triglyceride, and total cholesterol levels and urinary albumin/creatinine ratio were all higher among persons with CVD hospitalizations. In adjusted analyses, women had lower odds of experiencing a CVD hospitalization, but advancing age, diabetes duration, SBP, and LDL cholesterol were all associated with greater odds. CONCLUSIONS: In this predominantly African American patient sample with diabetes, specific factors (age, sex, diabetes duration, LDL cholesterol, SBP) were associated with CVD hospitalizations. Additional studies are needed to determine whether management of metabolic risk factors in outpatient settings will translate into lower hospitalization rates due to CVD in this population.

Poor glycemic control increases risk of hospitalization in urban African Americans with diabetes.

OBJECTIVE: Hospitalizations due to diabetes are more frequent among African Americans, but risk factors are not known. We analyzed data from an urban African American patient population to identify variables associated with hospitalizations attributable principally to diabetes. DESIGN: Demographic, disease, and metabolic characteristics on patients seen in an outpatient diabetes clinic during 1991 to 1997 were extracted from an electronic patient tracking system. Data were linked to a statewide hospital discharge dataset to capture all in-state hospitalizations from 1998 to 2001. Persons who required a hospitalization for diabetes were compared to the remainder of individuals in the database. RESULTS: A total of 3397 diabetes patients (average age 56 years; 65% women; 92% African American) were included in the analysis; 12% had a hospitalization primarily due to diabetes. Persons with a diabetes hospitalization were younger and had diabetes longer, and fewer were women. In addition, persons who had a diabetes-related hospitalization had evidence of poorer glycemic control with higher hemoglobin A1C (HbA1C) levels. Both the absolute change and rate of decline in HbA1C was less in persons who were hospitalized. In adjusted analyses, duration of diabetes and HbA1C remained significantly associated with risk of a diabetes hospitalization. CONCLUSIONS: In this predominantly African American patient sample with diabetes, poorer glycemic control increased the chances of hospitalization due to diabetes. Continued efforts to aggressively control hyperglycemia could decrease the need for a diabetes hospitalization in this population.

Common reasons for hospitalization in urban diabetes patients.

OBJECTIVES: Determine principal reasons for hospitalization in a predominantly urban, African American diabetes patient population. DESIGN: Data for outpatients with a diagnosis of diabetes were abstracted from electronic records. The number of hospitalizations from 1998 through 2001 was determined after linking our dataset with a statewide discharge dataset. Principal diagnoses were grouped into 18 multilevel diagnostic classes using the Agency for Healthcare Research and Quality's Clinical Classifications Software. PATIENTS: A total of 6505 unique patients had 20,344 discharges from 1998 through 2001; 92% were listed as African Americans and 61% as women. MAIN OUTCOME MEASURES: Frequency of each multilevel diagnostic class and the most commonly occurring diagnoses. RESULTS: The most common multilevel diagnostic classes were "diseases of the circulatory system" (29.0% of all discharges) and "endocrine, nutritional, and metabolic; immunity disorders" (17.1%). The five most commonly occurring unique diagnoses were "congestive heart failure," "diabetes with ketoacidosis or uncontrolled diabetes," "coronary atherosclerosis," "diabetes with other manifestations," and "pneumonia, organism unspecified." Nearly 16% of all discharged patients had diagnoses related to infection. The five most frequent diagnoses related to infection were "pneumonia, organism unspecified," "urinary tract infection, site not specified," "infection and inflammation, internal prosthetic device," "cellulitis and abscess of leg," and "postoperative infection." CONCLUSIONS: In this predominantly urban, African American diabetes patient population, potentially preventable hospitalizations involving diseases such as congestive heart failure and diabetes occur with high frequency. Better understanding of the risk factors underlying these hospitalizations--particularly those involving modifiable metabolic variables--requires further investigation.

Disparities in diabetes-related hospitalizations: relationship of age, sex, and race/ethnicity with hospital discharges, lengths of stay, and direct inpatient charges.

OBJECTIVE: To identify any differences in hospitalization rates of diabetes patients by age, sex, or race/ethnicity. DESIGN: A cross-sectional study of Georgia hospital discharge data between 1998 and 2001. PATIENTS/PARTICIPANTS: Patients with a principal discharge diagnosis of diabetes. MAIN OUTCOME MEASURES: Adjusted hospitalization data (discharge rates, length of stay, direct charges) reported as standardized rates per 10,000 person-years, standardized rate differences, and standardized rate ratios, compared by age, sex, and race/ethnicity. RESULTS: Diabetes was the principal diagnosis in 50,301 discharges (average age, 51 years; length of stay, 5.1 days; median total charge, $5893). Persons > or = 60 years old had higher discharge rates, longer stays, and higher charges than persons 18-29 years old. Women had fewer hospitalizations, shorter stays, and lower charges than men. Non-Hispanic Blacks had more than three times as many hospitalizations, markedly longer stays, and higher charges than non-Hispanic Whites. Hispanics with diabetes had lower hospitalization rates, shorter stays, and lower charges than Whites. CONCLUSIONS: Differences by age, sex, and race/ethnicity in hospital discharge rates, lengths of stay, and charges exist for diabetes inpatients. Further study should examine potential causes (severity of disease, comorbidity, and differential access to preventive care) of these disparities.

Estrogen receptor (ER)beta isoforms rather than ERalpha regulate corticotropin-releasing hormone promoter activity through an alternate pathway.

The hypothalamic-pituitary-adrenal axis regulates mammalian stress responses by secreting glucocorticoids. The magnitude of the response is in part determined by gender, for in response to a given stressor, circulating glucocorticoids reach higher levels in female rats than in males. This gender difference could result from estrogen regulation of the corticotropin-releasing hormone (CRH) promoter via either of its receptors: estrogen receptor (ER)alpha or ERbeta. Immunocytochemistry revealed that a subset (12%) of medial parvocellular CRH neurons in the rat hypothalamus contain ERbeta but not ERalpha. To determine whether ERs could regulate CRH promoter activity, we cotransfected cells with a CRH promoter construct and either ERalpha or individual ERbeta isoforms. ERalpha weakly stimulated CRH promoter transcriptional activity in a ligand-independent manner. Conversely, all ERbeta isoforms tested stimulated CRH promoter activity with different ligand profiles. ERbeta1 and ERbeta2delta3 displayed constitutive activity (ERbeta1 more than ERbeta2delta3). Ligand-dependent activity of beta isoforms 1 and 2 was altered by an Exon3 splice variant (delta3) or by the additional 18 amino acids in the ligand-binding domain of ERbeta2 isoforms. Lastly, we suggest that ER regulation of CRH takes place through an alternate pathway, one that requires protein-protein interactions with other transcription factors or their associated complexes. However, a pure ER-activator protein-1 alternate pathway does not appear to be involved.

Mechanically induced reactive gliosis causes ATP-mediated alterations in astrocyte stiffness.

Reactive gliosis is a process triggered in astrocytes after traumatic injury, yet the exact consequences of gliosis on cellular survival and neural regenerative processes in the injured brain remain only partly understood. One recently discovered feature influencing neuronal growth and differentiation is the physical stiffness of the environment surrounding pioneering neurites. In this study, the mechanical properties of cultured cortical astrocytes are measured following a mechanical stretch injury that induces reactive gliosis. In mechanically injured cultures, there was a significant increase in glial fibrillary acidic protein (GFAP) immunoreactivity 24 h following a rapid, transient 15% strain. In these same cultures, astrocytes in the surrounding region--the "mechanical penumbra"--also exhibited increased GFAP immunoreactivity compared to naive cultures. Correlated with these changes in GFAP was a general softening of the non-nuclear regions of the astrocytes, both in the injured and penumbra cells, as measured by atomic force microscopy (AFM). The elastic modulus in naive cultures was observed to be 57.7+/-5.8 kPa in non-nuclear regions of naive cultures, while 24 h after injury the modulus was observed to be 26.4+/-4.9 kPa in the same region of injured cells. In the penumbra of injured cultures, the modulus was 23.7+/-3.6 kPa. Alterations in astrocyte stiffness in the area of injury and mechanical penumbra were ameliorated by pretreating cultures with a nonselective P2 receptor antagonist (PPADS). Since neuronal cells generally prefer softer substrates for growth and neurite extension, these findings may indicate that the mechanical characteristics of reactive astrocytes are favorable for neuronal recovery after traumatic brain injury.

Matrices with compliance comparable to that of brain tissue select neuronal over glial growth in mixed cortical cultures.

Cortical neurons and astrocytes respond strongly to changes in matrix rigidity when cultured on flexible substrates. In this study, existing polyacrylamide gel polymerization methods were modified into a novel method for making substrates capable of engaging specific cell-adhesion receptors. Embryonic cortical dissociations were cultured on polyacrylamide or fibrin gel scaffolds of varying compliance. On soft gels, astrocytes do not spread and have disorganized F-actin compared to the cytoskeletons of astrocytes on hard surfaces. Neurons, however, extend long neurites and polymerize actin filaments on both soft and hard gels. Compared to tissue culture plastic or stiff gel substrates coated with laminin, on which astrocytes overgrow neurons in mixed cultures, laminin-coated soft gels encourage attachment and growth of neurons while suppressing astrocyte growth. The number of astrocytes on soft gels is lower than on hard even in the absence of mitotic inhibitors normally used to temper the astrocyte population. Dissociated embryonic rat cortices grown on flexible fibrin gels, a biomaterial with potential use as an implant material, display a similar mechano-dependent difference in cell population. The stiffness of materials required for optimal neuronal growth, characterized by an elastic modulus of several hundred Pa, is in the range measured for intact rat brain. Together, these data emphasize the potential importance of material substrate stiffness as a design feature in the next generation of biomaterials intended to promote neuronal regeneration across a lesion in the central nervous system while simultaneously minimizing the ingrowth of astrocytes into the lesion area.