Efficacy and safety of a sodium-glucose co-transporter-2 inhibitor versus placebo as an add-on therapy for people with type 2 diabetes inadequately treated with metformin and a dipeptidyl peptidase-4 inhibitor: a systematic review and meta-analysis of randomised controlled trials.

AIMS: To conduct a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor dual therapy in type 2 diabetes. METHODS: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number: CRD42018099398). A search was conducted via PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials of relevant randomised controlled trials up until 14 August 2020 that compared sodium-glucose co-transporter-2 inhibitors vs placebo as add-on therapy after metformin and dipeptidyl peptidase-4 inhibitor therapy. A random-effects model was used. RESULTS: Six randomised controlled trials (1661 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on to metformin and dipeptidyl peptidase-4 inhibitor therapy, was associated with a significant reduction in HbA1c level [mean difference -8 mmol/mol, 95% CI -10, -6 (-0.7%, 95% CI -0.9, -0.6); P < 0.00001], in fasting plasma glucose level [mean difference -1.70 mmol/l, 95% CI -1.91, -1.49; P < 0.00001], in weight (mean difference -1.76 kg, 95% CI -2.04, -1.48; P < 0.00001) and in blood pressure (systolic blood pressure: mean difference -3.6 mmHg, 95% CI -4.8, -2.4; P < 0.00001; diastolic blood pressure: mean difference -1.5 mmHg; 95% CI -2.4, -0.6; P = 0.002). Genital mycotic infections (odds ratio 7.37, 95% CI 3.06, 17.76; P < 0.00001) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (odds ratio 1.16, 95% CI 0.63, 2.13; P = 0.64), in hypoglycaemia (odds ratio 1.36, 95% CI 0.61, 3.04; P = 0.45), or in discontinuation rates due to adverse events (odds ratio 1.52, 95% CI 0.78, 2.97; P = 0.22) between the two groups. CONCLUSIONS: In comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c , fasting plasma glucose and weight in people with type 2 diabetes following inadequate glycaemic control with metformin and a dipeptidyl peptidase-4 inhibitor. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.

What happens to cancer survivors attending a structured cancer survivorship clinic? Symptoms, quality of life and lifestyle changes over the first year at the Sydney Cancer Survivorship Centre clinic.

BACKGROUND: Sydney Cancer Survivorship Centre (SCSC) clinic provides multidisciplinary care after primary adjuvant treatment, with ~ 40% of attendees continuing follow-up with SCSC. METHODS: SCSC survivors completed measures of symptoms, quality-of-life and lifestyle factors at initial visit (T1), first follow-up (T2) and 1 year (T3). Analyses used mixed effect models, adjusted for age, sex and tumour type. RESULTS: Data from 206 survivors (2013-2019) were included: 51% male; median age 63 years; tumour types colorectal 68%, breast 12%, upper gastrointestinal 12%, other 8%. Mean time from: T1 to T2, 3.6 months; T1 to T3, 11.8 months. Mean weight remained stable, but 45% (35/77) of overweight/obese survivors lost weight from T1 to T3. Moderately-intense aerobic exercise increased by 63 mins/week at T2, and 68 mins/week T3. Proportion meeting aerobic exercise guidelines increased from 20 to 41%. Resistance exercise increased by 26 mins/week at T2. Global quality-of-life was unchanged from T1 to T2, improving slightly by T3 (3.7-point increase), mainly in males. Mean distress scores were stable, but at T3 the proportion scoring 4+/10 had declined from 41 to 33%. At T3, improvements were seen in pain, fatigue and energy, but > 20% reported moderate-severe fatigue, pain or sleep disturbance. Proportion reporting 5+ moderate-severe symptoms declined from 35% at T1 to 26% at T3, remaining higher in women. CONCLUSIONS: Survivors attending SCSC increased exercise by 3 months, and sustained it at 1 year. Most overweight/obese survivors avoided further weight gain. Survivors had relatively good quality-of-life, with improvement in many symptoms and lifestyle factors at 1 year.

An Irish National Diabetes in Pregnancy Audit: aiming for best outcomes for women with diabetes.

AIMS: The purpose of this study was to identify the number of pregnancies affected by pre-gestational diabetes in the Republic of Ireland; to report on pregnancy outcomes and to identify areas for improvement in care delivery and clinical outcomes. METHODS: Healthcare professionals caring for women with pre-gestational diabetes during pregnancy were invited to participate in this retrospective study. Data pertaining to 185 pregnancies in women attending 15 antenatal centres nationally were collected and analysed. Included pregnancies had an estimated date of delivery between 1 January and 31 December 2015. RESULTS: The cohort consisted of 122 (65.9%) women with Type 1 diabetes and 56 (30.3%) women with Type 2 diabetes. The remaining 7 (3.8%) pregnancies were to women with maturity-onset diabetes of the young (MODY) (n = 6) and post-transplant diabetes (n = 1). Overall women were poorly prepared for pregnancy and lapses in specific areas of service delivery including pre-pregnancy care and retinal screening were identified. The majority of pregnancies 156 (84.3%) resulted in a live birth. A total of 103 (65.5%) women had a caesarean delivery and 58 (36.9%) infants were large for gestational age. CONCLUSIONS: This audit identifies clear areas for improvement in delivery of care for women with diabetes in the Republic of Ireland before and during pregnancy.

De Novo Donor-Specific HLA Antibodies Are Associated With Rapid Loss of Graft Function Following Islet Transplantation in Type 1 Diabetes.

Outcomes after islet transplantation continue to improve but etiology of graft failure remains unclear. De novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) posttransplant are increasingly recognized as a negative prognostic marker. Specific temporal associations between DSA and graft function remain undefined particularly in programs undertaking multiple sequential transplants. Impact of de novo DSA on graft function over 12 months following first islet transplant was determined prospectively in consecutive recipients taking tacrolimus/mycophenolate immunosuppression at a single center. Mixed-meal tolerance test was undertaken in parallel with HLA antibody assessment pretransplant and 1-3 months posttransplant. Sixteen participants received a total of 26 islet transplants. Five (19%) grafts were associated with de novo DSA. Five (31%) recipients were affected: three post-first transplant; two post-second transplant. DSA developed within 4 weeks of all sensitizing grafts and were associated with decreased stimulated C-peptide (median [interquartile range]) at 3 months posttransplant (DSA negative: 613(300-1090); DSA positive 106(34-235) pmol/L [p = 0.004]). De novo DSA directed against most recent islet transplant were absolutely associated with loss of graft function despite maintained immunosuppression at 12 months in the absence of a rescue nonsensitizing transplant. Alemtuzumab induction immunosuppression was associated with reduced incidence of de novo DSA formation (p = 0.03).

Bacterial contamination of surgical scrub suits worn outside the operating theatre: a randomised crossover study.

In this study, we aimed to evaluate the bacterial contamination of surgical scrub suits worn outside the operating theatre. We randomised 16 anaesthetists on separate occasions into one of 3 groups: restricted to the operating theatre only; theatre and surgical wards; and theatre and departmental office. For each group, sample fabric pieces attached to the chest, waist and hip areas of each suit were removed at 150 min intervals between 08:30 and 16:00 on the day of study, and sent for microbiological assessment. Mean bacterial counts increased significantly over the course of the working day (p = 0.036), and were lower in the chest compared to the hip (p = 0.007) and waist areas (p = 0.016). The mean (SD) bacterial counts, expressed as colony-forming units per cm(2) at 16:00 on the day of study, were 25.2 (43.5) for those restricted to theatre and 18.5 (25.9) and 17.9 (31.0) for those allowed out to visit the ward and office, respectively (p = 0.370). We conclude that visits to ward and office did not significantly increase bacterial contamination of scrub suits.

Perception of cure in prostate cancer: human-led and artificial intelligence-assisted landscape review and linguistic analysis of literature, social media and policy documents.

BACKGROUND: Understanding stakeholders' perception of cure in prostate cancer (PC) is essential to preparing for effective communication about emerging treatments with curative intent. This study used artificial intelligence (AI) for landscape review and linguistic analysis of definition, context and value of cure among stakeholders in PC. MATERIALS AND METHODS: Subject-matter experts (SMEs) selected cure-related key words using Elicit, a semantic literature search engine, and extracted hits containing the key words from Medline, Sermo and Overton, representing academic researchers, health care providers (HCPs) and policymakers, respectively. NetBase Quid, a social media analytics and natural language processing tool, was used to carry out key word searches in social media (representing the general public). NetBase Quid analysed linguistics of key word-specific hit sets for key word count, geolocation and sentiments. SMEs qualitatively summarised key word-specific insights. Contextual terms frequently occurring with key words were identified and quantified. RESULTS: SMEs identified seven key words applicable to PC (number of acquired hits) across four platforms: Cure (12429), Survivor (6063), Remission (1904), Survivorship (1179), Curative intent (432), No evidence of disease (381) and Complete remission (83). Most commonly used key words were Cure by the general public and HCPs (11815 and 224 hits), Survivorship by academic researchers and Survivor by policymakers (378 hits each). All stakeholders discussed Cure and cure-related key words primarily in early-stage PC and associated them with positive sentiments. All stakeholders defined cure differently but communicated about it in relation to disease measurements (e.g. prostate-specific antigen) or surgery. Stakeholders preferred different terms when discussing cure in PC: Cure (academic researchers), Cure rates (HCPs), Potential cure and Survivor/Survivorship (policymakers) and Cure and Survivor (general public). CONCLUSION: This human-led, AI-assisted large-scale qualitative language-based research revealed that cure was commonly discussed by academic researchers, HCPs, policymakers and the general public, especially in early-stage PC. Stakeholders defined and contextualised cure in their communications differently and associated it with positive value.

Structural engineering from an inverse problems perspective.

The field of structural engineering is vast, spanning areas from the design of new infrastructure to the assessment of existing infrastructure. From the onset, traditional entry-level university courses teach students to analyse structural responses given data including external forces, geometry, member sizes, restraint, etc.-characterizing a forward problem (structural causalities → structural response). Shortly thereafter, junior engineers are introduced to structural design where they aim to, for example, select an appropriate structural form for members based on design criteria, which is the inverse of what they previously learned. Similar inverse realizations also hold true in structural health monitoring and a number of structural engineering sub-fields (response → structural causalities). In this light, we aim to demonstrate that many structural engineering sub-fields may be fundamentally or partially viewed as inverse problems and thus benefit via the rich and established methodologies from the inverse problems community. To this end, we conclude that the future of inverse problems in structural engineering is inexorably linked to engineering education and machine learning developments.

Routine screening and rates of metabolic syndrome in patients treated with clozapine and long-acting injectable antipsychotic medications: a cross-sectional study.

OBJECTIVES: To examine the rate of monitoring of metabolic syndrome and actual rates of metabolic syndrome in two patient cohorts [clozapine treatment and long-acting injectable (LAI) antipsychotic] who are reviewed on an equally regular basis (1-4 weekly) for administration of treatment. METHODS: Clinical and laboratory data are examined on 119 patients treated with clozapine and 116 patients treated with LAI antipsychotic medications to determine the rates of metabolic syndrome and evidence of monitoring for metabolic syndrome in the previous 6 months. Individuals with insufficient data from these cohorts were invited to attend for metabolic screening to determine actual rates of metabolic syndrome in these two cohorts of patients. RESULTS: All metabolic parameters were monitored to a significantly greater extent in the clozapine cohort (>90%), compared to those treated with LAI antipsychotic medications (<50%) (blood pressure, weight, lipid and glucose levels; p < 0.001). Metabolic syndrome was present in 38.9% of those treated with clozapine compared to 31.1% of patients treated with LAI antipsychotic medications (X2 = 0.54, p = 0.46). CONCLUSIONS: These findings suggest that a robust screening plan should be in place to monitor for metabolic syndrome in individuals treated with LAI antipsychotic medications. This screening should include measurement of body weight, waist circumference, fasting glucose, lipids and fasting insulin levels. Early recognition of abnormal metabolic parameters allows early intervention, therefore, improving long-term cardiovascular outcomes.

Diabetes care and pregnancy outcomes for women with pregestational diabetes in Ireland.

AIMS: Pre-gestational diabetes mellitus (PGDM) is associated with adverse outcomes. We aimed to examine pregnancies affected by PGDM; report on these pregnancy outcomes and compare outcomes for patients with type 1 versus type 2 diabetes mellitus; compare our findings to published Irish and United Kingdom (UK) data and identify potential areas for improvement. METHODS: Between 2016 and 2018 information on 679 pregnancies from 415 women with type 1 Diabetes Mellitus and 244 women with type 2 diabetes was analysed. Data was collected on maternal characteristics; pregnancy preparation; glycaemic control; pregnancy related complications; foetal and maternal outcomes; unscheduled hospitalisations; congenital anomalies and perinatal deaths. RESULTS: Only 15.9% of women were adequately prepared for pregnancy. Significant deficits were identified in availability and attendance at pre-pregnancy clinic, use of folic acid, attaining appropriate glycaemic targets and appropriate retinal screening. The majority of pregnancies (n = 567, 83.5%) resulted in a live birth but the large number of infants born large for gestational age (LGA) (n = 280, 49.4%), born prematurely <37 weeks and requiring neonatal intensive care unit (NICU) admission continue to be significant issues. CONCLUSIONS: This retrospective cohort study identifies multiple targets for improvements in the provision of care to women with pre-gestational DM which are likely to translate into better pregnancy outcomes.

Burden of disease, disability-adjusted life years and frailty prevalence.

BACKGROUND: Burden of disease (BoD) using disability-adjusted life years (DALY) is a useful summary measure of population health and estimates are provided for Ireland annually. We hypothesized that BoD may be used as a predictor of frailty prevalence. AIM: To examine the correlation between frailty measured by the accumulation of deficits (frailty index, FI) and Fried frailty phenotype (FFP) classifications and BoD, in an Irish context. DESIGN: Cross-sectional secondary analysis. METHODS: Data were obtained from waves two and three of The Survey of Health, Ageing and Retirement in Europe for Irish adults aged ≥65 in 2007. Frailty was defined by a 70-item FI and the FFP. Years lived with disability (YLD), years of life lost (YLL) and DALY were calculated using adapted equations from the World Health Organization and, where possible, disability weights, sequelae and durations as in the Global BoD (GBD) project (2016). RESULTS: Of 1035 participants, 442 were ≥65 years. Mean DALY were significantly higher in those identified as frail (FI: 3.31, P < 0.0001, n = 406; FFP: 2.46, P = 0.005, n = 319). For the FI, stronger correlation was found for DALY (r = 0.5431, P < 0.0001) than for age (r = 0.275, P < 0.0001). Controlling for confounders, DALY were an independent predictor of frailty when measured with the FI (OR 1.17, 95% CI: 1.10-1.24) but not with the FFP (OR 1.079, 95%% CI 1.00-1.17). CONCLUSIONS: Frailty correlates significantly with DALY, and more so with the FI than the FFP, reaffirming that these measures are different constructs. GBD data could represent a predictor of population-level frailty estimates, facilitating improved comparisons.

Integrated Care Models for Managing and Preventing Frailty: A Systematic Review for the European Joint Action on Frailty Prevention (ADVANTAGE JA).

Frailty requires concerted integrated approaches to prevent functional decline. Although there is evidence that integrating care is effective for older people, there is insufficient data on outcomes from studies implementing integrated care to prevent and manage frailty. We systematically searched PubMed and Cochrane Library database for peer-reviewed medical literature on models of care for frailty, published from 2002 to 2017. We considered the effective and transferable components of the models of care and evidence of economic impact, where available. Information on European Union-funded projects or those registered with the European Innovation Partnership on Active and Healthy Ageing, and grey literature (including good practices) were also considered. We found 1,065 potential citations and 170 relevant abstracts. After excluding reports on specific diseases, processes or interventions and service models that did not report data, 42 full papers met the inclusion criteria. The evidence showed that few models of integrated care were specifically designed to prevent and tackle frailty in the community and at the interface between primary and secondary (hospital) care. Current evidence supports the case for a more holistic and salutogenic response to frailty, blending a chronic care approach with education, enablement and rehabilitation to optimise function, particularly at times of a sudden deterioration in health, or when transitioning between home, hospital or care home. In all care settings, these approaches should be supported by comprehensive assessment and multidimensional interventions tailored to modifiable physical, psychological, cognitive and social factors.

Endothelial progenitor cells for the treatment of diabetic vasculopathy: panacea or Pandora's box?

The discovery of endothelial progenitor cell (EPC) a decade ago has refuted the previous belief that vasculogenesis only occurs during embryogenesis. The reduced circulating concentration of EPCs is a surrogate marker of endothelial function and has been implicated in the pathogenesis of many vascular diseases. To date, the therapeutic benefit of neovascularization in ischaemic conditions in a non-diabetic setting has been demonstrated. This article aims to review the biology of EPCs in the diabetic setting with special emphasis on the effects of cardiovascular risk factor modification on EPC phenotype and methods to reverse or augment EPC dysfunction. The potential of the use of EPCs in the treatment of the diabetic vascular dysfunction will also be discussed.

Projecting the Burden of Chronic Kidney Disease in a Developed Country and Its Implications on Public Health.

BACKGROUND: Chronic Kidney Disease (CKD) is a major public health problem worldwide. There is limited literature on a model to project the number of people with CKD. This study projects the number of residents with CKD in Singapore by 2035 using a Markov model. METHODS: A Markov model with nine mutually exclusive health states was developed according to the clinical course of CKD, based on a discrete time interval of 1 year. The model simulated the transition of cohorts across different health states from 2007 to 2035 using prevalence, incidence, mortality, disease transition, and disease detection rates. RESULTS: From 2007 to 2035, the number of residents with CKD is projected to increase from 316,521 to 887,870 and the prevalence from 12.2% to 24.3%. Patients with CKD stages 1-2 constituted the largest proportion. The proportion of undiagnosed cases will decline from 72.1% to 56.4%, resulting from faster progression to higher CKD stages and its eventual detection. CONCLUSION: By 2035, about one-quarter of the Singapore residents are expected to have CKD. National policies need to focus on primary disease prevention and early disease detection to avoid delayed treatment of CKD which eventually leads to end-stage renal disease.

Key Messages for a Frailty Prevention and Management Policy in Europe from the ADVANTAGE JOINT ACTION Consortium.

In the 2015 Ageing Report, the European Commission (EC) and the Economic Policy Committee stated that coping with the challenge posed by an ageing population will require determined policy action in Europe, particularly in reforming pension, health care and long-term care systems. The concern for this situation motivated the EC, the Parliament and many of the Member States (MS) to co-fund, in the 2015 call of the Third European Health Programme of the European Union 2014-2020, the first Joint Action (JA) on the prevention of frailty. ADVANTAGE JA brings together 33 partners from 22 MSs for 3 years. It aims to build a common understanding on frailty to be used in the MSs by policy makers and other stakeholders involved in the management, both at individual and population level, of older people who are frail or at risk for developing frailty throughout the European Union (EU). It is a formidable challenge but also a great opportunity for concerted action resulting in fostering effective and successful policies in frailty prevention and management in the participating MS. The Consortium has 2 years of hard work ahead to contribute to the needed change for frailty related disability free Europe. The first practical step towards this aim was the preparation of a document: the State of the Art on Frailty Report to support an overview of evidence of what works and what does not work on frailty prevention and management. Subsequently, this will be reflected in the advice that the JA will give to policy makers at MS level. Overall, these messages intend to be an instrument of added value to advocate for policy driven decisions on frailty prevention and management in the JA participating MSs and subsequently towards a frailty related disability free older population in Europe. The aim of this paper is to describe ADVANTAGE JA general structure, approach and recommendations towards a European health and social policy which will support frailty prevention in the participating MS.

Allogeneic Mesenchymal Stromal Cells (MSCs) are of Comparable Efficacy to Syngeneic MSCs for Therapeutic Revascularization in C57BKSdb/db Mice Despite the Induction of Alloantibody.

Intramuscular administration of mesenchymal stromal cells (MSCs) represents a therapeutic option for diabetic critical limb ischemia. Autologous or allogeneic approaches may be used but disease-induced cell dysfunction may limit therapeutic efficacy in the former. Our aim was to compare the efficacy of allogeneic and autologous MSC transplantation in a model of hindlimb ischemia in diabetes mellitus and to determine whether allogeneic transplantation would result in the activation of an immune response. MSCs were isolated from C57BL/6 (B6) and diabetic obese C57BKSdb/db mice. Phosphate-buffered saline (control group), and MSCs (1 × 106) from B6 (allogeneic group) or C57BKSdb/db (syngeneic group) were administered intramuscularly into the ischemic thigh of C57BKSdb/db mice following the induction of hindlimb ischemia. MSCs derived from both mouse strains secrete several angiogenic factors, suggesting that the potential therapeutic effect is due to paracrine signaling. Administration of allogeneic MSCs significantly improved blood perfusion as compared with the control group on week 2 and 3, post-operatively. In comparison with the control group, syngeneic MSCs significantly improved blood perfusion at week 2 only. There was no statistical difference in blood perfusion between allogeneic and syngeneic MSC groups at any stages. There was no statistical difference in ambulatory and necrosis score among the three groups. Amputation of toes was only observed in the control group (one out of seven animals). Alloantibody was detected in three out of the eight mice that received allogeneic MSCs but was not observed in the other groups. In summary, we demonstrated comparable efficacy after transplantation of autologous and allogeneic MSCs in a diabetic animal model despite generation of an immune response.

Distinct effects of high-glucose conditions on endothelial cells of macrovascular and microvascular origins.

Recent studies implicate hyperglycemia as an important cause of macrovascular and ocular complications in diabetes mellitus. In this study, the authors examined the effect of high glucose on macrovascular and microvascular endothelial cell viability and apoptosis in culture. Human aortic endothelial cells (HAECs) and human retinal endothelial cells (HRECs) were exposed to normal-glucose conditions (NG) and high-glucose conditions (NG supplemented with 25 mM D-glucose) for 72 h in vitro. D-Mannitol was used as an osmotic control. Cell viability was assessed by methlythiazolydiphenyltetrazolium bromide (MTT) assay, and induction of apoptosis was assessed by Hoechst staining. Statistics were analyzed by paired t tests. In HAECs, cell viability was decreased by 12.9% in high-glucose conditions, and apoptotic cells were significantly increased by 77%. However, in HRECs, cell viability was increased by 14.9% in high-glucose conditions, and apoptotic cells were significantly decreased by 33.3%. Mannitol did not show any effect on cell survival or apoptosis ruling out an osmotic effect. High-glucose conditions reduce cell viability and induce apoptosis in HAECs, which may contribute to macrovascular complications associated with diabetes. In contrast, high-glucose increases viability in HRECs and inhibits apoptosis, which may contribute to the development of diabetic retinopathy.

Omega-3 fatty acids in the management of autism spectrum disorders: findings from an open-label pilot study in Singapore.

The goal of this open-label trial was to examine the efficacy and safety of a 12-week omega-3 fatty acids supplementation among children suffering with Autism Spectrum Disorders (ASD). A total of 41 children and adolescents aged 7-18 years (36 boys, 5 girls; mean age = 11.66, s.d. = 3.05) diagnosed with ASD participated in the study. At post-treatment, participants showed significant improvements on all subscales of the Social Responsiveness Scale (P < 0.01) and the Social and Attention Problems syndrome scales of the Child Behavior Checklist (P < 0.05). Blood fatty acid levels were significantly correlated with changes in the core symptoms of ASD. Baseline levels of blood fatty acid levels were also predictive of response to the omega-3 treatment. Omega-3 fatty acids supplementation was well-tolerated and did not cause any serious side effects. Our findings lend some preliminary support for the use of omega-3 fatty acids supplementation in addressing ASD. Future randomized controlled trials of omega-3 fatty acids in ASD with blood fatty acid measurements with a larger sample and longer follow-up period is warranted.

Neutrophil alkaline phosphatase score in chronic granulocytic leukaemia: effects of splenectomy and antileukaemic drugs.

Staining with naphthol AS phosphate and Fast Blue BB salt has been used for the estimation of neutrophil alkaline phosphatase (NAP) scores in patients with chronic granulocytic leukaemia (CGL). The very low scores found at diagnosis rise when the disease is treated, and there is some inverse correlation between the NAP score and the absolute neutrophil count. Patients treated intensively developed high NAP scores. Elective splenectomy performed during the chronic phase of CGL is followed by a pronounced but transient neutrophilia and a concurrent striking rise in the NAP score. Similar changes were observed in patients without CGL who underwent splenectomy. These observations can be explained by assuming that newly formed neutrophils in CGL have a normal content of NAP but are rapidly sequestered in non-circulating extramedullary pools, whereas the circulating neutrophil with a typically low NAP content is a relatively aged cell which has lost enzyme activity. In subjects with or without CGL, removal of the spleen, a major site of such pooling, temporarily permits the circulation of newly formed neutrophils but eventually other organs assume the sequestering functions of the spleen. Thus the aberrations of NAP score seen in CGL might be attributable not to an intrinsic cellular defect but to an exaggeration of the granulocyte storage phenomena which also occur in subjects without CGL.

Comparison of the expression of p53, p21, Bax and the induction of apoptosis between patients with basal cell carcinoma and normal controls in response to ultraviolet irradiation.

AIM: Ultraviolet light (UV) is known to cause DNA damage in the epidermis. The damaged DNA is repaired or deleted by apoptosis to prevent the generation of cancer. It has been suggested that a deficient apoptotic mechanism may predispose individuals to skin cancer. Therefore, the response of normal controls and patients with basal cell carcinoma (BCC) to UV irradiation was investigated. METHODS: The buttock skin from normal volunteers and patients with BCC was irradiated using solar simulated radiation (SSR). SSR mimics the effect of natural sunlight. Skin biopsies were excised and examined for p53, p21, and Bax protein expression and for the induction of apoptosis. RESULTS: At 33 hours after UV irradiation, the induction of apoptosis was significantly higher (p = 0.04) in patients with BCC than in normal volunteers (Mann Whitney test). A trend towards higher p21 expression was found at 33 hours in patients with BCC (mean, 18.69 positive cells/field) than in normal volunteers (mean, 9.89), although this difference was not significant (p = 0.05 positive cells/field). CONCLUSION: These results may imply that patients with BCC have enhanced sensitivity to UV irradiation or that there is some defect in the cell arrest or repair pathways, which results in damaged cells been pushed into apoptosis rather than repair.