Mean kinetic temperature evaluations through simulated temperature excursions and risk assessment with oral dosage usage for health programs.

BACKGROUND: Temperature excursions occur during the transport and storage of pharmaceuticals, and often result in considerable losses for public health programs operating in countries with limited resources. After a temperature excursion has been identified, often products are discarded without any additional risk assessments. Consulting the manufacturer is the preferred approach but can be challenging depending on the responsiveness of the manufacturer. However, decisions are often required quickly depending on program needs and available stock in country. METHODS: To provide further guidance, simulations have been conducted based on mean kinetic temperature evaluations using accepted default kinetic parameters to assess loss of shelf-life for scenarios involving various levels of temperature excursions on a model pharmaceutical at different recommended storage conditions, shelf-life, and long-term storage conditions. RESULTS: Although an immediate loss to shelf-life occurred with excursions when the product was stored at the maximum allowed temperature, more extended excursion could be withstood before loss of shelf-life was detected when long-term storage was maintained at temperatures below the maximum storage condition for the product. With the assumption that a shelf-life loss of 2 weeks was negligible when managing program stock, a risk assessment was conducted to outline the various times that excursions at different temperatures could be considered low risk to the program. CONCLUSIONS: Depending on the level of the temperature excursion and the guidance provided by the manufacturer, public health programs will have further information with this assessment to guide decisions that impact safety to the end user and resource management due to temperature excursions that can occur.

Understanding the link between childhood trauma and schizophrenia: A systematic review of neuroimaging studies.

Increasing evidence suggests that childhood trauma (CT) is a major risk factor for schizophrenia but the underpinning mechanisms of their association remain unclear. Our aim is to review the literature on the association between CT and brain imaging measurements in adult schizophrenia subjects. We conducted a systematic review of the existing neuroimaging literature on CT and schizophrenia. We reviewed studies considering adult subjects with schizophrenia, schizoaffective disorder or first episode schizophrenia. A total of 15 studies were included. The most replicated result was the association in schizophrenia patients between CT and decreased total cerebral grey matter, particularly in the prefrontal cortex. In addition, studies suggest a different sensitivity to early stressors between schizophrenia subjects, their sibling and healthy unrelated subjects. In schizophrenia, CT is associated with alterations of white matter integrity in the inferior and superior longitudinal fasciculus, the inferior fronto-occipital fasciculus and the forceps major. Functional connectivity studies suggest an association between CT and a network including the amygdala, the anterior cingulate cortex, the precuneus/posterior cingulate cortex region and the temporo-parietal junction.

Poor quality male latex condoms found in Dominican Republic: Quality assurance evaluation and public health impact.

Male condoms are important to prevent transmission of HIV (and other STIs) and unwanted pregnancies. Research was conducted to evaluate the quality of male condoms available in the Dominican Republic market based on preliminary concerns of suspect product. Based on international testing standards (ISO 4074 and ASTM D 3492-08), condoms were sampled across ten prominent brands within the market and evaluated for airburst pressure / volume, freedom from holes, visual defects, package seal integrity, packaging and marking, lubricant quantity, and dimensions. Five of the brands were found to have extensive quality problems, where holes were found in 5.7% to 17.5% of the condoms (depending on the brand). Between 5.1% and 30.5% of these condoms failed to meet the requirements for airburst properties, and violations in regulatory labeling where observed. Three additional brands were compliant for the other tests, but were found to have the same challenges with labeling violations as the previous five brands. Two brands were found to be fully compliant with all aspects of the evaluation. The level of defects observed in these samples would greatly increase the risk of HIV transmission (and other STIs) and unwanted pregnancies. When projected on the annual market of male condoms sold in the Dominican Republic (~26 million), potentially over 1 million condoms could be estimated to adversely impact the health risk of the end-user. These results prompted action by the Dominican Republic regulatory authorities to investigate and remove poor quality product from the market. This research study emphasizes the need for continued vigilance towards increased regulatory and market surveillance efforts to better protect public health interests.

Fear extinction learning improvement in PTSD after EMDR therapy: an fMRI study.

Objective: Neurobiological models of Posttraumatic Stress Disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Eye Movement Desensitization and Reprocessing (EMDR) is one of the most efficient psychotherapies to treat PTSD. We aimed at exploring the brain mechanisms of the fear circuitry involved in PTSD patients' symptom remission after EMDR therapy. Method: Thirty-six PTSD participants were randomly assigned to either EMDR group receiving EMDR therapy or Wait-List (WL) group receiving supportive therapy. Participants underwent a behavioural fear conditioning and extinction paradigm during functional magnetic resonance (fMRI). In the EMDR group, patients were scanned at baseline, before EMDR and one week after remission. In the WL group, patients were scanned at baseline and within the same time interval as the EMDR group. Results: In the EMDR group after treatment, fear responses in the late extinction were significantly lower than before therapy. In parallel, significant functional activity and connectivity changes were found in the EMDR group versus the WL during the late extinction. These changes involve the fear circuit (amygdalae, left hippocampus), the right inferior frontal gyrus, the right frontal eye field and insula (pFWE < .05). Conclusion: These functional modifications underlie a significant improvement of fear extinction learning in PTSD patients after EMDR therapy.

Objetivo: Los modelos neurobiológicos del TEPT implican deficiencias en el procesamiento del miedo en el mantenimiento del trastorno. EMDR es una de las psicoterapias más eficaces para tratar el TEPT. Nuestro objetivo fue explorar los mecanismos cerebrales de los circuitos de miedo implicados en la remisión de los síntomas de los pacientes con el TEPT después de la terapia EMDR.Método: Treinta y seis participantes con el TEPT fueron asignados aleatoriamente a un grupo EMDR que recibió terapia EMDR o un grupo de Lista de Espera (LE) que recibió terapia de apoyo. Los participantes se sometieron a un paradigma de condicionamiento y extinción del miedo conductual durante la resonancia magnética funcional (fMRI). En el grupo EMDR, los pacientes fueron escaneados al inicio del estudio, antes de EMDR y una semana después de la remisión. En el grupo LE, los pacientes fueron escaneados al inicio y en el mismo intervalo de tiempo que el grupo EMDR.Resultados: En el grupo EMDR después del tratamiento, las respuestas de miedo en la extinción tardía fueron significativamente más bajas que antes de la terapia. En paralelo, se encontraron cambios significativos en la actividad funcional y en la conectividad en el grupo EMDR v/s el grupo LE durante la extinción tardía. Estos cambios involucran el circuito de miedo (amígdala, hipocampo izquierdo), el giro frontal inferior derecho, los campos del ojo frontal derecho y la ínsula (pFWE < .05).Conclusión: Estas modificaciones funcionales subyacen a una mejora significativa del aprendizaje de extinción del miedo en pacientes con el TEPT después de la terapia EMDR.

Taste at first (person) sight: Visual perspective modulates brain activity implicitly associated with viewing unhealthy but not healthy foods.

Every day, people are exposed to images of appetizing foods that can lead to high-calorie intake and contribute to overweight and obesity. Research has documented that manipulating the visual perspective from which eating is viewed helps resist temptation by altering the appraisal of unhealthy foods. However, the neural basis of this effect has not yet been examined using neuroimaging methods. Moreover, it is not known whether the benefits of this strategy can be observed when people, especially overweight, are not explicitly asked to imagine themselves eating. Last, it remains to be investigated if visual perspective could be used to promote healthy foods. The present work manipulated camera angles and tested whether visual perspective modulates activity in brain regions associated with taste and reward processing while participants watch videos featuring a hand grasping (unhealthy or healthy) foods from a plate during functional magnetic resonance imagining (fMRI). The plate was filmed from the perspective of the participant (first-person perspective; 1PP), or from a frontal view as if watching someone else eating (third-person perspective; 3PP). Our findings reveal that merely viewing unhealthy food cues from a 1PP (vs. 3PP) increases activity in brain regions that underlie representations of rewarding (appetitive) experiences (amygdala) and food intake (superior parietal gyrus). Additionally, our results show that ventral striatal activity is positively correlated with body mass index (BMI) during exposure to unhealthy foods from a 1PP (vs. 3PP). These findings suggest that unhealthy foods should be promoted through third-person (video) images to weaken the reward associated with their simulated consumption, especially amongst overweight people. It appears however that, as such, manipulating visual perspective fails to enhance the perception of healthy foods. Their promotion thus requires complementary solutions.

Impaired cortico-limbic functional connectivity in schizophrenia patients during emotion processing.

Functional dysconnection is increasingly recognized as a core pathological feature in schizophrenia. Aberrant interactions between regions of the cortico-limbic circuit may underpin the abnormal emotional processing associated with this illness. We used a functional magnetic resonance imaging (fMRI) paradigm designed to dissociate the various components of the cortico-limbic circuit (i.e. a ventral automatic circuit that is intertwined with a dorsal cognitive circuit), in order to explore bottom-up appraisal as well as top-down control during emotion processing. In schizophrenia patients compared to healthy controls, bottom-up processes were associated with reduced interaction between the amygdala and both the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC). Contrariwise, top-down control processes led to stronger connectivity between the ventral affective and the dorsal cognitive circuits, i.e. heightened interactions between the ventral ACC and the DLPFC as well as between dorsal and ventral ACC. These findings offer a comprehensive view of the cortico-limbic dysfunction in schizophrenia. They confirm previous results of impaired propagation of information between the amygdala and the prefrontal cortex and suggest a defective functional segregation in the dorsal cognitive part of the cortico-limbic circuit.

Modeling a linkage between blood transcriptional expression and activity in brain regions to infer the phenotype of schizophrenia patients.

Hundreds of genetic loci participate to schizophrenia liability. It is also known that impaired cerebral connectivity is directly related to the cognitive and affective disturbances in schizophrenia. How genetic susceptibility and brain neural networks interact to specify a pathological phenotype in schizophrenia remains elusive. Imaging genetics, highlighting brain variations, has proven effective to establish links between vulnerability loci and associated clinical traits. As previous imaging genetics works in schizophrenia have essentially focused on structural DNA variants, these findings could be blurred by epigenetic mechanisms taking place during gene expression. We explored the meaningful links between genetic data from peripheral blood tissues on one hand, and regional brain reactivity to emotion task assayed by blood oxygen level-dependent functional magnetic resonance imaging on the other hand, in schizophrenia patients and matched healthy volunteers. We applied Sparse Generalized Canonical Correlation Analysis to identify joint signals between two blocks of variables: (i) the transcriptional expression of 33 candidate genes, and (ii) the blood oxygen level-dependent activity in 16 region of interest. Results suggested that peripheral transcriptional expression is related to brain imaging variations through a sequential pathway, ending with the schizophrenia phenotype. Generalization of such an approach to larger data sets should thus help in outlining the pathways involved in psychiatric illnesses such as schizophrenia. IMAGING: SEARCHING FOR LINKS TO AID DIAGNOSIS: Researchers explore links between the expression of genes associated with schizophrenia in blood cells and variations in brain activity during emotion processing. El Chérif Ibrahim and Eric Fakra at Aix-Marseille Université, France, and colleagues have developed a method to relate the expression levels of 33 schizophrenia susceptibility genes in blood cells and functional magnetic resonance imaging (fMRI) data obtained as individuals carry out a task that triggers emotional responses. Although they found no significant differences in the expression of genes between the 26 patients with schizophrenia and 26 healthy controls they examined, variations in activity in the superior temporal gyrus were strongly linked to schizophrenia-associated gene expression and presence of disease. Similar analyses of larger data sets will shed further light on the relationship between peripheral molecular changes and disease-related behaviors and ultimately, aid the diagnosis of neuropsychiatric disease.

Grey matter density changes of structures involved in Posttraumatic Stress Disorder (PTSD) after recovery following Eye Movement Desensitization and Reprocessing (EMDR) therapy.

Recovery of stress-induced structural alterations in Posttraumatic Stress Disorder (PTSD) remains largely unexplored. This study aimed to determine whether symptoms improvement is associated with grey matter (GM) density changes of brain structures involved in PTSD. Two groups of PTSD patients were involved in this study. The first group was treated with Eye Movement Desensitization and Reprocessing (EMDR) therapy and recovered from their symptoms (recovery group) (n = 11); Patients were scanned prior to therapy (T1), one week (T2) and five months after the end of therapy (T3). The second group included patients which followed a supportive therapy and remained symptomatic (wait-list group) (n = 7). They were scanned at three time-steps mimicking the same inter-scan intervals. Voxel-based morphometry (VBM) was used to characterize GM density evolution. GM density values showed a significant group-by-time interaction effect between T1 and T3 in prefrontal cortex areas. These interaction effects were driven by a GM density increase in the recovery group with respect to the wait-list group. Symptoms removal goes hand-in-hand with GM density enhancement of structures involved in emotional regulation.

Childhood trauma and emotional processing circuits in schizophrenia: A functional connectivity study.

Childhood trauma strongly impacts emotional responses in schizophrenia. We have explored an association between early trauma and the amygdala functional connectivity using generalized psychophysiological interaction during an emotional task. Twenty-one schizophrenia patients and twenty-five controls were included. In schizophrenia patients, higher levels of sexual abuse and physical neglect during childhood were associated with decreased connectivity between the amygdala and the posterior cingulate/precuneus region. Additionally, patients showed decreased coupling between the amygdala and the posterior cingulate/precuneus region compared to controls. These findings suggest that early trauma could impact later connectivity in specific stress-related circuits affecting self-consciousness and social cognition in schizophrenia.

In vivo release of levonorgestrel from Sino-implant (II) ­ an innovative comparison of explant data.

OBJECTIVES: Measuring the amount of progestin remaining in contraceptive implants used for different lengths of time provides useful information on in vivo release kinetics including change over time. We compared estimated in vivo levonorgestrel (LNG) release rates derived from Sino-implant (II) explants with similar data from removed Jadelle. STUDY DESIGN: We measured LNG remaining in 44 sets of Sino-implant (II) used for up to 7 years and removed in four Chinese clinics. Results were compared with published data for Jadelle explants used for up to 36 months. We estimated and compared monthly and daily LNG release rates for the two products using prediction models for drug release. We also estimated the dissolution profile similarity factor, f2, for LNG release. RESULTS: Both Sino-implant (II) and Jadelle release approximately 30% of total LNG load after 3 years. Results of fitting the data to a biologically plausible modified Higuchi prediction model indicate comparable release through 3 years. An estimated similarity factor of 80.6 (90% confidence interval: 70.8-85.7) indicates similarity in the dissolution profiles of the two implants. CONCLUSIONS: LNG release in vivo measured through explant analysis suggest that Sino-implant (II) and Jadelle may perform similarly through 3 years of use and could remain highly effective beyond this time point. These results align with published data for Jadelle and Sino-implant (II) showing high effectiveness for 5 years. Ongoing clinical studies comparing the products over 5 years present an opportunity to verify this supportive measure of clinical effectiveness. IMPLICATIONS: This innovative approach provides evidence that Sino-implant (II) may perform clinically similarly to Jadelle over 3 years and remain a highly effective contraceptive beyond this time point. Data from explant analyses show promise for investigating the equivalence of elusion profiles of contraceptive implants.

Effect of trait anxiety on prefrontal control mechanisms during emotional conflict.

Converging evidence points to a link between anxiety proneness and altered emotional functioning, including threat-related biases in selective attention and higher susceptibility to emotionally ambiguous stimuli. However, during these complex emotional situations, it remains unclear how trait anxiety affects the engagement of the prefrontal emotional control system and particularly the anterior cingulate cortex (ACC), a core region at the intersection of the limbic and prefrontal systems. Using an emotional conflict task and functional magnetic resonance imaging (fMRI), we investigated in healthy subjects the relations between trait anxiety and both regional activity and functional connectivity (psychophysiological interaction) of the ACC. Higher levels of anxiety were associated with stronger task-related activation in ACC but with reduced functional connectivity between ACC and lateral prefrontal cortex (LPFC). These results support the hypothesis that when one is faced with emotionally incompatible information, anxiety leads to inefficient high-order control, characterized by insufficient ACC-LPFC functional coupling and increases, possibly compensatory, in activation of ACC. Our findings provide a deeper understanding of the pathophysiology of the neural circuitry underlying anxiety and may offer potential treatment markers for anxiety disorders.

Development and implementation of a quality assurance program for a hormonal contraceptive implant.

BACKGROUND: The importance of the distribution of safe, effective and cost-effective pharmaceutical products in resource-constrained countries is the subject of increasing attention. FHI 360 has developed a program aimed at evaluating the quality of a contraceptive implant manufactured in China, while the product is being registered in an increasing number of countries and distributed by international procurement agencies. The program consists of (1) independent product testing; (2) ongoing evaluation of the manufacturing facility through audits and inspections; and (3) post-marketing surveillance. STUDY DESIGN: This article focuses on the laboratory testing of the product. The various test methods were chosen from the following test method compendia, the United States Pharmacopeia (USP), British Pharmacopeia (BP), International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), or lot release tests mandated by Chinese regulatory requirements. Each manufactured lot is independently tested prior to its distribution to countries supported by this program. In addition, a more detailed annual testing program includes evaluation of the active ingredient (levonorgestrel), the final product and the packaging material. RESULTS: Over the first 4 years of this 5-year project, all tested lots met the established quality criteria. CONCLUSIONS: The quality assurance program developed for this contraceptive implant has helped ensure that a safe product was being introduced into developing country family planning programs. This program provides a template for establishing quality assurance programs for other cost-effective pharmaceutical products that have not yet received stringent regulatory approval and are being distributed in resource-poor settings.

A lifetime cancer bioassay of quinacrine administered into the uterine horns of female rats.

This study investigated if quinacrine can induce a tumorigenic response in rats when administered in a manner similar to the intended human use for female non-surgical sterilization. Young sexually mature female rats received two doses of quinacrine (or 1% methylcellulose control) into each uterine horn approximately 21 days apart, and were observed for 23 months after the second dose administration. Dose levels were 0/0, 0/0, 10/10, 70/70, and 70/250-350 mg/kg (first dose/second dose), which represent local doses in the uterus at approximate multiples of 1x, 8x and 40x the human dose (mg quinacrine/g uterine weight) used for female non-surgical sterilization. Rats were observed for viability, clinical signs of toxicity, and changes in body weight and food consumption. At necropsy, selected organs were weighed, macroscopic observations were recorded, and tissues were collected, fixed, processed, and examined for microscopic pathologic findings. Acute quinacrine toxicity was evident during the dosing period but did not affect long-term survival. Non-neoplastic findings were more common in treated animals than controls, providing evidence of the appropriateness of the bioassay. The incidence of uncommon tumors of the reproductive tract was similar to controls at doses of 10/10mg/kg but increased with dose level and was significantly greater than controls at >or=70/70 mg/kg. We conclude that two doses of quinacrine administered approximately 21 days apart into the uterus of young sexually mature rats at a local dose approximately 8 times the human dose used for non-surgical female sterilization increased the lifetime risk of tumor development in the reproductive tract.

A one-year neonatal mouse carcinogenesis study of quinacrine dihydrochloride.

Quinacrine is an acridine derivative under investigation for its use in nonsurgical female sterilization. Safety issues regarding the carcinogenic potential of quinacrine have been raised because it is mutagenic and clastogenic in vitro. The objective of the study was to evaluate the carcinogenic potential of quinacrine dihydrochloride (quinacrine) in neonatal mice treated with single intraperitoneal doses on postpartum days 8 and 15 and observed for 52 weeks. Neonatal Crl: CD-1 mice of each sex were randomly allocated into four treatment groups (0, 10, 50, and 150 mg/kg), dosed twice with quinacrine suspended in carboxymethylcellulose, observed for 52 weeks post dose, and then euthanized, necropsied, and subjected to a full histopathological examination. In male mice, tumor incidence was not significantly increased at any site at any dose level. In female mice, the incidence of benign uterine endometrial stromal polyps was slightly greater at the mid and high dose (> or = 50 mg/kg), as was the incidence of endometrial hyperplasia. The incidence of polyps in these groups was not significantly greater than in controls by pair-wise comparison but was significantly greater (p = .042) by the linear trend test. The authors conclude that quinacrine administered twice to neonatal mice may have enhanced or accelerated the development of endometrial hyperplasia and uterine stromal polyps at higher doses. Because uterine stromal polyps are a commonly observed benign tumor in older mice, the significance of this finding is unclear and will require a weight of evidence evaluation for a conclusion on the carcinogenic potential of quinacrine.