The relationships among Flory-Huggins specific interaction parameters, maximum amorphous capacity, and solid-state interactions of spray dried amorphous drug dispersions with conventional and novel pharmaceutical polymers / Las relaciones entre los parámetros de interacción específicos de Flry-Huggins, la capacidad amorfa máxima y las interacciones en estado sólido de las dispersiones de fármacos amorfos secados por aspersión con polímeros farmacéuticos convencionales y nuevos

This study evaluated the specific interactions between drug and polymers in amorphous spray dried dispersions (SDDs). Four Biopharmaceutics Classification System (BCS) II class drugs were evaluated. Binary and ternary SDDs were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between drug and polymer were determined using theoretical calculations and DSC data. Analytical methods were used to evaluate solid and solution state interactions. Maximum amorphous content for each formulation was calculated using DSC. Flory-Huggins Specific Interaction Parameters were calculated. Negative specific parameters were associated with solid-state interactions and improved capacity of drug in the amorphous state. Ternary SDDs containing drug, polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary SDDs. Solution-state interactions observed in binary systems may be used in tertiary systems to improve the amorphous drug capacity and improved dissolution compared to the binary. The resultant tertiary systems are an improvement over binary drug polymer systems.

Este estudio evaluó las interacciones específicas entre el fármaco y los polímeros en dispersiones amorfas secadas por pulverización (SDD). Se evaluaron cuatro fármacos de clase II del Sistema de Clasificación Biofarmacéutica (BCS). Los SDD binarios y ternarios se fabricaron con polímeros convencionales y arabinogalactano. Los parámetros de interacción específicos entre el fármaco y el polímero se determinaron utilizando cálculos teóricos y datos de DSC. Se utilizaron métodos analíticos para evaluar las interacciones del estado sólido y de la solución. El contenido amorfo máximo para cada formulación se calculó usando DSC. Se calcularon los parámetros de interacción específicos de Flory-Huggins. Los parámetros específicos negativos se asociaron con interacciones en estado sólido y una capacidad mejorada del fármaco en el estado amorfo. Los SDD ternarios que contienen fármaco, polímero y arabinogalactano mostraron enlaces de hidrógeno similares a los observados con los SDD binarios. Las interacciones de estado de solución observadas en sistemas binarios pueden usarse en sistemas terciarios para mejorar la capacidad del fármaco amorfo y mejorar la disolución en comparación con el binario. Los sistemas terciarios resultantes son una mejora con respecto a los sistemas de polímeros de fármacos binarios.

Borderline Personality Disorder and Psychosis: A Case Managed by Transference-Focused Psychotherapy.

Transient stress-related paranoia is the descriptive definition of psychotic phenomena associated with borderline personality disorder. Although psychotic symptoms usually do not qualify patients for a separate diagnosis in the psychotic spectrum, statistical probabilities predict the co-occurrence of cases with comorbid borderline personality disorder and major psychotic disorder. This article presents three perspectives on a complex case of borderline personality disorder and psychotic disorder: one from a medication prescribing psychiatrist who is a transference-focused psychotherapist responsible for care, one from the anonymous patient, and one from a specialist in psychotic disorder. A discussion of clinical implications concludes this multidimensional presentation of borderline personality disorder and psychosis.

Distinguishing the relevant features of frequent suicide attempters.

BACKGROUND: In spite of the high prevalence of suicide behaviours and the magnitude of the resultant burden, little is known about why individuals reattempt. We aim to investigate the relationships between clinical risk factors and the repetition of suicidal attempts. METHODS: 1349 suicide attempters were consecutively recruited in the Emergency Room (ER) of two academic hospitals in France and Spain. Patients were extensively assessed and demographic and clinical data obtained. Data mining was used to determine the minimal number of variables that blinded the rest in relation to the number of suicide attempts. Using this set, a probabilistic graph ranking relationships with the target variable was constructed. RESULTS: The most common diagnoses among suicide attempters were affective disorders, followed by anxiety disorders. Risk of frequent suicide attempt was highest among middle-aged subjects, and diminished progressively with advancing age of onset at first attempt. Anxiety disorders significantly increased the risk of presenting frequent suicide attempts. Pathway analysis also indicated that frequent suicide attempts were linked to greater odds for alcohol and substance abuse disorders and more intensive treatment. CONCLUSIONS: Novel statistical methods found several clinical features that were associated with a history of frequent suicide attempts. The identified pathways may promote new hypothesis-driven studies of suicide attempts and preventive strategies.

Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation.

Early adversity, for example poor caregiving, can have profound effects on emotional development. Orphanage rearing, even in the best circumstances, lies outside of the bounds of a species-typical caregiving environment. The long-term effects of this early adversity on the neurobiological development associated with socio-emotional behaviors are not well understood. Seventy-eight children, who include those who have experienced orphanage care and a comparison group, were assessed. Magnetic resonance imaging (MRI) was used to measure volumes of whole brain and limbic structures (e.g. amygdala, hippocampus). Emotion regulation was assessed with an emotional go-nogo paradigm, and anxiety and internalizing behaviors were assessed using the Screen for Child Anxiety Related Emotional Disorders, the Child Behavior Checklist, and a structured clinical interview. Late adoption was associated with larger corrected amygdala volumes, poorer emotion regulation, and increased anxiety. Although more than 50% of the children who experienced orphanage rearing met criteria for a psychiatric disorder, with a third having an anxiety disorder, the group differences observed in amygdala volume were not driven by the presence of an anxiety disorder. The findings are consistent with previous reports describing negative effects of prolonged orphanage care on emotional behavior and with animal models that show long-term changes in the amygdala and emotional behavior following early postnatal stress. These changes in limbic circuitry may underlie residual emotional and social problems experienced by children who have been internationally adopted.

Neural mechanisms of grief regulation.

BACKGROUND: The death of an attachment figure triggers intrusive thoughts of the deceased, sadness, and yearning for reunion. Recovery requires reduction of symptoms. We hypothesized that symptoms might correlate with a capacity to regulate attention toward reminders of the deceased, and activity in, and functional connectivity between, prefrontal regulatory regions and the amygdala. METHODS: Twenty recently bereaved subjects rated intrusive thoughts of the deceased versus a capacity to avoid thoughts (grief style). Reaction time was measured while subjects completed an Emotional Stroop (ES) task contrasting deceased-related with control words during functional magnetic resonance imaging (fMRI). Subjects subsequently visualized the death of the deceased and rated induced emotions. RESULTS: Subjects demonstrated attentional bias toward deceased-related words. Bias magnitude correlated with amygdala, insula, dorsolateral prefrontal cortex (DLPFC) activity. Amygdala activity predicted induced sadness intensity. A double dissociation between grief style and both prefrontal and amygdala subregion activity was found. Intrusiveness correlated with activation of ventral amygdala and rostral anterior cingulate (rACC); avoidance correlated with deactivation of dorsal amygdala and DLPFC. A double dissociation between regulatory region and task-dependent functional connectivity (FC) was found. High DLPFC-amygdala FC correlated with reduced attentional bias, while low rACC-amygdala FC predicted sadness intensity. CONCLUSIONS: Results are consistent with a model in which activity in and functional connectivity between the amygdala and prefrontal regulatory regions indexes differences in mourners' regulation of attention and sadness during pangs of grief, and may be used to distinguish between clinically relevant differences in grief style.

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale.

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is critical, however, for both basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brainwide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brainwide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open-access data repository; compatibility with existing resources; and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.

Plasma polyunsaturated fatty acids and regional cerebral glucose metabolism in major depression.

Deficiencies in polyunsaturated essential fatty acids (PUFA) are implicated in mood disorders, although mechanisms of action and regional specificity in the brain are unknown. We hypothesized that plasma phospholipid PUFA levels are correlated with regionally specific relative cerebral metabolic rates of glucose (rCMRglu). Medication-free depressed subjects (N=29) were studied using [(18)F]-fluoro-2-deoxyglucose positron emission tomography. Docosahexaenoic acid (22:6n-3), arachidonic acid (20:4n-6), and eicosapentaenoic acid (20:5n-3) were assessed as a percentage of total phospholipid PUFA (DHA%, AA%, and EPA%, respectively). DHA% and AA% correlated positively with rCMRglu in temporoparietal cortex. In addition, DHA% correlated negatively with rCMRglu in prefrontal cortex and anterior cingulate. No correlations were seen with EPA%. Thus, under conditions of low plasma DHA, rCMRglu was higher in temporoparietal cortex and lower in anterior cingulate/prefrontal cortex. Opposing effects of DHA on these regions is a hypothesis that could be addressed in future prospective studies with n-3 supplementation. This pilot study is the first to demonstrate fatty acid and regionally specific correlations in the brain between plasma PUFA and rCMRglu in humans.