The comorbidity of bipolar and anxiety disorders: prevalence, psychobiology, and treatment issues

BACKGROUND: Although symptoms of anxiety as well as anxiety disorders commonly occur in patients with bipolar disorder, the pathophysiologic, theoretical, and clinical significance of their co-occurrence has not been well studied. METHODS: The epidemiological and clinical studies that have assessed the overlap of bipolar and anxiety disorders are reviewed, with focus on panic disorder and obsessive-compulsive disorder (OCD), and to a lesser extent, social phobia and post-traumatic stress disorder. Potential neural mechanism and treatment response data are also reviewed. RESULTS: A growing number of epidemiological studies have found that bipolar disorder significantly co-occurs with anxiety disorders at rates that are higher than those in the general population. Clinical studies have also demonstrated high comorbidity between bipolar disorder and panic disorder, OCD, social phobia, and post-traumatic stress disorder. Psychobiological mechanisms that may account for these high comorbidity rates likely involve a complicated interplay among various neurotransmitter systems, particularly norepinephrine, dopamine, gamma-aminobutyric acid (GABA), and serotonin. The second-messenger system constituent, inositol, may also be involved. Little controlled data are available regarding the treatment of bipolar disorder complicated by an anxiety disorder. However, adequate mood stabilization should be achieved before antidepressants are used to treat residual anxiety symptoms so as to minimize antidepressant-induced mania or cycling. Moreover, preliminary data suggesting that certain antimanic agents may have anxiolytic properties (e.g. valproate and possibly antipsychotics), and that some anxiolytics may not induce mania (e.g. gabapentin and benzodiazepines other than alprazolam) indicate that these agents may be particularly useful for anxious bipolar patients. CONCLUSIONS: Comorbid anxiety symptoms and disorders must be considered when diagnosing and treating patients with bipolar disorder. Conversely, patients presenting with anxiety disorders must be assessed for comorbid mood disorders, including bipolar disorder. Pathophysiological, theoretical, and clinical implications of the overlap of bipolar and anxiety disorders are discussed.     

CaT1 knock-down strategies fail to affect CRAC channels in mucosal-type mast cells

CaT1, the calcium transport protein 1 encoded by TRPV6 , is able to generate a Ca²⁺ conductance similar but not identical to the classical CRAC current in mucosal-type mast cells. Here we show that CaT1-derived Ca²⁺ entry into HEK293 cells is effectively inhibited either by expression of various dominant negative N-terminal fragments of CaT1 (N₃₃₄-CaT1, N₁₉₈-CaT1 and N₁₅₄-CaT1) or by antisense suppression. By contrast, the endogenous CRAC current of the mast cells was unaffected by CaT1 antisense and siRNA knockdown but markedly suppressed by two (N₃₃₄-CaT1, N₁₉₈-CaT1) of the dominant negative N-CaT1 fragments. Inhibition of CRAC current was not an unspecific, toxic effect, as inward rectifier K⁺ and MagNuM currents of the mast cells were not significantly affected by these N-CaT1 fragments. The shortest N₁₅₄-CaT1 fragment inhibited CaT1-derived currents in mast cells, but failed to inhibit CRAC currents. Thus, the structural requirements of rCaT N-terminal fragments for inhibition of rCaT1 and CRAC channels are different. These results together with the lack of CaT1 antisense and siRNA effects on currents render it unlikely that CaT1 is a component of native CRAC channels in mast cells. The data further demonstrate a novel strategy for CRAC current inhibition by an N-terminal structure of CaT1.     

Coronary Stent Strut Size Dependent Stress–Strain Response Investigated Using Micromechanical Finite Element Models

Cardiovascular stents are metal scaffolds that are used in the treatment of atherosclerosis. These devices are typically composed of very thin struts (< or = 100 microm thickness, for coronary applications). At this size-scale the question arises as to the suitability of using bulk material properties in stent design. This paper investigates the use of finite element analysis to predict the mechanical failure of stent struts, typical of the strut size used in coronary stents. 316 L stainless steel in uniaxial loading was considered. To accurately represent the constitutive behavior of the material at this size-scale, a computational micromechanics approach was taken involving an explicit representation of the grain structure in the steel struts, and the use of crystal plasticity theory to represent the constitutive behavior of the individual grains. The development of the finite element models is discussed and results are presented for the predictions of tensile mechanical behavior as a function of strut thickness. The results showed that using this modelling approach, a size effect, already seen experimentally, is produced. This has significant implications for stent design, especially in the context of the desire to produce smaller stents for small bore neurovascular and peripheral artery applications.     

Computational Modelling of the Mechanics of Trabecular Bone and Marrow Using Fluid Structure Interaction Techniques

Bone marrow found within the porous structure of trabecular bone provides a specialized environment for numerous cell types, including mesenchymal stem cells (MSCs). Studies have sought to characterize the mechanical environment imposed on MSCs, however, a particular challenge is that marrow displays the characteristics of a fluid, while surrounded by bone that is subject to deformation, and previous experimental and computational studies have been unable to fully capture the resulting complex mechanical environment. The objective of this study was to develop a fluid structure interaction (FSI) model of trabecular bone and marrow to predict the mechanical environment of MSCs in vivo and to examine how this environment changes during osteoporosis. An idealized repeating unit was used to compare FSI techniques to a computational fluid dynamics only approach. These techniques were used to determine the effect of lower bone mass and different marrow viscosities, representative of osteoporosis, on the shear stress generated within bone marrow. Results report that shear stresses generated within bone marrow under physiological loading conditions are within the range known to stimulate a mechanobiological response in MSCs in vitro. Additionally, lower bone mass leads to an increase in the shear stress generated within the marrow, while a decrease in bone marrow viscosity reduces this generated shear stress.     

Digital Pathology Consultations—a New Era in Digital Imaging, Challenges and Practical Applications

Digital pathology has grown dramatically in the last 10 years and has created opportunities to not only support the triaging of difficult cases among specialists within an organization, but also enable remote pathology consultations with external organizations across the world. This study investigated one organization's need for a vendor agnostic Digital Pathology Consultation workflow solution that overcomes the challenges associated with the transfer of large studies across a local area network or across the Internet. The organization investigated is a large multifacility healthcare organization that consists of 20 hospitals spread across a wide geographical area. The organization has one of the largest academic pathology departments in the USA, with more than 100 diagnostic anatomic pathologists. This organization developed a set of web-based tools to support the workflow of digital pathology consultations and allow the viewing of whole slide images. The challenges and practical implementations of two different use cases are addressed: the occasional end user (professional or patient) requesting a second opinion and the external laboratory or hospital looking for an established consultative relationship with a large volume of cases. The solution presented in this study addresses the challenges associated with the distribution of large images and the lack of established imaging standards, while providing for a convenient and secure portal for pathologist report entry and distribution.     

Nanomechanical properties of poly(lactic-co-glycolic) acid film during degradation

Despite the potential applications of poly(lactic-co-glycolic) acid (PLGA) coatings in medical devices, the mechanical properties of this material during degradation are poorly understood. In the present work, the nanomechanical properties and degradation of PLGA film were investigated. Hydrolysis of solvent-cast PLGA film was studied in buffer solution at 37 °C. The mass loss, water uptake, molecular weight, crystallinity and surface morphology of the film were tracked during degradation over 20 days. Characterization of the surface hardness and Young’s modulus was performed using the nanoindentation technique for different indentation loads. The initially amorphous films were found to remain amorphous during degradation. The molecular weight of the film decreased quickly during the initial days of degradation. Diffusion of water into the film resulted in a reduction in surface hardness during the first few days, followed by an increase that was due to the surface roughness. There was a significant delay between the decrease in the mechanical properties of the film and the decrease in the molecular weight. A sudden decline in mechanical properties indicated that significant bulk degradation had occurred.     

The role of metabotropic glutamate receptor mGlu5 in control of micturition and bladder nociception

In micturition control, the roles of ionotropic glutamate (iGlu) receptors NMDA and AMPA are well established, whereas little is known about the function of metabotropic glutamate (mGlu) receptors. Since antagonists for mGlu5 receptors are efficacious in animal models of inflammatory and neuropathic pain, we examined whether mGlu5 receptors play a role in the voiding reflex and bladder nociception and, if so, via centrally or peripherally localized receptors. The mGlu5 receptor antagonist MPEP dose-dependently increased the micturition threshold (MT) volume in the volume-induced micturition reflex (VIMR) model in anesthetized rats. Following doses of 5.2, 15.5 and 51.7 μmol/kg of MPEP (intraduodenal), the MT was increased by 24.7 ± 5.0%, 97.2 ± 12.5% (P < 0.01) and 128.0 ± 28.3% (P < 0.01) from the baseline, respectively (n = 4–5; compared with 0.8 ± 9.1% in the vehicle group). Infusing MPEP (0.3, 1 mM) directly into the bladder also raised MT. However, the efficacious plasma concentrations of MPEP following intravesical dosing were similar to that after intraduodenal dosing (EC₅₀ of 0.11 and 0.27 μM, respectively, P > 0.05). MPEP also dose-dependently attenuated the visceromotor responses (VMR, total number of abdominal EMG spikes during phasic bladder distension) in anesthetized rats. The VMR was decreased to 1332.4 ± 353.9 from control of 2886.5 ± 692.2 spikes/distension (n = 6, P < 0.01) following MPEP (10 μmol/kg, iv). Utilizing the isolated mouse bladder/pelvic nerve preparation, we found that neither MPEP (up to 3 μM) nor MTEP (up to 10 μM) affected afferent discharge in response to bladder distension (n = 4–6). In contrast, MPEP attenuated the responses of the mesenteric nerves to distension of the mouse jejunum in vitro. These data suggest that mGlu5 receptors play facilitatory roles in the processing of afferent input from the urinary bladder, and that central rather than peripheral mGlu5 receptors appear to be responsible.     

Characteristics of persons with recently acquired HIV infection: application of the serologic testing algorithm for recent HIV seroconversion in 10 US cities

BACKGROUND: Information about the characteristics of persons whose HIV diagnosis was made soon after infection contributes to a better understanding of the HIV epidemic and to appropriate targeting of care and prevention efforts. METHODS: In 10 US cities from 1997 through 2001, specimens from consenting persons for whom a diagnosis of HIV was made within the past 12 months in were tested using the serologic testing algorithm for recent HIV seroconversion. The characteristics of those whose HIV diagnosis occurred within 170 days (on average) from seroconversion were identified. RESULTS: For 191 (20%) of the 964 participants, an HIV diagnosis was made during the period of recent infection. These diagnoses of recent infection were made more frequently among men (21.7%), whites (29.3%), men who have sex with men (25.5%), persons with a known HIV-infected partner (24.9%), and persons with a diagnosis of gonorrhea made in the 12 months before interview (27.0%). Recent infection was diagnosed less frequently among African Americans (15.5%), Latinos (15.5), and heterosexual men (14.7%) and women (14.4%). CONCLUSIONS: To increase early diagnosis of HIV, HIV testing should be more routinely offered to persons with a recent history of sexually transmitted diseases and to African Americans and Latinos in a variety of settings.     

Men who have sex with men: estimated population sizes and mortality rates by race/ethnicity, Miami-Dade County, Florida

BACKGROUND: Estimated numbers of men who have sex with men (MSM) by race/ethnicity and mortality rates among such MSM with HIV/AIDS are unavailable. This hampers efficient targeting of HIV/AIDS prevention and care resources. METHODS: An existing estimation methodology was adapted to develop MSM population estimates by race/ethnicity for Miami-Dade County, Florida. We ascertained and characterized deaths that occurred during 2003 to 2005 among MSM HIV/AIDS cases, matching HIV/AIDS surveillance and vital statistics registries. We calculated estimated average annual racial/ethnic-specific mortality rates and rate ratios (RRs) among MSM HIV/AIDS cases. RESULTS: An estimated 63,020 men aged > or =18 years in the county are MSM (7.5% of all men aged > or =18 years; point estimate). Among 754 MSM HIV/AIDS deaths, point-estimate mortality rates per 100,000 MSM were higher for blacks (733.5) than for whites (229.2) (P < 0.01) and Hispanics (360.5) (P < 0.01). The best estimate of the black/white MSM mortality RR among HIV/AIDS cases was 3.20:1 (P < 0.01); for Hispanic/white MSM, it was 1.57:1 (P < 0.01). Sensitivity analyses suggested the estimates were reasonably robust to biases that we examined. CONCLUSIONS: Black and Hispanic MSM were more likely to die with HIV/AIDS than white MSM. Plausible racial/ethnic-specific MSM population and mortality rate estimates can inform effective HIV/AIDS prevention efforts and program planning.