Solubilization of flurbiprofen into aptamer-modified PEG–PLA micelles for targeted delivery to brain-derived endothelial cells in vitro

Abstract

Novel aptamer-functionalized polyethylene glycol–polylactic acid (PEG–PLA) (APP) micelles were developed with the objective to target the transferrin receptor on brain endothelial cells. Flurbiprofen, a potential drug for therapeutic management of Alzheimer’s disease (AD), was loaded into the APP micelles using the co-solvent evaporation method. Results indicated that 9.03% (w/w) of flurbiprofen was entrapped in APP with good retention capacity in vitro. Targeting potential of APPs was investigated using the transferring receptor-expressing murine brain endothelial bEND5 cell line. APPs significantly enhanced surface association of micelles to bEND5 cells as quantified by fluorescence spectroscopy. Most importantly, APPs significantly enhanced intracellular flurbiprofen delivery when compared to unmodified micelles. These results suggest that APP micelles may offer an effective strategy to deliver therapeutically effective flurbiprofen concentrations into the brain for AD patients.     

The influence of lower cervical joint pain on range of motion and interpretation of the flexion–rotation test

Abstract

Objective: The purpose of this study was to investigate the impact of lower cervical facet joint pain (CFP) on the flexion–rotation test (FRT).

Methods: A single blind, comparative group design was used to investigate whether lower CFP influences FRT mobility and examiner interpretation. Twenty-four subjects were evaluated, 12 with cervicogenic headache (age 26–63 years) and 12 with lower CFP (age 44–62 years), confirmed by therapeutic cervical facet joint intervention. A single blinded examiner conducted the FRT, reporting the test state (positive or negative) before measuring range of motion using a goniometer. Subjects with lower CFP were evaluated by the FRT prior to therapeutic intervention and were excluded from analysis if they did not gain complete symptomatic relief following the procedure. Only subjects with immediate complete relief were included.

Results: The average range of unilateral rotation to the limited side during the FRT was 26 and 37.5° for the cervicogenic headache and lower CFP groups respectively. The difference between groups was significant (P<0.01). Sensitivity and specificity for cervicogenic headache diagnosis was 75 and 92% respectively. A receiver operating curve revealed that an experienced examiner using the FRT was able to make the correct diagnosis 90% of the time (P<0.01), with a positive cut-off value of 32°.

Discussion: These findings provide further evidence for the clinical utility of the FRT in cervical examination and cervicogenic headache diagnosis.     

Diphenhydramine dose–response: a novel approach to determine triage thresholds

Context. It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose–response studies have had conflicting results. Objective. We sought to evaluate DPH dose–response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. Methods. We retrospectively analyzed APAP/DPH-only exposures in patients 2–80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. Results. There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at ≥ 7.5 mg/kg DPH and ≥1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log₁₀ mg/kg dose (p < 0.05). By this model, for every 1 log₁₀ unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1-specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). Conclusion. Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH.     

Intentional ingestion of cyanoacrylate

Abstract

Background. Diphenidine (1-(1,2-diphenylethyl)piperidine) and its 2-methoxylated derivative methoxphenidine (MXP, 2-MeO-diphenidine) are substances with dissociative effects that were recently introduced for “recreational” purpose through the online-based sale of new psychoactive substances (NPS). A number of analytically confirmed non-fatal intoxications associated with diphenidine or MXP have occurred in Sweden and were included in the STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS and requiring intensive treatment in an emergency room and hospitalization in Sweden. Patients and methods. Blood and urine samples were collected from intoxicated patients presenting at emergency departments all over the country. NPS analysis was performed by multi-component liquid chromatography–mass spectrometry methods. Data on clinical features were collected during telephone consultations with the Poisons Information Centre and retrieved from medical records. Information was also obtained from online drug discussion forums. Case series. Over a 12-month period from January to December 2014, 750 cases of suspected NPS intoxication originating from emergency departments were enrolled in the STRIDA project of which 14 (1.9%) tested positive for diphenidine and 3 (0.4%) tested positive for MXP. Co-exposure to several other NPS (e.g., 5-/6-(2-aminopropyl)benzofuran, 2-4-bromomethcathinone, butylone, 3,4-dichloromethylphenidate, 5-methoxy-N-isopropyltryptamine, methiopropamine, and α-pyrrolidinopentiothiophenone), also including other dissociative substances (3-/4-methoxyphencyclidine), and classical drugs of abuse (e.g., cannabis and ethanol) was documented in 87% of these cases. The 17 patients were aged 20–48 (median: 32) years, and 13 (76%) were men. They commonly presented with hypertension (76%), tachycardia (47%), anxiety (65%), and altered mental status (65%) including confusion, disorientation, dissociation, and/or hallucinations. Eight patients (47%) displayed severe intoxication (Poisoning Severity Score 3). The diphenidine- or MXP-positive patients required hospitalization for 1–3 (median: 2) days. In addition to standard supportive therapy, half of the cases were treated with benzodiazepines and/or propofol. Conclusion. The adverse effects noted in analytically confirmed cases of NPS intoxication involving diphenidine or MXP were similar to those reported for other dissociative substances such as ketamine and methoxetamine. However, the high proportion of polysubstance use might have played a role in the intoxication and clinical features in some cases.     

Test–Retest Reliability of the Preroad DriveABLE Competence Screen

ABSTRACT

Objective: To determine the test–retest reliability of a computerized preroad screen of prerequisite skills required for safe driving. Subjects & Methods: Driveable Screen administered to 39 individuals referred for driving evaluation due to cognitive decline or stroke. The Screen provides three recommendations—driving cessation, indeterminate, no evidence of reduced competence. Predicted probability of failing the road test is also generated. Results: Reliability according to the recommendation was substantial for the entire group (K = 0.654; CI = 0.459–0.848) and subgroup with stroke (K = 0.742; CI = 0.540–0.944). The numbers of participants with cognitive decline was too small to allow subgroup analyses. Of the nine participants with test–retest disagreement in recommendation, Test 2 was always better (McNemar's X² = 9.00, p = 0.01). Excellent reliability was found on probability of failing the Road Test (Intraclass Correlation Coefficient = 0.908; CI = 0.832–0.950). The test–retest reliability of the subtests ranged from fair to substantial. Conclusions: The Screen demonstrates sufficient test–retest reliability to encourage its use. However, the finding of significantly better scores on Test 2 for a portion of participants raises concern regarding its validity with repeat testing.     

Home Modification Assessments: Clinical Utility and Treatment Context

ABSTRACT

Occupational therapists need effective assessments to help evaluate the physical, social, and psychological aspects of the home environment when planning home modification interventions. Assessment tools need to have a client-centered focus, emphasis on occupation or occupational performance, comprehensive evaluation of the environment, strong psychometric properties, and clinical utility. When selecting an assessment tool, occupational therapists also need to take into an account the type of home modification interventions that they will be able to complete in a given treatment context. Because of the unique needs of each home modification intervention, there is no one-fits-all assessment; the best tool will depend on the context of care. This paper details six assessment tools for use in three different contexts of care.     

Cancer–germline antigen vaccines and epigenetic enhancers: future strategies for cancer treatment

Importance of the field: Immunotherapy holds great potential for disseminated cancer, and cancer–germline (CG) antigens are among the most promising tumor targets. They are widely expressed in different cancer types and are essentially tumor-specific, since their expression in normal tissues is largely restricted to immune-privileged sites. Although the therapeutic potential of these antigens may be compromised by their highly heterogeneous expression in many tumors and low frequency in some cancers, recent developments suggest that tumor-cell-selective enhancement of CG antigen gene expression can be achieved using epigenetic modifiers.

Areas covered in this review: We provide an overview of the potential of CG antigens as targets for cancer immunotherapy, including advantages and disadvantages. We also discuss the current state of development of CG antigen vaccines, and the potential synergistic effect of combining CG antigen immunotherapeutic strategies with epigenetic modifiers.

What the reader will gain: The reader will gain an overview of the past, present and future role of CG antigens in cancer immunotherapy.

Take home message: Chemoimmunotherapy using epigenetic drugs and CG antigen vaccines may be a useful approach for treating cancer.     

Current intravesical therapy for non-muscle invasive bladder cancer

Introduction: Transurethral resection of the bladder tumour (TURBT) is still the standard initial treatment for non-muscle invasive bladder cancer (NMIBC). However, even after a radical resection, recurrence (30 – 80%) and progression (1 – 45%) are commonly seen. Intravesical therapy provides direct contact of the agent with the bladder mucosa and clearly has improved the outcome, especially in high-risk disease.

Areas covered: The role of a good initial TURBT is emphasized. Risk assessment tools are discussed. Different intravesical therapies are enumerated according to the latest literature, with the emphasis on Bacillus Calmette–Guérin (BCG), including the discussion on the optimal dose and schedule. New developments are mentioned.

Expert opinion: A radical TURBT is essential for good prognosis. For optimal visualisation of tumours, fluorescence techniques should be used with low threshold, especially in case of suspicion of carcinoma in situ (CIS). Increased completeness of the resection will lead to less persisting disease and less need for adjuvant treatment. A re-TURBT should be done when in doubt of radical resection (judged by the pathologist or the surgeon). Risk assessment is essential, but the available tools are outdated. A single post-operative instillation (SPI) with chemotherapy is only indicated in low-risk disease. BCG is the treatment of choice for high-grade disease. BCG should be given as maintenance. Awareness of deterioration of the prognosis after progression is of great importance. In BCG failures, cystectomy should be strongly advised. Chemotherapy in combination with hyperthermia seems to be a new promising treatment.     

Students' and lecturers' perceptions of support in a UK pre-registration midwifery programme

This paper reports on a study that explored the perceptions of students and lecturers regarding support within a pre-registration midwifery programme in one Higher Education Institution in England. A mixed method design was used: questionnaires were completed by first year and third year students and lecturers, complemented by focus groups with each of the three sets of participants. The findings showed that there are multi-focal challenges for student midwives in undertaking their programme of study. The main theme that emerged was of the difficulties involved in maintaining an appropriate work–life balance, especially within what was seen as a relatively inflexible programme structure. The value of peer support was also highlighted as a key factor in helping the students succeed in their studies. There were a number of implications for midwifery educators to consider in optimising support for students. These include ensuring that students have realistic expectations at the outset of their studies, formalising peer support mechanisms and reviewing programmes to provide more flexibility to better underpin the maintenance of an appropriate work–life balance. Further study is warranted to explore perceptions of support in practice and to identify the factors that help students to persevere in their studies.     

Risk stratification in surgically repaired tetralogy of Fallot

Tetralogy of Fallot is the most common form of congenital heart disease in implantable cardioverter–defibrillator (ICD) recipients. Indeed, sudden death of presumed arrhythmic etiology is the most frequent mode of demise in patients with surgically repaired tetralogy of Fallot, often in early-to-mid adulthood. Nevertheless, the overall annual incidence of sudden death is actually low. Therein lies the major challenge of risk stratification. This review highlights some of the complexities involved in risk stratifying patients with tetralogy of Fallot, underscoring the importance of avoiding oversimplification by means of a rigid algorithm that dictates therapy. To complement sound clinical judgment, a quantitative probabilistic approach is presented, which considers the body of literature from primary prevention ICD trials, risk factors identified by observational studies, the value of programmed ventricular stimulation and insights gleaned from studying ICD recipients with tetralogy of Fallot.