Percutaneous image-guided treatment of mucoid degeneration of the ACL in advanced knee osteoarthritis-Preliminary observations.

OBJECTIVES: To describe the percutaneous image-guided treatment of mucoid degeneration of the ACL causing deep knee pain on flexion in patients with advanced knee osteoarthritis. METHODS: Five patients with mucoid degeneration of the ACL complicating knee osteoarthritis underwent percutaneous image-guided steroid bupivacaine ACL sleeve injections over a 3-year period. RESULTS: There were four males and one female of mean age 54 (range 48-59 years). Each patient had Kellgren and Lawrence grade 4 medial compartment knee osteoarthritis with coexistent mucoid degeneration of the ACL sleeve. Each patient complained of deep knee pain on flexion as a dominant symptom. Each patient underwent image-guided (CT or ultrasound) steroid bupivacaine injection of the ACL sleeve resulting in symptom resolution and improved mobility for a mean duration of 8 months, (range 6-15 months.) CONCLUSION: Mucoid degeneration of the ACL should be sought in patients with osteoarthritis presenting with deep knee pain on flexion. Image-guided ACL sleeve injection in affected patients may result in symptom resolution and potential deferral of planned knee replacement surgery. ADVANCES IN KNOWLEDGE: Emphasises Image guided percutaneous treatment of Mucoid degeneration of ACL in patients with knee osteoarthritis.

Effectiveness of one and two doses of ivermectin mass drug administration in reducing the prevalence and intensity of soil-transmitted helminth (STH) infections in Western Province, Solomon Islands: a cluster-randomised, before-after analysis.

Background: Ivermectin mass drug administration (MDA) is effective for controlling onchocerciasis and scabies, with evidence supporting its role in some species of soil-transmitted helminth (STH) infections. In the context of RISE, a cluster-randomised trial for scabies, this study evaluated the effectiveness of ivermectin MDA in reducing STH burden in the Western Province of Solomon Islands. Methods: Twenty villages were randomised 1:1 to receive ivermectin MDA as one dose (IVM-1) or two doses (IVM-2) for scabies. The effectiveness of one and two doses in reducing STH prevalence and intensity was evaluated before (May 2019) and 21 months after (February 2021) MDA in May 2019. All residents aged 12 months or older in the study villages were eligible to participate and provide stool specimens. Species-specific STH infection and intensity were assessed using quantitative PCR. We compared prevalence and intensity of infection between baseline and 21 months in each intervention arm individually using cluster-level analysis (adjusted for clustering) and individual-level analysis (adjusted for sex, age, and clustering). The primary outcomes were the prevalence risk difference (RD) from the cluster-level analysis, and the change in adjusted odds of infection from the individual-level analysis. Secondary outcomes included change in incident rates of mean eggs per gram (epg) of stool from baseline to 21 months, relative risk difference in prevalence and relative change in odds of infection between arms at 21 months. Sex data (male/female) were self-reported. Findings: Overall, STH infection was assessed in 830 participants from 18 villages at baseline and 1172 from 20 villages at follow-up. Females represented 58% (n = 478) of the sample at baseline and 59% (n = 690) at follow-up. We observed a reduction in Strongyloides spp. prevalence following two doses of ivermectin MDA in the cluster-level analysis from 7.0% (32/458 participants) to 1.2% (8/674 participants), corresponding to a RD of -0.07 (95% CI -0.14 to -0.01, p = 0.036), and in the individual-level analysis (OR 0.11, 95% CI 0.04-0.33, p < 0.001). T. trichiura prevalence decreased following one dose from 19.4% (74/372 participants) to 11.7% (56/505 participants) (OR 0.44, 95% CI 0.26-0.73, p = 0.0040), while egg count reduced in both arms (IVM-1: IRR 0.28, 95% CI 0.11-0.70, p = 0.0070; IVM-2: IRR 0.18, 95% CI 0.08-0.40, p < 0.001), in the individual-level analysis. We did not detect a significant difference in effect measures between the one- and two-dose arms for any species after 21 months. Interpretation: Our study highlights the long-term benefits of ivermectin MDA in reducing the burden of Strongyloides spp. and T. trichiura. STH control programs should leverage the geographical overlap of NTDs, existing drug distribution channels, and broad-spectrum agents. Funding: The National Health and Medical Research Council of Australia.

Diuretics use in the management of bronchopulmonary dysplasia in preterm infants: A systematic review.

AIM: Bronchopulmonary dysplasia (BPD), a respiratory complication associated with neonatal prematurity, presents opportunities for pharmacological intervention due to its contributing risk factors. Despite diuretics' controversial usage in BPD treatment and varying institutional practices, this review aims to consolidate evidence from clinical trials regarding diuretic use in BPD. METHODS: We conducted a systematic review following PRISMA guidelines, searching EMBASE, Medline, Web of Science and CINAHL databases (PROSPERO 2022: CRD42022328292). Covidence facilitated screening and data extraction, followed by analysis and formatting in Microsoft Excel. RESULTS: Among 430 screened records, 13 were included for analysis. Three studies assessed spironolactone and chlorothiazide combinations, two studied spironolactone and hydrochlorothiazide, while eight examined furosemide. All studies evaluated drug effects on dynamic pulmonary compliance and pulmonary resistance, serving as comparative measures in our review. CONCLUSION: Diuretics' effectiveness in treating bronchopulmonary dysplasia remains uncertain. The limited number of identified randomised controlled trials (RCTs) hampers high-level evidence-based conclusions when applying the Population, Intervention, Comparison, Outcome (PICO) approach. Conducting large prospective studies of good quality could provide more definitive insights, but the rarity of outcomes and eligible patients poses challenges. Further research, primarily focusing on RCTs assessing diuretics' safety and efficacy in this population, is warranted.

Socket outcomes following enucleation for uveal melanoma: post enucleation socket syndrome can be challenging.

PURPOSE: To evaluate socket outcomes of enucleation for uveal melanoma. METHODS: This study was a retrospective chart review conducted in December 2022 of all patients who underwent enucleation surgery for uveal melanoma between 2010 and 2015 in the Royal Victoria Eye and Ear Hospital, to evaluate socket outcomes including completion of revision surgery, type of surgery, and completion of multiple revision surgeries, and potential associations. RESULTS: Between June 2010 and December 2015, 72 patients underwent enucleation for uveal melanoma in the ocular oncology service, including 25 females and 47 males, mean age 65, range 11-91 years old. There were 68 primary enucleations and 4 secondary enucleations. Complete follow-up data was available for mean 4 years, range 1-11 years. Fourteen patients underwent further surgery, including one exenteration for local recurrence. Oculoplastic surgery (n = 6, 8%), implant exposure repair (n = 3, 6%), and orbit volume expanding surgery (n = 4, 6%) were also performed. Eight patients (11%) underwent one further surgery and five patients (7%) underwent a series of procedures. There was a significant association with younger age at enucleation (age <65) with undergoing further surgery (p = 0.03, Fisher's Exact Test (FET)), and also an association of younger age with undergoing multiple further surgeries (p = 0.02, FET). There was no association found with other predictor variables, including primary versus secondary enucleation status. Most patients (75%) with PESS underwent more than one surgery. CONCLUSION: Post enucleation surgery 82% of patients did not undergo further surgery, but younger patients were more likely to undergo anophthalmic socket revision or oculoplastic surgery. Management of post enucleation socket syndrome was challenging and usually involved a series of procedures.

Increased rates of invasive bacterial disease in late 2022.

Invasive bacterial disease is associated with significant morbidity and mortality. In winter 2022, there was an apparent increased rate of invasive bacterial disease compared to preceding years. Cross-site retrospective analysis of the three Children's Health Ireland (CHI) hospitals looking at children admitted between 1st October 2022-31st December 2022 (Q4) with community-acquired invasive bacterial disease, defined as an abscess in a normally sterile site in the head, neck and chest or isolation or PCR detection of Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus pyogenes (Group A streptococcus) or Haemophilus influenzae from a normally sterile site. Case numbers were compared to Q4 in each of 2018-2021. Eighty-two children met the case definition in Q4 2022 vs 97 (Q4 2018-2021). In 2022, 42/82 (51%) were female, median age 3.75 years (1.5-8.25 years). Only 2 (2%) were immunosuppressed and 2 others (2%) had underlying neurodisability. Fifty (61%) were admitted on second or subsequent presentation to a healthcare setting. Fifty-six (68%) had an abscess in a sterile site. Bloodstream infection (positive blood culture or PCR: 24 (29%)) was the most common site of infection, followed by neck 22 (27%) and intracranial 12 (15%). Group A streptococcus (GAS) 27 (33%) was the most common organism isolated. Seven cases (9%) died in 2022 compared to 2 patients (2%) from 2018 to 2021 (p < 0.05). More children had Paediatric Overall Performance Category (POPC) scores > 1 in 2022 than 2018-2021 (p = 0.003).  Conclusion: Invasive bacterial diseases increased in Q4 2022 with higher morbidity and mortality than in the preceding 4 years. Group A streptococcal infection was the most significant organism in 2022. What is known: • Invasive bacterial disease is the leading cause of childhood mortality globally. • There was an increase in cases of invasive Group A streptococcus infections reported in many countries (including Ireland) during the winter of 2022/23. What is new: • Head, neck and chest abscesses increased in Q4 of 2022 compared to the previous 4 years combined. • Invasive bacterial infections in Q4 of 2022 were associated with higher rates of mortality (9%), paediatric intensive care unit (PICU) admission (24%) and requirement for surgical drainage or intervention (67%) than in the preceding years.

Ocular oncology service during the COVID-19 outbreak: uveal melanoma characteristics presenting in 2019 compared to 2020.

AIM: We aim to evaluate the impact of the COVID-19 pandemic on ocular oncology in Ireland, comparing uveal melanoma trends in 2019 to 2020. METHODS: Patients included for analysis were those that presented to the ocular oncology service from January 2019 to December 2020 in the Royal Victoria Eye and Ear Hospital in Dublin, who underwent primary treatment for uveal melanoma-proton beam therapy, brachytherapy or enucleation. RESULTS: Ninety-seven patients presented in 2019 (n = 46) and 2020 (n = 51) who underwent primary treatment for uveal melanoma. Presentation via the eye casualty department was more common in 2020. Dimensions of choroidal melanomas were increased both in basal diameter and thickness compared to those in 2019. More patients had enucleations in 2020 than in 2019 (21.6% vs 9.3%, respectively) and less had proton beam therapy (6.2% vs 12.4%). More patients had evidence of extra-scleral extension at the time of surgery in 2020 compared to 2019 (4.1%, n = 4 versus 0%, respectively). The mean duration of brachytherapy therapy was longer in 2020 (5.3 days ± 35.8) compared to 2019 (4.6 days ± 38.7). Mean time between presentation and primary treatment was 35.6 ± 28.8 days in 2019 and 24.1 ± 20.4 days in 2020. CONCLUSIONS: More advanced disease is suggested by the increased mean basal diameter and tumour thickness, extra-scleral extension and longer duration of brachytherapy. Time from diagnosis to treatment was not delayed in 2020.

Defining operative experience targets in surgical training: A systematic review.

BACKGROUND: The surgical learning curve is an observable and measurable phenomenon. Operative experience targets are well established as a proxy measure for operative competence in surgical training across jurisdictions. The aim of this study was to critique the available evidence regarding the relationship between operative experience in surgical training and trainee competence. METHODS: A systematic review of the PubMed, Embase, Web of Science, and Cochrane library databases was conducted in accordance with the Preferred Items for Systematic Reviews and Meta-Analyses guidelines. Articles were sought that defined the relationship between procedural volume in surgical training and trainee competence, proficiency, or mastery. The educational impact of included studies was evaluated using a modified Kirkpatrick model. RESULTS: Of 3,672 records identified on database searching, 30 papers were ultimately included. Fourteen studies defined operative experience thresholds using operative time as a surrogate measure of competence, whereas another 8 used trainer assessments of operative performance (Kirkpatrick level 3). A further 5 studies were able to determine the relationship between trainee case volumes and subsequent patient outcomes (Kirkpatrick level 4b). CONCLUSION: Many studies have recorded competent trainee performance in key index procedures after reaching experience threshold numbers in excess of currently mandated targets across jurisdictions. The evidence relating current operative experience targets to patient outcomes across a range of surgical subspecialties of surgical subspecialties is lacking. This review supports a move toward criterion-based referencing of operative performance targets in surgical training.

Using quantitative PCR to identify opportunities to strengthen soil-transmitted helminth control in Solomon Islands: A cross-sectional epidemiological survey.

BACKGROUND: The Kato-Katz microscopy technique is the global standard for assessment of soil-transmitted helminth (STH) burden. However, major limitations include its poor sensitivity, requirement for rapid sample processing, and inability to differentiate hookworm species nor detect Strongyloides spp. infections. We assessed the prevalence and intensity of STH species in Solomon Islands by conducting a province-wide survey using quantitative PCR (qPCR) for diagnosis, which can provide much better characterisation of STH burden than microscopy. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional survey in 18 villages in Western Province to detect infections with six STH species and quantify intensity with three. We used linear mixed model regression to identify potential water, sanitation, and hygiene (WASH) and environmental risk factors for infection. We collected stool specimens from 830 village residents. Overall STH prevalence was 63.3% (range 27.5 to 91.5% across villages), led by Necator americanus (54.5% [range 17.5-89.4%]), followed by Ancylostoma ceylanicum (15.5% [range 2.8-45.8%]), Trichuris trichiura (9.1% [range 0-79.2%]), and Strongyloides spp. (3.2% [range 0-29.2%]). Most infections were of light intensity for N. americanus (85.7%) and T. trichiura (90.7%). Owning a household latrine was associated with a lower risk of N. americanus infection (AOR 0.41, 95% CI 0.24-0.68) while greater precipitation was linked to more common T. trichiura infection (AOR 1.14, 95% CI 1.04-1.25). CONCLUSION/SIGNIFICANCE: In this first large-scale population survey of STH in the Pacific using qPCR, we found evidence that ivermectin should be incorporated into STH control programmes because of the presence of T. trichiura and Strongyloides spp., both of which are poorly responsive to albendazole. Furthermore, One Health strategies are needed for improved A. ceylanicum and Strongyloides spp. control, WASH access and use should be improved to complement deworming programmes, and control efforts should ideally be expanded to entire communities. TRIAL REGISTRATION: ClinicalTrials.gov Australian and New Zealand Clinical Trials Registry ACTRN12618001086257.

Harnessing artificial intelligence in cardiac rehabilitation, a systematic review.

Aim: This systematic review aims to evaluate the current body of research surrounding the efficacy of artificial intelligence (AI) in cardiac rehabilitation. Presently, AI can be incorporated into personal devices such as smart watches and smartphones, in diagnostic and home monitoring devices, as well as in certain inpatient care settings. Materials & methods: The PRISMA guidelines were followed in this review. Inclusion and exclusion criteria were set using the Population, Intervention, Comparison and Outcomes (PICO) tool. Results: Eight studies meeting the inclusion criteria were found. Conclusion: Incorporation of AI into healthcare, cardiac rehabilitation delivery, and monitoring holds great potential for early detection of cardiac events, allowing for home-based monitoring, and improved clinician decision making.

Lay abstract Artificial intelligence (AI) involves the use of technologies capable of making decisions based on data provided. AI can be used in healthcare to provide actionable data for a clinician by analyzing patterns in patient data to predict outcomes and guide treatment. Cardiovascular disease is the leading cause of death worldwide. Cardiac rehabilitation is a therapy proven to reduce mortality and morbidity from cardiovascular disease. This study outlines three cases of AI based healthcare tools in cardiac rehabilitation. This includes the provision of personalized, home-based cardiac rehabilitation, the early detection of cardiac events through smart watch monitoring and by providing clinician decision making support in cardiac failure rehabilitation.

Progress towards control and elimination of neglected tropical diseases targeted by preventive chemotherapy in São Tomé e Príncipe.

The São Tomé e Príncipe government is committed to achieving neglected tropical disease (NTD) control and elimination as a public health problem by 2025. In 2014, the Ministry of Health led a national survey to determine the prevalence of soil-transmitted helminths (STHs) and schistosomiasis across the country. Following this survey, a preventive chemotherapy (PC) campaign with mebendazole and praziquantel reached 31 501 school-age children in 2015. A follow-up 2017 survey to determine the impact of the intervention showed success in controlling schistosomiasis, as no infections were found, but limited impact on STHs, with prevalence similar to pretreatment levels. The survey also investigated the prevalence of a third NTD, lymphatic filariasis (LF), which was found to be endemic in the country. Since then the Ministry of Health has developed the Strategic Plan for the Fight Against Neglected Tropical Diseases 2019-2025 and identified gaps to be addressed. This narrative review systematises the existing literature reporting on the epidemiology of NTDs for which there are PC programs in São Tomé e Príncipe. PubMed was searched for relevant papers that measured the prevalence of LF, schistosomiasis and STHs. Additionally, data provided by the Ministry of Health surveys were analysed. Finally, we discuss current NTD control, including the impact of the coronavirus disease 2019 pandemic and identify priorities for program strengthening and operational research.

Impact of hookworm infection and preventive chemotherapy on haemoglobin in non-pregnant populations.

OBJECTIVE: To assess the impact of hookworm infection and preventive chemotherapy on haemoglobin levels in non-pregnant populations in endemic areas. METHOD: Systematic review and meta-analysis searching PubMed and Web of Science for articles published since 2010 reporting either hookworm prevalence and Hb concentration (cross-sectional studies) or Hb concentration before and after the implementation of preventive chemotherapy (before-after studies and randomised controlled trials [RCTs]). For papers published before 2010, data were extracted from a previously published systematic review. Random effects meta-analyses were conducted to examine the relationship between Hb concentration and hookworm infection intensity (from cross-sectional studies) and the effect of preventive chemotherapy on Hb concentration (from before-after studies and RCTs). Sensitivity analyses investigated the impact of malaria endemicity and combined interventions for schistosomiasis and nutrition status on Hb concentration. RESULTS: Among cross-sectional studies, both light- and heavy-intensity hookworm infections were associated with lower Hb in school-aged children. School-aged children with heavy hookworm infection in settings of high malaria endemicity had lower mean Hb than those in settings of low malaria endemicity. In non-pregnant populations, deworming with albendazole was associated with an increase in Hb of 3.02 g/L (95% CI 0.1, 6.0 g/L). No additional benefit was seen with deworming using albendazole co-administered with praziquantel for schistosomiasis infection or iron supplementation for nutrition status. CONCLUSION: Our findings confirm the benefits of preventive chemotherapy as a public health intervention.

Lyme neuroborreliosis causing unilateral cerebellitis presenting as horizontal nystagmus in a 7-year-old: an unusual presentation to an ophthalmology service.

Acute cerebellitis is a rare condition with a highly heterogenous clinical course, ranging from self-limiting mild symptoms to a fulminant presentation. Symptoms include headache, vomiting, fever, ataxia, dysarthria, intention tremor, meningism, seizures, and altered level of consciousness. It warrants a high level of suspicion because of the risk of intracranial hypertension and acute hydrocephalus due to compression of the posterior fossa. We present the case of a 7-year-old boy who presented emergently with new-onset left head turn and horizontal nystagmus. Acute inflammation of a single cerebellar hemisphere (hemicerebellitis) in childhood is extremely rare, diagnosed in this case with magnetic resonance imaging. Symmetrical, diffuse cerebellar hemisphere involvement is more typical of cerebellitis. Our patient was unusual in that he presented initially with predominantly ophthalmological signs, with an otherwise normal neurological assessment. Subsequent positive serological Borrelia burgdorferi antibodies led to a diagnosis of Lyme neuroborreliosis.

Community optometrist-led post-operative cataract care: how many patients re-present to the hospital ophthalmic department?

BACKGROUND: Cataract surgery represents a significant workload for ophthalmologists in Ireland. Post-operative shared care with community optometrists can reduce the need for hospital follow-up appointments. AIMS: Eight years after the introduction of a shared-care pathway, we wished to quantify the proportion of patients discharged to the community for post-operative follow-up, and the number that re-present to the hospital due to cataract-related issues. METHODS: We collected data on all patients who underwent cataract surgery in our centre over a three month period. Electronic patient records were used to establish whether the patient was discharged on the day of surgery, and whether they re-attended the department post-operatively. Post-operative complications were recorded. RESULTS: 394 cataract procedures were carried out over the three months. 369 patients were discharged to an optometrist for their post-operative care. Of those, 38 were re-referred or re-presented to the hospital ophthalmic service. 21 of these had a post-operative complication. Complications included seven cases of post-operative uveitis, 5 patients with cystoid macular oedema, one retinal detachment and one retained lens fragment. CONCLUSIONS: Community optometrist-led post-operative care for uncomplicated patients is an effective way of reducing the workload associated with cataract surgery. Re-referral pathways must be in place to facilitate timely management of post-operative complications.

Gender and ethnic differences in pterygium prevalence: an audit of remote Australian clinics.

CLINICAL RELEVANCE: Developing an accurate picture of the demographic profile and refractive status of Aboriginal and non-Aboriginal individuals with pterygium will facilitate health planning and appropriate deployment of health-care resources in rural Australia. BACKGROUND: To date, there is a paucity of reports in the literature regarding Aboriginal ocular health and refractive error. This study examines clinical data from a rural ophthalmology outreach clinic - a predominantly Aboriginal population. METHODS: An assessment was undertaken of data of 293 patients noted to have pterygium present in at least one eye, from a sample of 2,072 individuals seen in rural northern Western Australia in 2017 by the Lions Outback Vision Visiting Optometry Service. RESULTS: Pterygium was found in 14.1 per cent (n = 293) of patients using the Lions Outback Vision service. The mean age of those with pterygium (n = 293) was 57.1 ± 11.9-years (mean ± standard deviation); 188 were female (64.1 per cent); 260 identified as Aboriginal (88.7 per cent), 22 identified as non-Aboriginal (7.5 per cent) and 11 did not specify (3.8 per cent). There were more males than females with pterygium in the non-Aboriginal group (18.0 per cent versus 6.4 per cent); however, the reverse was true in the Aboriginal group (11.7 per cent versus 17.0 per cent). Analysis of the subjective refractive data in those with pterygium revealed an overall mean spherical equivalent value of +0.66 ± 1.28 DS. The median (interquartile range) best-corrected visual acuity was 0.0 (-0.1 to 0.0) logMAR (6/6 Snellen equivalent). CONCLUSIONS: This paper increases our knowledge of ocular health in a remote Australian population, with an emphasis on the differences between Aboriginal and non-Aboriginal individuals, males and females.

Inclusion of medical fitness to drive in medical postgraduate training curricula.

BACKGROUND: Transport mobility and access to driving are important factors in social inclusion and wellbeing. Doctors have an important role to play in supporting safe mobility through applying the knowledge developed in the field of traffic medicine and incorporating state of the art national and international medical fitness to drive (MFTD) guidelines. Little is known about the profile of MFTD in postgraduate curricula for core and higher specialist training. AIMS: We profiled the inclusion of MFTD in the curricula of postgraduate core, higher and streamlined medical and surgical specialties in the Republic of Ireland (ROI) and the UK. METHODS: All publicly available syllabi of basic and higher/ streamlined specialist training in postgraduate medical and surgical colleges in both jurisdictions were analysed (n = 122). RESULTS: In Ireland 25% of basic training schemes included MFTD in the curriculum. Two-thirds of curricula of higher specialty and streamlined training schemes also included MFTD. For the UK 44% of core and 36% of higher training scheme curricula included MFTD. Just under one-quarter of all curricula reviewed included MFTD for more than one medical condition or treatment. Common topics in both Irish and UK curricula included seizures/epilepsy, syncope and visual disturbances. CONCLUSION: There are notable deficits in MFTD training for specialists in Ireland and the UK. Common conditions which can significantly impair MFTD such as stroke, diabetes and alcohol use disorders are severely underrepresented and curricula should be revisited to include relevant training and guidance on MFTD for trainees.

Photophysics and Cell Uptake of Self-Assembled Ru(II)Polypyridyl Vesicles.

Effective delivery of luminescent probes for cell imaging requires both cell membrane permeation and directing to discrete target organelles. Combined, these requirements can present a significant challenge for metal complex luminophores, that have excellent properties as imaging probes but typically show poor membrane permeability. Here, we report on highly luminescent Ruthenium polypyridyl complexes based on the parent; [Ru(dpp)2(x-ATAP)](PF6)2 structure, where dpp is 4,7-diphenyl-1,10-phenanthroline and x-ATAP is 5-amino-1,10-phenanthroline with pendant alkyl-acetylthio chains of varying length; where x is 6; 5-Amido-1,10-phenanthroline-(6-acetylthio-hexanyl). 8; 5-Amido-1,10-phenanthroline-(8-acetylthio-octanyl). 11; 5-Amido-1,10-phenanthroline-(11-acetylthio-undecanyl); and 16; 5-Amido-1,10-phenanthroline-(16-acetylthio-hexadecanyl). Soluble in organic media, the alkyl-acetylthiolated complexes form nanoaggregates of low polydispersity in aqueous solution. From dynamic light scattering the nanoaggregate diameter was measured as 189 nm and 135 nm for 5 × 10-6 M aqueous solutions of [Ru(dpp)2(N∧N)](PF6)2 with the hexadecanoyl and hexanyl tails respectivly. The nanoaggregate exhibited dual exponential emission decays with kinetics that matched closely those of the [Ru(dpp)2(16-ATAP)]2+ incorporated into the membrane of a DPPC liposome. Cell permeability and distribution of [Ru(dpp)2(11-ATAP)]2+ or [Ru(dpp)2(16-ATAP)]2+ were evaluated in detail in live HeLa and CHO cell lines and it was found from aqueous media, that the nanoaggregate complexes spontaneously cross the membrane of mammalian cells. This process seems, on the basis of temperature dependent studies to be activated. Fluorescence imaging of live cells reveal that the complexes localize highly specifically within organelles and that organelle localization changes dramatically in switching the pendent alkyl chains from C16 to C11 as well as on cell line identity. Our data suggests that building metal complexes capable of self-assembling into nano-dimensional vesicles in this way may be a useful means of promoting cell membrane permeability and driving selective targeting that is facile and relatively low cost compared to use of biomolecular vectors.

Photostable NIR emitting ruthenium(II) conjugates; uptake and biological activity in live cells.

A photostable Ru(2,2-biquinoline)2(3-(2-pyridyl)-5-(4-carboxyphenyl)-1,2,4-triazolate) (Ru(biq)2(trzbenzCOOH)) complex that exhibits near-infrared (NIR) emission centred at 786 nm is reported. The parent complex was conjugated via amide coupling to a cell-penetrating peptide sequence octa-arginine (R8), and two signal peptide sequences; the nuclear localizing sequence (NLS) VQRKRQKLMP and the mitochondria penetrating peptide (MPP) FrFKFrFK(Ac) (r = D isomer of arginine, Ac = terminal lysine amine acetyl blocked). Notably, none of the peptide conjugates were cell-permeable as chloride salts but efficient and rapid membrane permeation was observed post ion exchange with perchlorate counterion. Also, surprisingly, all three peptide conjugates exhibited potent dark cytotoxicity in both CHO and HeLa cell lines. The peptide conjugates induce cell death through a caspase dependent apoptotic pathway. At the minimum concentration of dye (approx. 15 µM) required for cell imaging, only 20% of the cells were viable after a 24 h incubation period. To overcome cytotoxicity, the parent complex was PEGylated; this dramatically decreased cytotoxicity, where 50% of cells were viable even at 150 µM concentration after 24 h. Confocal luminescence microscopy indicated that all four bioconjugates, peptides in perchlorate form and polyethylene glycol (PEG) in chloride form, were rapidly internalized within the cell. However, interestingly the precise localisation by the signal peptides observed in related complexes was not observed here and the peptide conjugates were unsuitable as luminescent probes for cell microscopy due to their high cell toxicity. The poor targeting of signal peptides in this instance is attributed to the high lipophilicity of the metal centre.

High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report.

BACKGROUND: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. In this report, high-resolution ocular imaging reveals unexpected findings that reject previous hypotheses. CASE PRESENTATION: The proband is a 37-year-old female with a history of neonatal patent ductus arteriosus (PDA) ligation, left-sided choreiform movements at the age of 11 and a transient aphasia with right-sided weakness at the age of 30. Her older sister also had PDA ligation and congenital mydriasis but no neurological deficit up to age 41. Magnetic resonance angiogram demonstrated cerebrovascular lesions resembling but distinct from Moyamoya disease, characterised by internal carotid artery dilatation, terminal segment stenosis and absent basal collaterals. Their mother had poorly reactive pupils with asymptomatic cerebral arteriopathy resembling her daughters. All three had prominent retinal arteriolar tortuosity. The daughters were heterozygous and the mother was a somatic mosaic for a novel c.351C > G (p.Asn117Lys) transversion in ACTA2. Iris optical coherence tomography (OCT) showed a hyporeflective band anterior to the pigment epithelium indicating the presence of dysfunctional sphincter muscle. Adaptive optics retinal imaging showed no thickening of the arteriolar vessel wall whilst OCT angiography showed extreme corkscrew course of arterioles suggesting vessel elongation. CONCLUSIONS: In addition to the known association between Met46, Arg179 and Arg258 substitutions and ACTA2-related arteriopathy, this case illustrates the possibility that Asn117 also plays an important role in α-SMA function within the cerebrovascular smooth muscle cell. MSMDS-related congenital mydriasis is due to reduced iris sphincter contractility rather than its absence. Retinal arteriolar tortuosity might be due to longitudinal proliferation of arteriolar smooth muscle cells. The described cerebrovascular and ocular signs are consistent with predicted effects of the novel Asn117Lys substitution in ACTA2.