A Novel Measure of Real-Time Perseverative Thought.

Perseverative thinking (PT), or repetitive negative thinking, has historically been measured using global self-report scales. New methods of assessment are needed to advance understanding of this inherently temporal process. We developed an intensive longitudinal method for assessing PT. A mixed sample of 77 individuals ranging widely in trait PT, including persons with PT-related disorders (generalized anxiety disorder, major depression) and persons without psychopathology, used a joystick to provide continuous ratings of thought valence and intensity following exposure to scenarios of differing valence. Joystick responses were robustly predicted by trait PT, clinical status, and stimulus valence. Higher trait perseverators exhibited more extreme joystick values overall, greater stability in values following threatening and ambiguous stimuli, weaker stability in values following positive stimuli, and greater inertia in values following ambiguous stimuli. The joystick method is a promising measure with the potential to shed new light on the dynamics and precipitants of perseverative thinking.

A memory-based theory of emotional disorders.

Learning and memory play a central role in emotional disorders, particularly in depression and posttraumatic stress disorder. We present a new, transdiagnostic theory of how memory and mood interact in emotional disorders. Drawing upon retrieved-context models of episodic memory, we propose that memories form associations with the contexts in which they are encoded, including emotional valence and arousal. Later, encountering contextual cues retrieves their associated memories, which in turn reactivate the context that was present during encoding. We first show how our retrieved-context model accounts for findings regarding the organization of emotional memories in list-learning experiments. We then show how this model predicts clinical phenomena, including persistent negative mood after chronic stressors, intrusive memories of painful events, and the efficacy of cognitive-behavioral therapies. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Doxebo (doxorubicin-free Doxil-like liposomes) is safe to use as a pre-treatment to prevent infusion reactions to PEGylated nanodrugs.

The increasing use in the last decade of PEGylated nanodrugs such as Doxil® has seen a rise in the number of associated occurrences of hypersensitivity reactions (HSRs). These reactions (also called infusion reactions or IR), can range from harmless symptoms to life-threatening reactions. Current means to prevent IR include the prophylactic use of antihistamines and steroids, but they cannot ensure total prevention. We previously showed that an intravenous injection of doxorubicin-free Doxil-like PEGylated nano-liposomes (Doxebo) prior to Doxil treatment suppresses Doxil-induced complement activation-related pseudoallergy (CARPA) in pigs, a model of human hypersensitivity reactions to Doxil. However, in order to use Doxebo to prevent Doxil-induced IR, we have to prove its safety and that it does not affect Doxil's performance. Here we show that Doxebo itself does not have toxic effects on the host or tumor, and it does not interfere with Doxil's antitumor activity in mice. Blood, microscopic and macroscopic organ evaluation of rats after repeated administration confirm the lack of intrinsic adverse effect of Doxebo. Likewise, the repeated injection of Doxebo before Doxil did not impact Doxil's pharmacokinetics in plasma and therefore does not cause accelerated blood clearance (ABC). Taken together with our previous publications, these data suggest that the injection of Doxebo prior to Doxil administration can help protect against Doxil-induced IR without adversely affecting treatment efficacy and safety.

Relations of anxiety sensitivity dimensions to nonsuicidal self-injury frequency and versatility among patients with substance use disorders.

OBJECTIVE: Despite the theoretical and empirical relevance of anxiety sensitivity (AS) to nonsuicidal self-injury (NSSI), few studies have investigated this association. This study examined the incremental validity of AS dimensions in NSSI frequency and versatility, above and beyond emotion dysregulation and relevant covariates (racial/ethnic background, negative affectivity). AS dimensions were expected to account for additional unique variance in NSSI outcomes. METHOD: Participants included 204 patients (50.5% female) with substance use disorders in residential treatment. RESULTS: In this sample, 37.2% reported a history of NSSI. The hierarchical regression models revealed a unique positive association between AS social concerns and NSSI outcomes when adjusting for model variables. In contrast, AS physical concerns were uniquely negatively associated with NSSI outcomes. CONCLUSION: Findings provide support for AS social concerns as a vulnerability for engagement in NSSI behaviors and highlight this particular AS dimension as a potential treatment target for NSSI prevention and intervention programs.

"Practice What You Teach" Public Health Nurses Promoting Healthy Lifestyles (PHeeL-PHiNe): Program Evaluation.

Healthy lifestyle programs are essential for meeting the challenge of noncommunicable diseases. The Public Health Nurses Promoting Healthy Lifestyles (PHeeL-PHiNe) program engaged nurses from family health clinics in Jerusalem District and included physical activity, healthy nutrition, and motivational skills. Questionnaires were completed at baseline, postintervention, and at 18 months. Results showed a marked effect on health practices. The proportion of nurses consuming a balanced diet and the use of food labels significantly increased and were maintained over time. Short-term improvements in physical activity were also observed. Nurses who practiced a healthy lifestyle were significantly more likely to provide guidance and counseling to families on healthy behaviors.

PTSD Symptom Severity and Emotion Regulation Strategy Use During Trauma Cue Exposure Among Patients With Substance Use Disorders: Associations With Negative Affect, Craving, and Cortisol Reactivity.

The co-occurrence of posttraumatic stress disorder (PTSD) pathology with a substance use disorder (SUD) is associated with emotion regulation deficits. However, studies in this area generally rely on trait-based emotion regulation measures, and there is limited information on the relation of PTSD pathology to the use of specific emotion regulation strategies in response to trauma-related distress among SUD patients or the consequences of these strategies for trauma cue reactivity. This study examined the relation of PTSD symptom severity to the use of specific emotion regulation strategies during trauma cue exposure among trauma-exposed SUD patients, as well as the indirect relations of PTSD symptom severity to changes in negative affect, cravings, and cortisol levels pre- to posttrauma cue exposure through different emotion regulation strategies. Participants were 133 trauma-exposed SUD patients. Participants listened to a personalized trauma script and reported on emotion regulation strategies used during the script. Data on negative affect, cravings, and cortisol were collected pre- and postscript. PTSD symptom severity related positively to the use of more adaptive (e.g., distraction) and maladaptive (e.g., suppression) regulation strategies. Moreover, evidence for the indirect effects of PTSD symptom severity on negative affect and cortisol reactivity through both adaptive and maladaptive emotion regulation strategies was found. Implications of findings are discussed.

Insights into composition/structure/function relationships of Doxil® gained from "high-sensitivity" differential scanning calorimetry.

Thermotropic behavior of Doxil® and its generic, Lipodox®, was characterized using "high-sensitivity" differential scanning calorimetry (DSC). This is the first report that two distinct endotherms were observed in Doxil and Lipodox upon heating. The first (Tm at 51±2°C) is broad and of low enthalpy, representing the membrane lipid phase transition, which occurs despite having high (38mole%) cholesterol. The second (Tm at ∼70°C) is narrow, representing melting of the intraliposomal doxorubicin-sulfate nanocrystals. The thermograms of Doxil and Lipodox are practically identical. The membrane phase transition is similar to that of drug-free nanoliposomes of the same size and lipid composition as Doxil, suggesting lack of significant drug-membrane interaction. The melting endotherm of the intraliposomal nanocrystals is 2.0-2.5-fold narrower than that of the crystals formed in a solution of 250mM ammonium sulfate and >60mg/ml doxorubicin. This suggests that nanovolume of liposomes improves doxorubicin-sulfate crystallinity. Moreover, both phase transitions are reversible in cycled DSC scanning (15-90-15°C). This indicates an unexpected "non-leaky" phospholipid phase transition and excellent physical and chemical stabilities of Doxil after short exposure to high temperature. Reducing mole% of cholesterol results in a "leaky" membrane phase transition of higher enthalpy. Namely, high mole% cholesterol is essential for the resistance to drug leakage during phase transition. Pegylated liposomal doxorubicin in which HSPC was replaced by DPPC shows the same non-leaky phase transition but at a lower temperature, indicating this type of phase transition is not unique to Doxil. The presence of DSPE-PEG2k increases the cooperativity of the phase transition. High-sensitivity DSC helps illuminate composition/structure/function relationships of Doxil, and is useful for the equivalence/similarity studies.

Public Health Nurses Promoting Healthy Lifestyles (PHeeL-PHiNe): methodology and feasibility.

Mother and Child Health Clinics have provided preventive health services in Israel for nearly a century. The Public Health Nurses Promote Healthy Lifestyles Program was developed to assist families in adopting healthy behaviors. The program ran in the Jerusalem District from 2009 to 2011. After piloting, 175 public health nurses received training and interventions took place in 45 clinics serving parents of 167 213 infant and toddlers per year. When evaluation is completed, our hope is to incorporate the program into Mother and Child Health Clinic services regularly provided nationwide, thereby becoming an integral part of the initiative, Healthy Israel 2020.

Chemical and physical characterization of remotely loaded bupivacaine liposomes: comparison between large multivesicular vesicles and small unilamellar vesicles.

Large multivesicular liposomes (LMVV) remotely loaded with bupivacaine (Bupisome) were previously demonstrated to be a stable, long-acting local anesthetic. We demonstrate that this is not the case for small unilamellar vesicles (SUV) of the same lipid composition also remotely loaded with bupivacaine. We show that the trapped volume in LMVV is 21-fold higher and the drug-to-lipid mole ratio is 10-fold higher than in SUV. Cryo-transmission electron micrographs and differential interference contrast microscopy show that there are no bupivacaine crystals inside LMVV and SUV. The thermotropic characterization studied by DSC demonstrates that the drug interacts with the liposome membrane, which, together with the above results on the drug-to-lipid ratio, explains the small in vitro drug release from the SUV and large (but <100%) release from the LMVV after 24 h at 37 °C. The absence of analgesia in mice treated locally with SUV loaded with bupivacaine compared with prolonged analgesia from LMVV correlates well with the in vitro results. The study indicates that in LMVV and SUV, part of the bupivacaine is associated with the liposomal membrane, which is poorly available for analgesia. The membrane fraction is very high in SUV and much smaller in LMVV. The much larger trapped volume of the LMVV explains the higher drug availability and better analgesia of LMVV.

Factors affecting DNA binding and stability of association to cationic liposomes.

Lipoplexes are complexes formed between cationic liposomes (L(+)) and polyanionic nucleic acids (P(-)). They are commonly used in vitro and in vivo as a nucleic acid delivery system. Our study aims are to investigate how DOTAP-based cationic liposomes, which vary in their helper lipid (cholesterol or DOPE) and in media of different ionic strengths affect the degree, mode of association and degree of condensation of pDNA. This was determined by ultracentrifugation and gel electrophoresis, methods based on different physical principles. In addition, the degree of pDNA condensation was also determined using the ethidium bromide (EtBr) intercalation assay. The results suggest that for cationic lipid compositions (DOTAP/DOPE and DOTAP/cholesterol), 1.5 M NaCl, but not 0.15 M NaCl, both prevent lipoplex formation and/or induce partial dissociation between lipid and DNA of preformed lipoplexes. The higher the salt concentration the greater is the similarity of DNA condensation (monitored by EtBr intercalation) between lipoplex DNA and free DNA. As determined by ultracentrifugation and agarose gel electrophoresis, 30-90% of the DNA is uncondensed. SDS below its critical micellar concentration (CMC) induced "de-condensation" of DNA without its physical release (assessed by ultracentrifugation) for both DOTAP/DOPE and DOTAP/cholesterol lipoplexes. As was assessed by agarose gel electrophoresis SDS induced release of 50-60% of DNA from the DOTAP/cholesterol lipoplex but not from the DOTAP/DOPE lipoplex. This study shows that there are conditions under which DNA is still physically associated with the cationic lipids but undergoes unwinding to become less condensed. We also proved that the helper lipid affects level and strength of the L(+) and DNA(-) electrostatic association; these interactions are weaker for DOTAP/cholesterol than for DOTAP/DOPE, despite the fact that the positive charge and surface pH of DOTAP/cholesterol and DOTAP/DOPE are similar.

Prolonged analgesia from Bupisome and Bupigel formulations: from design and fabrication to improved stability.

There is a compelling need for an ultralong-acting local anesthetic. Previously, we demonstrated in mice and humans that encapsulation of bupivacaine into large multivesicular liposomes (Bupisome) prolongs drug residence time and analgesic duration at the injection site while reducing peak plasma concentration. However, we observed considerable leakage of bupivacaine from the liposomes during storage at 4 °C. This deficiency was overcome by modifying the lipid composition of Bupisome and by entrapping them in a Ca-alginate cross-linked hydrogel (Bupigel), forming stable, soft, injectable (3-5 mm) beads. Bupisome are not released from Bupigel, but their encapsulated bupivacaine is released into the bulk solution. Adding 0.5% to 2.0% free bupivacaine to the Bupigel prevented net loss of bupivacaine from the Bupisome after storage at 4 °C for 2 years, and at 37 °C enough bupivacaine was released to prolong analgesia. For injection subcutaneously into mice, the beads are drawn into a syringe, leaving the small amount of free bupivacaine behind. Both Bupisome and Bupigel formulations significantly prolonged analgesia in mice compared to standard bupivacaine, with Bupigel performing better than Bupisome.

Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome.

Hypersensitivity reactions to liposomal drugs, often observed with Doxil and AmBisome, can arise from activation of the complement (C) system by phospholipid bilayers. To understand the mechanism of this adverse immune reaction called C activation-related pseudoallergy (CARPA), we analyzed the relationship among liposome features, C activation in human serum in vitro, and liposome-induced cardiovascular distress in pigs, a model for human CARPA. Among the structural variables (surface charge, presence of saturated, unsaturated, and PEGylated phospholipids, and cisplatin vs. doxorubicin inside liposomes), high negative surface charge and the presence of doxorubicin were significant contributors to reactogenicity both in vitro and in vivo. Morphological analysis suggested that the effect of doxorubicin might be indirect, via distorting the sphericity of liposomes and, if leaked, causing aggregation. The parallelism among C activation, cardiopulmonary reactions in pigs, and high rate of hypersensitivity reactions to Doxil and AmBisome in humans strengthens the utility of the applied tests in predicting the risk of CARPA. FROM THE CLINICAL EDITOR: The authors studied complement activation-related pseudoallergy (CARPA) in a porcine model and demonstrate that high negative surface charge and drug effects leading to distortion of liposome sphericity might be the most critical factors leading to CARPA. The applied tests might be used to predict CARPA in humans.

High-dose bupivacaine remotely loaded into multivesicular liposomes demonstrates slow drug release without systemic toxic plasma concentrations after subcutaneous administration in humans.

BACKGROUND: Depot formulations prolong the analgesic effect of local anesthetics and reduce peak plasma drug concentration. This allows for safer administration of larger doses of local anesthetics, which further prolongs the duration of analgesic effect. We previously reported the development of large multivesicular vesicles (LMVVs) remotely loaded with bupivacaine (LMVV liposomal bupivacaine) and demonstrated a >5-fold prolongation of analgesic effect in animals and humans. In this study, we present pharmacokinetic data of LMVV liposomal bupivacaine in humans. METHODS: Healthy volunteers received subcutaneous injections of 20 mL plain 0.5% bupivacaine and, 1 week later, 20 mL of 2% LMVV liposomal bupivacaine in a prospective, open-label, crossover, controlled study. RESULTS: Eight subjects were studied. No subjective side effects of local anesthetics were observed. The maximal plasma concentration and the time to achieve maximal plasma concentration were assessed by modeling plasma concentration-time profiles. Maximal plasma concentration was not significantly different between groups (0.87 +/- 0.45 microg/mL and 0.83 +/- 0.34 microg/mL for plain and liposomal bupivacaine, respectively; P = not significant, 0.83). These values are well below the putative toxic plasma concentration of 2 to 4 microg/mL. Time to achieve maximal plasma concentration was 7-fold greater for the liposomal preparation (262 +/- 149 minutes vs 37.5 +/- 16 minutes, P < 0.01). CONCLUSIONS: Peak plasma bupivacaine concentrations were not different in the 2 groups, despite a 4-fold increase in total bupivacaine dose administered in the novel liposomal preparation. The delayed elimination and prolonged redistribution of liposomal bupivacaine to plasma is compatible with the depot-related slow-release effect leading to the prolonged pharmacodynamic effect previously reported.

[The in vivo pediculicidal efficac of Prioderm Cream Shampoo formulation].

BACKGROUND: Head louse infestations are prevalent worldwide. Over the past 20-25 years, 15-20% of all children in Israel between 4 and 13 years of age have been infested with head lice. This is mainly due to the existence of ineffective pediculicides on the market. OBJECTIVE: To examine the pediculicidal efficacy and safety of Prioderm Cream Shampoo in an open clinical study. METHODS: The active ingredient of Prioderm Cream Shampoo is malathion (1%) and it was applied to the hair of infested children three times for 10 minutes at 5-day intervals. RESULTS: Of 419 children examined, aged 6-14 years, from four schools in Jerusalem, 109 (26.0%) were infested with lice and eggs, while 110 (26.3%) were infested only with nits. All 109 louse-infested children were included in the study while 86 (78.8%) complied with the instructions for use. Treatment was successful in 79 children (91.8%), while failure was observed in 3 children after the first treatment and in 4 children after the third treatment. Although 21.5% of the children disliked the odor of the product, there were no significant side effects related to this formulation. CONCLUSIONS: The product was very effective in controlling louse infestations under clinical conditions and caused no serious side effects.

Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan.

We have conducted a pharmacological challenge experiment in 10 medication-free obsessive compulsive (OC) disorder (OCD) patients. We used a placebo-controlled paradigm for m-chlorophenylpiperazine (mCPP) and sumatriptan challenges. Endocrine, physiological and behavioral variables were assessed at baseline and over a 3-hour period after the challenge. Both cortisol and prolactin were significantly elevated in OCD patients following mCPP administration. Both mCPP and sumatriptan caused significant OC symptom exacerbation with the response to sumatriptan being more robust. We conclude that the 5-HT(1Dbeta) receptor may play a role in the pathophysiology of OCD.