Polymer Dots with Delayed Fluorescence and Tunable Cellular Uptake for Photodynamic Therapy and Time-Gated Imaging.

By combining bioimaging and photodynamic therapy (PDT), it is possible to treat cancer through a theranostic approach with targeted action for minimum invasiveness and side effects. Thermally activated delayed fluorescence (TADF) probes have gained recent interest in theranostics due to their ability to generate singlet oxygen (1O2) while providing delayed emission that can be used in time-gated imaging. However, it is still challenging to design systems that simultaneously show (1) high contrast for imaging, (2) low dark toxicity but high phototoxicity and (3) tunable biological uptake. Here, we circumvent shortcomings of TADF systems by designing block copolymers and their corresponding semiconducting polymer dots (Pdots) that encapsulate a TADF dye in the core and expose an additional boron-dipyrromethene (BODIPY) oxygen sensitizer in the corona. This architecture provides orange-red luminescent particles (ΦPL up to 18 %) that can efficiently promote PDT (1O2 QY=42 %) of HeLa cells with very low photosensitizer loading (IC50 ~0.05-0.13 µg/mL after 30 min). Additionally, we design Pdots with tunable cellular uptake but similar PDT efficiencies using either polyethylene glycol or guanidinium-based coronas. Finally, we demonstrate that these Pdots can be used for time-gated imaging to effectively filter out background fluorescence from biological samples and improve image contrast.

Dibenzodipyridophenazines with Dendritic Electron Donors Exhibiting Deep-Red Emission and Thermally Activated Delayed Fluorescence.

The development of deep-red thermally activated delayed fluorescence (TADF) emitters is important for applications such as organic light-emitting diodes (OLEDs) and biological imaging. Design strategies for red-shifting emission include synthesizing rigid acceptor cores to limit nonradiative decay and employing strong electron-donating groups. In this work, three novel luminescent donor-acceptor compounds based on the dibenzo[a,c]dipyrido[3,2-h:20-30-j]-phenazine-12-yl (BPPZ) acceptor were prepared using dendritic carbazole-based donors 3,3″,6,6″-tetramethoxy-9'H-9,3':6',9″-tercarbazole (TMTC), N3,N3,N6,N6-tetra-p-tolyl-9H-carbazole-3,6-diamine (TTAC), and N3,N3,N6,N6-tetrakis(4-methoxyphenyl)-9H-carbazole-3,6-diamine (TMAC). Here, dimethoxycarbazole, ditolylamine, and bis(4-methoxyphenyl)amine were introduced at the 3,6-positions of carbazole to increase the strength of these donors and induce long-wavelength emission. Substituent effects were investigated with experiments and theoretical calculations. The emission maxima of these materials in toluene were found to be 562, 658, and 680 nm for BPPZ-2TMTC, BPPZ-2TTAC, and BPPZ-2TMAC, respectively, highlighting the exceptional strength of the TMAC donor, which pushes the emission into the deep-red region of the visible spectrum as well as into the biological transparency window (650-1350 nm). Long-lived emission lifetimes were observed in each emitter due to TADF in BPPZ-2TMC and BPPZ-2TTAC, as well as room-temperature phosphorescence in BPPZ-2TMAC. Overall, this work showcases deep-red emissive dendritic donor-acceptor materials which have potential as bioimaging agents with emission in the biological transparency window.

Polymer dots and glassy organic dots using dibenzodipyridophenazine dyes as water-dispersible TADF probes for cellular imaging.

Fluorescence imaging of living cells is key to better understanding cellular morphology and biological processes. Water-dispersible nanoparticles exhibiting thermally activated delayed fluorescence (TADF) have recently emerged as useful probes for time-resolved fluorescence imaging (TRFI), circumventing interference from biological autofluorescence. Many existing approaches, however, require TADF dyes with specific structural features, precluding many high-performance TADF materials from being used in this application. Here, we describe the synthesis of two TADF emitters based on the rigid and strongly electron-withdrawing dibenzo[a,c]dipyrido[3,2-h:2'-3'-j]phenazine-12-yl (BPPZ) motif, and demonstrate two parallel approaches for the encapsulation of these fluorophores to yield water-dispersible nanoparticles suitable for TRFI. First, fluorescent polymer dots (Pdots) were formed by dye encapsulation within cell-penetrating amphiphilic copolymers. Glassy organic nanoparticles (g-Odots) were also prepared, giving nanoparticles with higher photoluminescence quantum yields and improved colour purity. Both approaches yielded nanoparticles suitable for imaging, with reasonable uptake and cytotoxicity on the timescale of standard imaging experiments using human cervical (HeLa) and liver (HepG2) cancer cell lines. This work demonstrates two flexible strategies for preparing water-dispersible TADF nanoparticles for TRFI, both of which should be readily adaptable to nearly any existing hydrophobic TADF dye.

An unusual case of lingual tonsillar hypertrophy.

Lingual tonsillar hypertrophy is an unusual presentation of voice change. If managed incorrectly this group of patients has the potential to deteriorate significantly causing airway obstruction and potentially death.

Alveolar ethmoidal rhabdomyosarcoma in a young adult male.

We report a 22-year-old man who presented with a 3 week history of left-sided headache, orbital pain and epiphora progressing to diplopia. He was being treated by his general practitioner with a ß-blocker and simple analgesia for possible diagnosis of cluster headaches. Initial examination revealed a reduction in visual acuity and poor abduction and upward gaze. Routine blood tests were normal. CT imaging was reported as a left ethmoid sinusitis with extension into a left orbit subperiosteal abscess. No pus was obtained on frontal sinus trephine and a biopsy was taken, which proved to be an alveolar-type rhabdomyosarcoma. The patient has completed a full course of chemoradiotherapy and has responded well to the treatment. His vision is back to normal and an MRI has shown complete regression of tumour.

Kikuchi-Fugimoto disease (Cervical Subacute Necrotising Lymphadenitis): an important benign disease often masquerading as lymphoma.

OBJECTIVES: We describe a rare cause of posterior triangle cervical lymphadenopathy in a third decade female, outline the clinical and histopathological features and discuss excision biopsy as the investigation of choice in this age group, with lymphoma as the diagnosis of exclusion. CASE REPORT: A thirty-four year old female was referred to our Head and Neck clinic with a one-month history of left posterior triangle lymphadenopathy. She reported no other symptoms and haematological investigations were normal. She was "Red Flagged" as a possible lymphoma. Excision biopsy revealed extensive histiocytic necrotising lymphadenitis providing a diagnosis of Kikuchi-Fujimoto disease. CONCLUSIONS: Persistent posterior triangle lymphadenopathy in the 16-40 year old age group warrants "Red Flag" referral to rule out serious pathology such as HIV, metastatic cancer or lymphoma. When the ENT examination and haematological work up is negative, we advocate proceeding straight to excision biopsy as the quickest way to obtain a diagnosis, which sometimes comes up with the unexpected as in this rare case of Kikuchi-Fujimoto disease.

Medical student attitudes toward older people and willingness to consider a career in geriatric medicine.

OBJECTIVES: To evaluate the attitudes of first- and fourth-year medical students toward older people and the relationship between these attitudes and possible career choice. To examine the effects of an intensive geriatric medicine (GM) teaching program on these attitudes and career aspirations. DESIGN: Observational study. SETTING: University of Aberdeen. PARTICIPANTS: Medical students. MEASUREMENTS: In September 2005, first-year students (n=163) at the start of their undergraduate training completed a questionnaire based on the University of California at Los Angeles Geriatrics Attitudes Scale. Students were asked how likely they were to consider a career in GM in the future on a 5-point Likert scale. From the beginning of the academic year 2005/06, fourth-year students completed the same questionnaire before and after an intensive 8-day GM teaching program. RESULTS: First-year medical students had a mean attitude score+/-standard deviation of 3.69+/-0.39. A more-positive attitude increased the likelihood of considering a career in GM (P<.001). Fourth-year students had better attitude scores than first-year students (3.86+/-0.36, P=.002). The GM teaching program did not significantly affect attitude scores but significantly increased the willingness to consider a career in GM by a mean 0.52 points (95% confidence interval=0.35-0.70, P<.001). CONCLUSION: Attitudes toward older people were better in fourth-year than first-year medical students. A more-positive attitude toward older people increased the likelihood of considering a career in GM. An intensive 8-day course in GM had no significant effect on attitudes but increased the likelihood of fourth-year students considering a career in GM.

A multi-centre European study of factors affecting the discharge destination of older people admitted to hospital: analysis of in-hospital data from the ACMEplus project.

OBJECTIVES: to examine the relationship between seven predictor variables (recorded on Day 3 of hospital admission) and discharge destination in non-elective medical patients aged 65+ years. DESIGN: prospective cohort. SETTING: eight centres in six European countries. PREDICTOR VARIABLES: age, gender, living alone, physical function (three categories based on Barthel Index), cognition (Katzman's orientation-memory-concentration test), main body system affected (based on International Classification of Diseases), number of geriatric giants (GGs) involved in the referral (a GG being a problem with falling, mobility, continence or cognition). MAIN OUTCOME MEASURES: discharge destination (by Day 90) in three categories: 'HOMESAME' (return to previous residence), 'INSTIN90' (discharge to alternative residence or still in hospital at 90 days), 'DEADINHO' (death in hospital), RESULTS: in 1,626 patients, discharge destination was HOMESAME in 84.7%, DEADINHO in 8.9% and INSTIN90 in 6.4%. Mean duration of stay was 17.7 days, median 12. Univariate analyses showed a statistically significant relationship between all seven predictor variables and discharge destination. Physical function was the best single predictor with a seven-fold difference in adverse outcome rates between the best and worst categories. On multiple logistic regression, significant predictor variables were as follows. (i) For DEADINHO: physical function, cognition, gender; (ii) for INSTIN90: physical function, living alone, GGs, age, gender. Multiple linear regression identified physical function, GGs and living alone as predictors of loge length of stay. CONCLUSION: case-mix systems to compare risk-adjusted hospital outcome in older medical patients need to incorporate information about physical function, cognition and presenting problems in addition to diagnosis.

Inhibitors of phosphopantetheine adenylyltransferase.

Phosphopantetheine adenylyltransferase (PPAT) is an essential enzyme in Coenzyme A biosynthesis. Because bacterial PPAT and mammalian PPAT are dissimilar, this enzyme is an attractive antibacterial target. Based on the structure of the substrate, 4-phosphopantetheine, a dipeptide library was designed, synthesised and tested against Escherichia coli PPAT. The most potent inhibitor PTX040334 was co-crystallised with E. coli PPAT. With this structural information, a rational iterative medicinal chemistry program was initiated, aimed at increasing the number of inhibitor-enzyme interactions. A very potent and specific inhibitor, PTX042695, with an IC(50) of 6 nM against E.coli PPAT, but with no activity against porcine PPAT, was obtained.

Long-term results of endoscopic stapling diverticulotomy for pharyngeal pouches.

OBJECTIVE: The aim of the present study was to evaluate the long-term success of endoscopic stapling as a primary procedure for the treatment of pharyngeal pouches. METHODS: This study is a retrospective case review of 25 patients with pharyngeal pouches treated by endoscopic stapling (23 stapled, 2 abandoned) over a 4-year period (1994 to 1998) at a University teaching hospital in the United Kingdom. Outcome measures used were relief of symptoms over a long-term follow-up of 2 to 5 years. RESULTS: Of the 25 patients analyzed, 12 patients (48%) have remained asymptomatic after their initial stapling. Eight patients (32%) were relieved of their symptoms after revision stapling. The overall long-term success rate for endoscopic stapling was 80% (20 of 25 patients) CONCLUSION: Reduced morbidity and few complications in the elderly make endoscopic stapling a favored primary technique of treating pharyngeal pouches. Open surgery is recommended only in healthy patients with very large pouches.