Impact of social care supply on healthcare utilisation by older adults: a systematic review and meta-analysis.

Objective: to investigate the impact of the availability and supply of social care on healthcare utilisation (HCU) by older adults in high income countries. Design: systematic review and meta-analysis. Data sources: medline, EMBASE, Scopus, Health Management Information Consortium, Cochrane Database of Systematic Reviews, NIHR Health Technology Assessment, NHS Economic Evaluation Database, Database of Abstracts of Reviews of Effectiveness, SCIE Online and ASSIA. Searches were carried out October 2016 (updated April 2017 and May 2018). (PROSPERO CRD42016050772). Study selection: observational studies from high income countries, published after 2000 examining the relationship between the availability of social care (support at home or in care homes with or without nursing) and healthcare utilisation by adults >60 years. Studies were quality assessed. Results: twelve studies were included from 11,757 citations; ten were eligible for meta-analysis. Most studies (7/12) were from the UK. All reported analysis of administrative data. Seven studies were rated good in quality, one fair and four poor. Higher social care expenditure and greater availability of nursing and residential care were associated with fewer hospital readmissions, fewer delayed discharges, reduced length of stay and expenditure on secondary healthcare services. The overall direction of evidence was consistent, but effect sizes could not be confidently quantified. Little evidence examined the influence of home-based social care, and no data was found on primary care use. Conclusions: adequate availability of social care has the potential to reduce demand on secondary health services. At a time of financial stringencies, this is an important message for policy-makers.

Equal North: how can we reduce health inequalities in the North of England? A prioritization exercise with researchers, policymakers and practitioners.

BACKGROUND: The Equal North network was developed to take forward the implications of the Due North report of the Independent Inquiry into Health Equity. The aim of this exercise was to identify how to reduce health inequalities in the north of England. METHODS: Workshops (15 groups) and a Delphi survey (3 rounds, 368 members) were used to consult expert opinion and achieve consensus. Round 1 answered open questions around priorities for action; Round 2 used a 5-point Likert scale to rate items; Round 3 responses were re-rated alongside a median response to each item. In total, 10 workshops were conducted after the Delphi survey to triangulate the data. RESULTS: In Round 1, responses from 253 participants generated 39 items used in Round 2 (rated by 144 participants). Results from Round 3 (76 participants) indicate that poverty/implications of austerity (4.87 m, IQR 0) remained the priority issue, with long-term unemployment (4.8 m, IQR 0) and mental health (4.7 m, IQR 1) second and third priorities. Workshop 3 did not diverge from findings in Round 1. CONCLUSIONS: Practice professionals and academics agreed that reducing health inequalities in the North of England requires prioritizing research that tackles structural determinants concerning poverty, the implications of austerity measures and unemployment.

Social determinants of emotional well-being in new refugees in the UK.

OBJECTIVES: Refugees are most vulnerable to mental health problems of all migrant groups, and an understanding of the role of postdisplacement social factors in refugee emotional well-being can help to shape the future interventions for this group. We aimed to investigate the effect of social determinants, such as employment, language ability and accommodation, on mental health in refugees in the UK. STUDY DESIGN: This prospective longitudinal cohort study was set in the UK. The study population of new UK refugees was drawn from an existing data set of the Longitudinal Survey of New Refugees (n = 5678), in which all new UK refugees (2005-2007) were sent a postal questionnaire at four time points across 2 years. METHODS: Ordered logistic regression models were used to evaluate associations between social determinants and the dependent variables, emotional well-being or change in emotional well-being, using a question from the Short Form-36 Health Survey Questionnaire. RESULTS: Refugees who were unemployed in the UK, could not speak English well or were unsatisfied with their accommodation had significantly higher odds of poorer emotional well-being in the cross-sectional analysis (P < 0.05 at all time points measured). CONCLUSIONS: Postdisplacement social factors, including language ability, employment status and accommodation satisfaction, were important determinants of refugee emotional well-being. Changes in these social determinants have the potential to improve refugee mental health, making them legitimate, modifiable targets for important public health interventions. Accounting for this, further research into how to improve refugee well-being is crucial given the increase in refugee numbers around the developed world.

Dental Public Health In Action: Barriers to oral healthcare provision for older people in residential and nursing care homes: A mixed method evaluation and strategy development in County Durham, North East England.

This paper presents a case study on the use of mixed methods in research into practice to inform policy. The study was undertaken as part of a review of oral healthcare for older people in residential and nursing care homes in County Durham, North East England. The findings highlighted challenges in the provision of good quality oral healthcare to older people in residential and nursing care homes and informed the county's oral health strategy (Durham County Council DCC, 2016). Key recommendations include the need to develop and implement a minimum set of best practice oral health standards within care home contracts and train care home staff in oral healthcare. The paper relates to two key dental public health competencies: (i) designing and using mixed method studies to address gaps in evidence and triangulating the findings from quantitative and qualitative methods; (ii) the development of evidence based policies. The research is relevant to: care home staff; commissioners in local authority adult and social care; public health practitioners; oral health improvement teams; domiciliary and special care dentists, dental commissioners, researchers and academics.

A qualitative study of the impact of the UK 'bedroom tax'.

BACKGROUND: The implementation of the 'Removal of the Spare Room Subsidy' in April 2013, commonly known as the 'bedroom tax', affects an estimated 660 000 working age social housing tenants in the UK, reducing weekly incomes by £12-£22. This study aimed to examine the impact of this tax on health and wellbeing in a North East England community in which 68.5% of residents live in social housing. METHODS: Qualitative study using interviews and a focus group with 38 social housing tenants and 12 service providers. RESULTS: Income reduction affected purchasing power for essentials, particularly food and utilities. Participants recounted negative impacts on mental health, family relationships and community networks. The hardship and debt that people experienced adversely affected their social relationships and ability to carry out normal social roles. Residents and service providers highlighted negative impacts on the neighbourhood, as well as added pressure on already strained local services. CONCLUSIONS: The bedroom tax has increased poverty and had broad-ranging adverse effects on health, wellbeing and social relationships within this community. These findings strengthen the arguments for revoking this tax.

Trends in the distribution of donor corneal tissue and indications for corneal transplantation: the New Zealand National Eye Bank Study 2000-2009.

BACKGROUND: To investigate the indications for corneal transplantation and the distribution of donor corneal tissue in New Zealand. DESIGN: Analysis of the prospective database of the New Zealand National Eye Bank. PARTICIPANTS: A total of 2205 corneal transplants were assessed. METHODS: New Zealand National Eye Bank records were analysed for the decade 2000-2009. MAIN OUTCOME MEASURES: Variables analysed included donor corneal tissue distribution (including public and private sectors), indications for transplantation, donor corneal tissue recipient demographics (age and gender) and corneal transplantation type. RESULTS: An average of 220 corneal transplants were performed each year over the 10-year period (n=2205). The median recipient age was 45years (range 3 to 102years) and 54.0% of recipients were male. In total 71.8% of transplants were performed in the public health sector. Surgeons in the Auckland metropolitan area performed 47.2% of all corneal transplants. The most common indications for corneal transplantation were: keratoconus (41.1%), repeat transplant (17.0%), aphakic/pseudophakic bullous keratopathy (13.9%), corneal dystrophy (10.7%), keratitis (7.9%) and trauma (3.7%). Overall, penetrating keratoplasty accounted for 90.7% of all corneal transplants, however, during the latter half of the study there was a progressive shift in transplantation type, with deep anterior lamellar keratoplasty and Descemet's stripping endothelial keratoplasty combined accounting for 32.3% of all transplants in the final year of the study period. CONCLUSIONS: This New Zealand National Eye Bank study provides valuable data regarding the indications for corneal transplantation, transplant recipient demographics and changes in transplantation type in New Zealand over the past decade.

Changing Trends in Corneal Transplantation in Aotearoa/New Zealand, 1991 to 2020: Effects of Population Growth, Cataract Surgery, Endothelial Keratoplasty, and Corneal Cross-Linking for Keratoconus.

PURPOSE: The purpose of this study was to identify trends in the primary indication for keratoplasty in New Zealand/Aotearoa (NZ) after significant population growth, increase in the number of cataract surgeries per population, widespread adoption of endothelial keratoplasty, and introduction of corneal cross-linking for keratoconus. METHODS: Statistical analysis of the New Zealand National Eye Bank's prospective database of all keratoplasties was performed between January 1991 and January 2020. Indications for keratoplasty were isolated for the primary diagnosis. RESULTS: In total, 6840 corneas were transplanted with mean 236 ± 57.5 transplants/year, increasing from 2.55 to 6.06 per 100,000 NZ population/year. Over the past decade, the number of transplant recipients aged 60 years or older has increased and recipients aged 20 to 39 years have plateaued. In 2019, for the first time, regraft became the most common indication (30.9%), followed by keratoconus (27.9%) and corneal dystrophy (18.8%), with a steady decline in bullous keratopathy. Proportions of the keratoplasty technique changed dramatically: penetrating keratoplasty fell from 91.4% in 2006 to 55.0% in 2019, Descemet's stripping endothelial keratoplasty increased from 0% to 29.5%, anterior lamellar keratoplasty increased from 2.5% to 5.7%, and Descemet membrane endothelial keratoplasty increased from 0% to 9.1%. CONCLUSIONS: Keratoplasty trends in Aotearoa/NZ have changed considerably because of the evolution of phacoemulsification and keratoplasty techniques. Unlike proportions observed overseas, NZ still performs penetrating keratoplasties in over half of all transplants. Corneal cross-linking may be having an early effect of reducing keratoplasty rates for keratoconus.

The spectrum of blunt abdominal trauma in Pietermaritzburg.

BACKGROUND: This study reviews the Pietermaritzburg Metropolitan Trauma Service (PMTS) experience with the management of blunt abdominal trauma (BAT). METHODS: A retrospective review of the hybrid electronic medical registry (HEMR) between December 2012 and September 2019 was conducted. All patients admitted following BAT were included. RESULTS: During the study period, 1 123 BAT patients were managed by the PMTS. The mean age was 29.19 years (SD 14.03). Of these admissions, 73.6% were male. The most common mechanism was road traffic crashes (RTCs) - 435 motor vehicle collisions (MVCs) and 250 pedestrian vehicle collisions (PVCs). There were 186 assaults, 118 falls, 62 community assaults, 22 accidents related to agriculture, construction or industry, 11 sporting injuries, nine animal injuries, seven patients injured by falling objects, five injured by trains, two hangings, one burn-related fall and two other causes. The mechanism of injury was unknown in 22 cases. There were 445 abdominal CT scans and 270 whole body CT scans. Surgical management was required for 395 patients. There were 259 index laparotomies and 176 repeat laparotomies. Four patients underwent selective arterial embolisation. Laparoscopy was undertaken in ten, and subsequently converted to laparotomy in five. There were 106 orthopaedic operations. Hospital stay ranged from 0-155 days (median stay three days). ICU admission was required in 24.9% of patients. The mortality rate was 7.5%. CONCLUSION: BAT is common in South Africa. Whilst the vast majority of patients require non-operative treatment, a welldefined subset require a laparotomy. Imaging is central to the management of patients with BAT.

Identification and characterization of novel superantigens from Streptococcus pyogenes.

Three novel streptococcal superantigen genes (spe-g, spe-h, and spe-j) were identified from the Streptococcus pyogenes M1 genomic database at the University of Oklahoma. A fourth novel gene (smez-2) was isolated from the S. pyogenes strain 2035, based on sequence homology to the streptococcal mitogenic exotoxin z (smez) gene. SMEZ-2, SPE-G, and SPE-J are most closely related to SMEZ and streptococcal pyrogenic exotoxin (SPE)-C, whereas SPE-H is most similar to the staphylococcal toxins than to any other streptococcal toxin. Recombinant (r)SMEZ, rSMEZ-2, rSPE-G, and rSPE-H were mitogenic for human peripheral blood lymphocytes with half-maximal responses between 0.02 and 50 pg/ml (rSMEZ-2 and rSPE-H, respectively). SMEZ-2 is the most potent superantigen (SAg) discovered thus far. All toxins, except rSPE-G, were active on murine T cells, but with reduced potency. Binding to a human B-lymphoblastoid line was shown to be zinc dependent with high binding affinity of 15-65 nM. Evidence from modeled protein structures and competitive binding experiments suggest that high affinity binding of each toxin is to the major histocompatibility complex class II beta chain. Competition for binding between toxins was varied and revealed overlapping but discrete binding to subsets of class II molecules in the hierarchical order (SMEZ, SPE-C) > SMEZ-2 > SPE-H > SPE-G. The most common targets for the novel SAgs were human Vbeta2.1- and Vbeta4-expressing T cells. This might reflect a specific role for this subset of Vbetas in the immune defense of gram-positive bacteria.

The streptococcal superantigen SMEZ exhibits wide allelic variation, mosaic structure, and significant antigenic variation.

The frequencies of the newly identified streptococcal superantigen genes smez, spe-g, and spe-h were determined in a panel of 103 clinical isolates collected between 1976 and 1998 at various locations throughout New Zealand. smez and spe-g were found in every group A Streptococcus (GAS) isolate, suggesting a chromosomal location. The spe-h gene was found in only 24% of the GAS isolates and is probably located on a mobile DNA element. The smez gene displays extensive allelic variation and appears to be in linkage equilibrium with the M/emm type. 22 novel smez alleles were identified from 21 different M/emm types in addition to the already reported alleles smez and smez-2 with sequence identities between 94. 5 and 99.9%. Three alleles are nonfunctional due to a single base pair deletion. The remaining 21 alleles encode distinct SMEZ variants. The mosaic structure of the smez gene suggests that this polymorphism has arisen from homologous recombination events rather than random point mutation. The recently resolved SMEZ-2 crystal structure shows that the polymorphic residues are mainly surface exposed and scattered over the entire protein. The allelic variation did not affect either Vbeta specificity or potency, but did result in significant antigenic differences. Neutralizing antibody responses of individual human sera against different SMEZ variants varied significantly. 98% of sera completely neutralized SMEZ-1, but only 85% neutralized SMEZ-2, a very potent variant that has not yet been found in any New Zealand isolate. SMEZ-specific Vbeta8 activity was found in culture supernatants of 66% of the GAS isolates, indicating a potential base for the development of a SMEZ targeting vaccine.

Penetrating trauma in children and adolescents in Pietermaritzburg.

BACKGROUND: This project aims to review the spectrum and outcome of penetrating trauma in children and adolescents with the objective of defining the extent of the problem and of developing strategies to reduce the incidence and severity of this form of trauma. METHODS: All patients less than eighteen years of age who were admitted to the Pietermaritzburg Metropolitan Trauma Service (PMTS) following penetrating trauma between December 2012 and December 2018 were identified from the Hybrid Electronic Medical Registry (HEMR). RESULTS: During the five-year period under review, a total of 164 patients less than eighteen years of age sustained penetrating trauma and were admitted to the PMTS. There were 138 males and 26 females. The mean age was 13.29 years and the median age 15 years. There were 70 stab wounds (SW) and 73 gunshot wounds (GSW). There were 21 non-intentional impalement injuries. The mean ISS was 9.04 and the median was 9. A total of 155 plain X-rays were performed, 50 CT scans and 51 CT angiograms in this cohort of patients. Only two ultrasound examinations were performed. A total of 76 patients required an operation, which included 50 laparotomies. Of the patients who underwent a laparotomy, 18 required a repeat laparotomy. There were 46 other procedures undertaken in this cohort of patients, which included two thoracotomies, three laparoscopies and two thoracotomies. The median hospital stay was 2 days and 17 (10%) patients required ICU admission and 7 (4%) died. CONCLUSION: Penetrating trauma in children and adolescents is associated with significant mortality and morbidity. There are similarities with the management of these injuries in adults, but further work is required to ensure that paediatric management algorithms are evidence based.

Trauma in pregnancy at a major trauma centre in South Africa.

BACKGROUND: Trauma in pregnancy poses a unique challenge to clinicians. Literature on this topic is limited in South Africa (SA). OBJECTIVES: To review our institution's experience with the management of trauma in pregnancy in a developing-world setting. METHODS: This study was based at Grey's Hospital, Pietermaritzburg, SA. All pregnant patients who were admitted to our institution following trauma between December 2012 and December 2018 were identified from the Hybrid Electronic Medical Registry (HEMR). RESULTS: During the 6-year study period, 2 990 female patients were admitted by the Pietermaritzburg Metropolitan Trauma Service (PMTS), of whom 89 were pregnant. The mean age of these patients was 25.64 (range 17 - 43) years. The mechanism of injury was road traffic crash (RTC) in 39, stab wounds (SW) in 19, assault other than SW or gunshot wounds (GSW) in 19, GSW in 8, snake bite in 5, impalement in 1, dog bite in 1, hanging in 1, sexual assault in 1 and a single case of a patient being hit by a falling object. A subset of patients sustained >1 mechanism of injury. Thirty patients were managed operatively. The mean time of gestation was 19.16 (5 - 36) weeks. Three patients died, and there were 16 fetal deaths (including 3 lost after the mother's death). Forty-five fetuses were recorded as surviving at discharge, while 25 fetal outcomes were not specifically recorded. There were 2 threatened miscarriages and/or patients with vaginal bleeding, 1 positive pregnancy test with no recorded outcome and no premature births as a result of trauma. CONCLUSIONS: Trauma in pregnancy is relatively uncommon and mostly due to a RTC or deliberately inflicted trauma. Fetal outcome is largely dependent on the severity of the maternal injury, with injuries requiring laparotomy leading to a high fetal mortality rate.

Sarcoidosis, asthma, and asthma-like symptoms among occupants of a historically water-damaged office building.

UNLABELLED: Sarcoidosis is a granulomatous disease of unknown etiology with evidence of association with exposure to microbial agents. In June 2006, we investigated a sarcoidosis cluster among office workers in a water-damaged building. In the course of the investigation, we became aware of a high rate of respiratory complaints including asthma and asthma-like symptoms. We conducted case finding for physician-diagnosed sarcoidosis and asthma and administered a health questionnaire survey and pulmonary function tests (PFTs) to consenting occupants. We compared prevalence ratios (PRs) to the Environmental Protection Agency's Building Assessment Survey and Evaluation study (BASE) and the National Health and Nutrition Examination Survey (NHANES). We identified six sarcoidosis cases. The current building prevalence is 2206 cases/100,000 population, elevated, compared with the US population range of <1-40 cases/100,000. Of current occupants, 77% (105) participated in the health questionnaire survey and 64% (87) in PFTs. Physician-diagnosed asthma was elevated, compared with the US adult population. Adult asthma incidence was 3.3/1000 person-years during the period before building occupancy and 11.5/1000 person-years during the period after building occupancy. Comparisons with US office workers (BASE) yielded elevated PRs for shortness of breath [PR, 9.6; 95% confidence interval (CI), 6.1-15.2], wheeze (PR, 9.1; 95% CI 5.6-14.6), and chest tightness (PR, 5.1; 95% CI 2.8-9.0). PFT results supported reports of respiratory symptoms and diagnoses. Based on our findings building occupants were relocated. PRACTICAL IMPLICATIONS: The remission of occupational asthma caused by certain known antigens improves with early diagnosis and removal from exposure. As a suspected antigen-mediated disease, sarcoidosis might also benefit if affected persons are isolated from continued exposure. Our investigation identified a high prevalence of new-onset sarcoidosis, and asthma among workers of a water damaged building with a history of indoor environmental quality complaints. Removal of all individuals from such environments until completion of building diagnostics, environmental sampling and complete remediation is a prudent measure when feasible.

The spectrum of self inflicted injuries managed at a major trauma centre in South Africa.

BACKGROUND: Infantile hypertrophic pyloric stenosis (IHPS) is the thickening of both muscle layers of the pylorus and is most commonly found in first-born males. It usually presents with projectile, non-bilious vomiting. Late presentation leads to severe dehydration and malnutrition with deranged serum-electrolytes and acid-base imbalance delaying treatment and prolonging hospital stay. This study aims to evaluate the profile, management and outcome of IHPS at a tertiary hospital in Bloemfontein, South Africa. METHOD: The study was a retrospective, descriptive record review including all patients with IHPS admitted to Universitas Hospital from January 2008 to February 2016. Of the 22 patients admitted, files for 19 patients were available for inclusion. RESULTS: Sixteen (84.2%) of the 19 patients were male. Of the 11 patients with available birth order, two were first-, two second-, six third- and one fourth-born. The patients' ages ranged from 27 to 194 days (median 51 days). The most common symptoms were projectile vomiting (78.9%) and poor weight gain (68.4%). Six patients had no ultrasound done, and 17 patients underwent a Ramstedt-pyloromyotomy. Eight patients received atropine as part of their initial management. The duration of symptoms ranged from 1 to 58 days (median 14 days). There was no reported mortality. The length of stay ranged from 2 to 60 days (median 7 days). CONCLUSION: The gender distribution and age at presentation were in keeping with the literature but not the birth order. The delay before surgery emphasises the poor general health and deranged biochemical state the patients present at the hospital.

The spectrum of animal related injuries managed at a major trauma centre in South Africa.

BACKGROUND: Humans come into contact and interact with an array of animals in a number of areas and environments. We set out to review our experience with animal-related injuries in Pietermaritzburg, KwaZulu-Natal, South Africa. METHOD: All patients who sustained an injury secondary to an interaction with an animal in the period December 2012-December 2017 were identified from the Hybrid Electronic Medical Registry (HEMR). RESULTS: There were 104 patients in the study sample. The mean age of patients in the study was 32.8 years, with a range from 1 to 76 years old. 75% (n = 78) were male and 25% (n = 26) female. Out of the 104 animal-related injuries, 67 were blunt trauma, 39 penetrating trauma and 3 a combination of blunt and penetrating trauma. The species causing trauma included dogs (53), horses (29), cows (18), buffalo (1), warthog (1), impala (1) and a single goat (1). The median time from injury to hospitalisation was 46.62 hours (range from 0 to 504 hours). Injuries occurred to the head (n = 32), face (n = 9), neck (n = 32), abdomen (n = 22), urogenital system (n = 6), upper limb (n = 39) and lower limb (n = 39). The Injury Severity Score (ISS) mean for the patients was 8.16, the range 1-4, the median 9 and the standard deviation 6.88. In 49 patients the treatment was non-operative. In the remaining 55 patients, a total of 68 operative procedures were required. Operations included wound debridement/surgical washout (n = 38), laparotomy (n = 9), arterial repair/ligation (n = 8), skin graft (n = 4), craniotomy (n = 5), fasciotomy (n = 2), amputation (n = 1), and placement of an ICP monitor (n = 1). 49 of these operations were for patients with dog bite injuries. The mean hospital stay was 0.13 days with a range of 0-4 days. Four patients were admitted to the Intensive Care Unit (ICU) and two patients died. CONCLUSION: Human interactions with animals may result in injuries which require surgical treatment. The most common animal injury is a dog bite but in the case of the larger domestic farm animals, blunt force type injuries and goring can result in significant injuries which require complex surgical interventions.

New Zealand trends in corneal transplantation over the 25†years 1991-2015.

AIMS: To report the 25-year longitudinal trends in indications and corneal transplantation techniques in New Zealand. METHODS: Statistical analysis of prospectively acquired New Zealand National Eye Bank (NZNEB) electronic database from 1991 to 2015 inclusive. Subjects were recipients of corneal transplants in 62 centres supplied by the NZNEB. Main outcome measures were indications, recipient age and transplantation techniques. RESULTS: From January 1991 to December 2015, NZNEB supplied tissue for 5574 corneal transplants, increasing annually from 89 (1991) to 290 (2015). Penetrating keratoplasty remained the most commonly performed technique throughout the 25-year period, although it decreased from 98.9% of all transplants in 1991 to 60.3% in 2015. There was a corresponding increase in deep anterior lamellar and endothelial keratoplasty over the most recent decade from 2.5% to 7.2% and 4.9% to 31.4%, respectively. Keratoconus remained the leading indication for keratoplasty through to 2015 (34.5%). Regrafts (23.1%) and Fuchs endothelial corneal dystrophy (17.0%) have become more common indications, while bullous keratopathy has become less common (10.8%). There was a bimodal distribution in age with peaks at 20-29 and 60-79 years. There was a reduction in recipients under age 40 and corresponding increase in the percentage of recipients aged 40-69. CONCLUSION: Changing indications and increasing uptake of lamellar keratoplasty have been significant international trends over the last 25 years. However, New Zealand's corneal disease and population characteristics create unique longitudinal trends, with keratoconus remaining the leading indication and penetrating keratoplasty the leading technique from 1991 to 2015.

Comparison between tacrolimus and cyclosporine as immunosuppressive agents compatible with tolerance induction by CD4/CD8 blockade.

BACKGROUND: Donor-specific tolerance can be induced in mice by transient antibody blockade of the CD4 and CD8 co-receptors of T cells. To evaluate the potential application of CD4/CD8 blockade in the clinic, we have asked if either tacrolimus or cyclosporine counteract the tolerogenic process. METHODS: Using the fully mismatched mouse cervical heart transplant model, BALB/c (H2d) to CBA (H2k), the experimental groups were (i) no therapy, (ii) tacrolimus (1 mg/kg, i.p., daily, days 0-14); (iii) cyclosporine (25 mg/kg, i.p., daily, days 0-14), (iv) blocking monoclonal antibodies (mAbs) to CD4 and CD8 (2 mg, i.p., starting day 0 and on alternating days thereafter for a total of six doses), (v) tacrolimus plus mAbs, and (vi) cyclosporine plus mAbs. RESULTS: Allograft survival was prolonged in both the tacrolimus and cyclosporine groups. mAbs alone induced tolerance, and mAbs combined with tacrolimus also induced tolerance. In contrast, the combination of mAbs and cyclosporine was toxic. CONCLUSIONS: The induction of tolerance by blocking CD4 and CD8 was not prevented by tacrolimus. However, combination of cyclosporine with the same tolerogenic protocol was toxic to mice.

STAT 6 up-regulation by FK506 in the presence of interleukin-4.

BACKGROUND: FK506 perturbs normal phosphorylation by inhibition of the PP2B protein phosphatase, calcineurin. Calcineurin activity is required for intracellular signal transduction via the T cell receptor that in turn leads to either TH1, or TH2, -type responses to antigen. This choice of response involves differential phosphorylation of STATS (Signal Transducers and Activators of Transcription) for induction of STAT activity. Interferon-gamma activates STAT1, a TH1-type mediator, and interleukin-4 activates STAT6, a TH2-type mediator. We ask if FK506 biases STAT activation toward a TH2-type response. METHODS: Cells of the RAW 264.7 mouse macrophage line were treated with interleukin-4, or interferon-gamma, plus or minus FK506, and any effect on STAT6 and STAT1 was compared. RESULTS: Interleukin-4 specifically induced activation of STAT6, and pretreatment with FK506 enhanced this activity. Interferon-y induced STAT1 activity but this was not influenced by FK506 pretreatment. CONCLUSION: FK506 protects against allograft rejection by inhibiting interleukin-2 production. Such protection may be enhanced by FK506-mediated up-regulation of STAT6 activity.

Potential for improved therapeutic index of FK506 in liposomal formulation demonstrated in a mouse cardiac allograft model.

BACKGROUND: FK506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue immunosuppressive agent. Despite these benefits, the potential value of FK506 is limited by toxic side effects that result in a narrow therapeutic index. By encapsulating the active drug within liposomes (LipoFK506), a new formulation has been developed that might improve this therapeutic index. METHODS: The biodistribution of tritiated-FK506 administered i.v. showed that the drug remained associated with the liposomal carrier in vivo, and that its tissue distribution was increased in heart and spleen compared to nonliposomal FK506. The immunosuppressive efficacy of lipoFK506 compared with conventional FK506 formulation was tested in vivo. CBA (H2k) mice were engrafted with BALB/c (H2d) mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg LipoFK506, from day 0 to 14. RESULTS: At day 7 the blood trough level of FK506 in the FK506 group was 10-fold higher (25 microg/L) than that in the LipoFK506 group. In both groups the median heart allograft survival was similar at around 26 days. The possibility that FK506, or LipoFK506, might influence antibody-mediated tolerogenesis was addressed in the same model: neither formulation prevented tolerance induction by CD4 and CD8 blockade. CONCLUSION: LipoFK506 is a novel formulation of FK506 that is efficacious at low blood trough FK506 levels. This property has a direct potential benefit for clinical organ transplantation.