High throughput screening aids clinical decision-making in refractory acute myeloid leukaemia.

BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.

Ocular co-morbidities in patients with atopic dermatitis - a cross-sectional study from a tertiary referral hospital, Malaysia.

INTRODUCTION: Atopic dermatitis (AD) is a chronic relapsing pruritic inflammatory skin disease that commonly occurs among children as well as adults. AD patients were reported to have high prevalence of ocular manifestations, which may be due to the disease nature or drug complications. This study aimed to determine the prevalence of ocular manifestations in patients with AD. MATERIALS AND METHODS: Eighty patients who fulfilled the UK Working Party's Diagnostic Criteria for Atopic Dermatitis were included in the cross-sectional study. A standardized case report form was formulated to collect the demographic data and disease profile of the participants. AD severity was evaluated using the EASI and SCORAD score. All patients underwent a complete ophthalmological evaluation. RESULTS: The prevalence of ocular manifestations among the patients with AD was 48.8%. Fifty-four (67.5%) patients had facial dermatitis and 37 (46.2%) showed periorbital signs. The mean AD disease duration was 10.99 ± 11.20 years. Majority of the patients had mild to moderate AD. The most frequent ocular manifestation was allergic conjunctivitis (18.75%) followed by cataract (8.75%) and ocular hypertension (8.75%). Among the patients with ocular manifestations, 27 (69.2%) patients regularly applied topical corticosteroids on the face. The use of systemic corticosteroids was seen in 19 (42.2%) patients. Prolonged AD duration was significantly associated with the development of ocular manifestations. CONCLUSIONS: Nearly half of the patients with AD were complicated with ocular disease regardless of the AD severity, facial dermatitis and presence of periorbital signs. Long disease duration is associated with ocular manifestations, especially steroid related complications.

Obesity Measures and Definitions of Sarcopenic Obesity in Singaporean Adults - the Yishun Study.

OBJECTIVES: Due to the lack of a uniform obesity definition, there is marked variability in reported sarcopenic obesity (SO) prevalence and associated health outcomes. We compare the association of SO with physical function using current Asian Working Group for Sarcopenia (AWGS) guidelines and different obesity measures to propose the most optimal SO diagnostic formulation according to functional impairment, and describe SO prevalence among community-dwelling young and old adults. DESIGN: Obesity was defined according to waist circumference (WC), percentage body fat (PBF), fat mass index (FMI), fat mass/fat-free mass ratio (FM/FFM), or body mass index (BMI). SO was defined as the presence of both obesity and AWGS sarcopenia. Muscle function was compared among phenotypes and obesity definitions using ANOVA. Differences across obesity measures were further ascertained using multiple linear regressions to determine their associations with the Short Physical Performance Battery (SPPB). SETTING: Community-dwelling adults 21 years old and above were recruited from a large urban residential town in Singapore. PARTICIPANTS: 535 community-dwelling Singaporeans were recruited (21-90 years old, 57.9% women), filling quotas of 20-40 participants in each sex- and age-group. MEASUREMENTS: We took measurements of height, weight, BMI, waist and hip circumferences, body fat, muscle mass, muscle strength, and functional assessments. Questionnaire-based physical and cognitive factors were also assessed. RESULTS: Overall prevalence of SO was 7.6% (WC-based), 5.1% (PBF-based), 2.7% (FMI-based), 1.5% (FM/FFM-based), and 0.4% (BMI-based). SO was significantly associated with SPPB only in the FMI model (p<0.05), and total variance explained by the different regression models was highest for the FMI model. CONCLUSIONS: Our findings suggest FMI as the most preferred measure for obesity and support its use as a diagnostic criteria for SO.

Melanoma-associated glycosyltransferase GCNT2 as an emerging biomarker and therapeutic target.

In metastatic melanoma, with a dismal survival rate and propensity for treatment resistance and recurrence, it is critical to establish biomarkers that better predict treatment response and disease severity. The melanoma glycome, composed of complex carbohydrates termed glycans, is an under-investigated area of research, although it is gaining momentum in the cancer biomarker and therapeutics field. Novel findings suggest that glycans play a major role in influencing melanoma progression and could be exploited for prognosticating metastatic activity and/or as therapeutic targets. In this review, we discuss the role of aberrant glycosylation, particularly the specialized function of ß1,6 N-acetylglucosaminyltransferase 2 (GCNT2), in melanoma pathogenesis and summarize mechanisms of GCNT2 regulation to illuminate its potential as a predictive marker and therapeutic target.

Malnutrition and Sarcopenia in Community-Dwelling Adults in Singapore: Yishun Health Study.

OBJECTIVES: To determine the overlapping prevalence of malnutrition and sarcopenia and the association between parameters of malnutrition with muscle mass and strength in a community-dwelling Singaporean adult population. DESIGN: This was a cross-sectional study. SETTING: Large north-eastern residential town of Yishun in Singapore. PARTICIPANTS: Random sampling of community-dwelling Singaporeans aged 21-90 years old (n=541). MEASUREMENTS: Anthropometry, body composition and handgrip strength (muscle strength) were measured. Sarcopenia was identified using dual-energy x-ray absorptiometry scan (muscle mass). Nutritional status was measured using Mini Nutritional Assessment (MNA-SF). Other questionnaires collected included physical activity and cognition. Associations between nutritional status with sarcopenia as well as with muscle mass and strength were analysed using multinomial logistics and linear regressions. RESULTS: The overall population-adjusted prevalence of those at nutritional risk and malnourished were 18.5% and 0.1% respectively. More than a third of participants (35%) who were at nutritional risk were sarcopenic. Malnourished participants were all sarcopenic (100%, N=2) whereas those who were sarcopenic, 27.0% (N=37) were at nutritional risk/malnourished. Being at nutritional risk/malnourished was significantly associated with 2 to 3 times increased odds of sarcopenia in multivariate analyses adjusting for age, gender, physical activity level and cognition, and fat mass index. Favourable MNA parameter scores on food intake and BMI were positively associated with greater muscle mass and handgrip strength (p<0.05). CONCLUSION: Given the overlapping clinical presentation of malnutrition and sarcopenia, community screening protocols should include combination screening of nutritional status and sarcopenia with appropriate interventions to mitigate risk of adverse health outcomes.

ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction

This American Society for Gastrointestinal Endoscopy guideline provides evidence-based recommendations for the endoscopic management of gastric outlet obstruction (GOO). We applied the Grading of Recommendations, Assessment, Development and Evaluation methodology to address key clinical questions. These include the comparison of (1) surgical gastrojejunostomy to the placement of self-expandable metallic stents (SEMS) for malignant GOO, (2) covered versus uncovered SEMS for malignant GOO, and (3) endoscopic and surgical interventions for the management of benign GOO. Recommendations provided in this document were founded on the certainty of the evidence, balance of benefits and harms, considerations of patient and caregiver preferences, resource utilization, and cost-effectiveness.

Short- and potential long-term adverse health outcomes of COVID-19: a rapid review.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of patients infected worldwide and indirectly affecting even more individuals through disruption of daily living. Long-term adverse outcomes have been reported with similar diseases from other coronaviruses, namely Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). Emerging evidence suggests that COVID-19 adversely affects different systems in the human body. This review summarizes the current evidence on the short-term adverse health outcomes and assesses the risk of potential long-term adverse outcomes of COVID-19. Major adverse outcomes were found to affect different body systems: immune system (including but not limited to Guillain-Barré syndrome and paediatric inflammatory multisystem syndrome), respiratory system (lung fibrosis and pulmonary thromboembolism), cardiovascular system (cardiomyopathy and coagulopathy), neurological system (sensory dysfunction and stroke), as well as cutaneous and gastrointestinal manifestations, impaired hepatic and renal function. Mental health in patients with COVID-19 was also found to be adversely affected. The burden of caring for COVID-19 survivors is likely to be huge. Therefore, it is important for policy makers to develop comprehensive strategies in providing resources and capacity in the healthcare system. Future epidemiological studies are needed to further investigate the long-term impact on COVID-19 survivors.

Cognitive Frailty and Its Association with Nutrition and Depression in Community-Dwelling Older People.

BACKGROUND: Cognitive frailty is a condition where physical frailty and mild cognitive impairment (MCI) co-exist. It is associated with increased risk of dementia and dependency. Previous studies reported that malnutrition and depression are associated with physical frailty and MCI; however, their relationships with cognitive frailty remained to be explored. The aims of this study were to examine the association of nutrition and depression with cognitive frailty, in comparison to having physical frailty or MCI alone. METHODS: This study employed a cross-sectional design. Data collection was conducted in the community settings on the older people without dementia. Dependent variables were cognitive frailty, physical frailty, and MCI. The independent variables were depression and nutrition. Multi-nominal regression was employed to examine the relationships between the dependent and independent variables. The associations were adjusted by four known co-variates, including age, gender, education and APOE ε4 carrier status. RESULTS: A total of 185 participants were recruited from four community centres and one elderly hostel and completed the data collection. Approximately 44.9% of the older people with physical frailty and 82.5% of elderly with MCI belonged to cognitive frailty. Multi-nominal regression models showed that depression is positively associated with cognitive frailty and with physical frailty, but not associated with solely MCI. Nutrition is negatively associated with cognitive frailty, but not associated with physical frailty or MCI alone. CONCLUSION: Cognitive frailty is associated with malnutrition and depression. Therapeutic interventions managing depression and malnutrition may focus the older people with cognitive frailty to improve efficacy and cost-effectiveness.

Sequential spine-hand radiography for assessing skeletal maturity with low radiation EOS imaging system for bracing treatment recommendation in adolescent idiopathic scoliosis: a feasibility and validity study.

PURPOSE: The EOS-imaging system is increasingly adopted for clinical follow-up in scoliosis with the advantages of simultaneous biplanar imaging of the spine in an erect position. Skeletal maturity assessment using a hand radiograph is an essential adjunct to spinal radiography in scoliosis follow-up. This study aims at testing the feasibility and validity of a newly proposed EOS workflow with sequential spine-hand radiography for skeletal maturity assessment and bracing recommendation. METHODS: EOS spine-hand radiographs from patients with diagnosis of idiopathic scoliosis, including both sexes and an age range of ten to 14 years, were scored using the Thumb Ossification Composite Index (TOCI), Sanders and Risser methods. Intraclass correlation coefficients (ICCs) were calculated for inter/intraobserver agreement and were tested with Cronbach's alpha values. RESULTS: In all, 60 EOS-spine hand radiographs selected from subjects with diagnosis of adolescent idiopathic scoliosis (AIS), including 32 male patients (mean age 11.53 years; 10 to 14) and 28 female patients (mean age 11.50 years; 10 to 13) who underwent sequential spine-hand low dose EOS imaging were generated for analysis. The overall interobserver (ICC = 0.997) and intraobserver agreement (α > 0.9) demonstrated excellent agreement for TOCI staging; ICC > 0.994 for both TOCI and Sanders staging comparing traditional digital versus EOS hand radiography; ICC ≥ 0.841 for agreement on bracing recommendation among TOCI versus the Risser and Sanders system. CONCLUSION: With the proposed new EOS workflow it was feasible to produce high image quality for skeletal maturity assessment with excellent reliability and validity to inform consistent bracing recommendation in AIS. The workflow is applicable for busy daily clinic settings in tertiary scoliosis centres with reduced time cost, improved efficiency and throughput of the radiology department. LEVEL OF EVIDENCE: III.

Faecal microbiota transplantation for treatment of recurrent or refractory Clostridioides difficile infection in Hong Kong.

INTRODUCTION: Clostridioides difficile infection (CDI) is a leading cause of healthcare-associated infection globally, causing significant morbidity and mortality. Faecal microbiota transplantation (FMT) has emerged as a promising option for recurrent and refractory CDI. This study aimed to assess the safety, efficacy, and feasibility of FMT for CDI in Hong Kong. METHODS: We conducted a single-centre, retrospective study for all consecutive cases of recurrent or refractory CDI who underwent FMT from 2013 to 2018. Clinical demographics, outcome, and safety parameters were collected. RESULTS: A total of 24 patients with recurrent or refractory CDI (median age 70 years, interquartile range=45.0-78.3 years; 67% male) were included. Over 80% had been recently hospitalised or were long-term care facility residents. Faecal microbiota transplantation was delivered by feeding tube in 11 (45.8%), oesophagogastroduodenoscopy in eight (33.3%), and colonoscopy in six (25%) of the patients. Resolution of diarrhoea without relapse within 8 weeks was achieved in 21 out of 24 patients (87.5%) after FMT. No deaths occurred within 30 days. The FMT was well tolerated and no serious adverse events attributable to FMT were reported. CONCLUSION: Our results confirm that FMT is a safe, efficacious, and feasible intervention for patients with refractory or recurrent CDI in Hong Kong. Given the increasing disease burden and the lack of effective alternatives in Hong Kong for difficult-to-treat cases of CDI, we recommend that a territory-wide FMT service be established to address increasing demand for this treatment.

Alzheimer's disease: insights for risk evaluation and prevention in the Chinese population and the need for a comprehensive programme in Hong Kong/China.

With the ageing of the global population, China is projected to be impacted significantly by the rising number of patients with Alzheimer's disease (AD). A cure for AD is not yet available, so society should be prepared for an increasing AD-related burden. In this review, we examine this impending problem and provide overviews on (a) the magnitude of the problem of AD in Hong Kong/China in the near future; (b) the genetic and lifestyle risk factors that contribute to AD; (c) current diagnostic approaches and the potential of newly discovered genetic biomarkers for early detection; (d) medications, non-pharmacological interventions, and possible preventive measures; and (e) the need for social and psychological care from the community. In Hong Kong, primary care and AD-related support for at-risk individuals, patients, and caregivers are inadequate. A joint effort from the medical community, government, universities, non-governmental organisations/charities, and industry should initiate the development of a long-term programme for AD. Finally, we outline recommendations for the relevant parties to consider.

Immunoglobulin G4-related disease in Hong Kong: clinical features, treatment practices, and its association with multisystem disease.

INTRODUCTION: Immunoglobulin G4-related disease remains an under-recognised and evolving disease. Local data are sparse and previous publications have been limited to individual case reports or case series only. We conducted this study to review the clinical features, treatment practices, and factors associated with multisystem involvement in Hong Kong. We described the clinical features and treatment modalities of the largest cohort of immunoglobulin G4-related disease in our locality thus far. METHODS: We retrospectively evaluated all patients with immunoglobulin G4-related disease between January 2003 and December 2015 in Queen Mary Hospital and combined this with patient data extracted from previous local publications. We analysed the clinical features, treatment practices, and factors associated with the number of organ systems involved. RESULTS: A total of 104 patients (55 from Queen Mary Hospital and 49 from literature review) were identified. Patients were predominantly older men (mean [standard deviation] age, 61.9 [12.7] years; male-to-female ratio=3:1) and 94.4% had elevated pre-treatment serum immunoglobulin G4 levels. Hepatobiliary and pancreatic system (40.4%), salivary gland (33.7%), lymph node (29.8%), and eye (19.2%) were the most common organ systems involved. Lymphadenopathy was associated with glucocorticoid use (odds ratio=2.65; 95% confidence interval, 1.08-6.54; P=0.034). Pre-treatment serum immunoglobulin G4 levels correlated with the number of organ systems involved (ß=0.347; P=0.004) and, specifically, more associated with patients having salivary gland involvement than those without (mean, 1109 mg/dL vs 599 mg/dL; P=0.012). CONCLUSION: We identified pre-treatment serum immunoglobulin G4 to be associated with multisystem disease, especially with salivary gland involvement, highlighting its potential for disease prognostication and monitoring. Increased physician awareness and multidisciplinary efforts are required for early diagnosis and optimal management of this masquerading disease.

The importance of international collaboration for rare diseases research: a European perspective.

Over the last two decades, important contributions were made at national, European and international levels to foster collaboration into rare diseases research. The European Union (EU) has put much effort into funding rare diseases research, encouraging national funding organizations to collaborate together in the E-Rare program, setting up European Reference Networks for rare diseases and complex conditions, and initiating the International Rare Diseases Research Consortium (IRDiRC) together with the National Institutes of Health in the USA. Co-ordination of the activities of funding agencies, academic researchers, companies, regulatory bodies, and patient advocacy organizations and partnerships with, for example, the European Research Infrastructures maximizes the collective impact of global investments in rare diseases research. This contributes to accelerating progress, for example, in faster diagnosis through enhanced discovery of causative genes, better understanding of natural history of rare diseases through creation of common registries and databases and boosting of innovative therapeutic approaches. Several examples of funded pre-clinical and clinical gene therapy projects show that integration of multinational and multidisciplinary expertize generates new knowledge and can result in multicentre gene therapy trials. International collaboration in rare diseases research is key to improve the life of people living with a rare disease.

The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide, and is on the rise in the United States. Previous studies showed that the matricellular protein CCN1 (CYR61) is induced during hepatic injuries and functions to restrict and resolve liver fibrosis. Here, we show that CCN1 suppresses hepatocarcinogenesis by inhibiting carcinogen-induced compensatory hepatocyte proliferation, thus limiting the expansion of damaged and potentially oncogenic hepatocytes. Consistent with tumor suppression, CCN1 expression is downregulated in human HCC. Ccn1(ΔHep) mice with hepatocyte-specific deletion of Ccn1 suffer increased HCC tumor multiplicity induced by the hepatocarcinogen diethylnitrosamine (DEN). Knockin mice (Ccn1(dm/dm)) that express an integrin α6ß1-binding defective CCN1 phenocopied Ccn1(ΔHep) mice, indicating that CCN1 acts through its α6ß1 binding sites in this context. CCN1 effectively inhibits epidermal growth factor receptor (EGFR)-dependent hepatocyte proliferation through integrin α6-mediated accumulation of reactive oxygen species (ROS), thereby triggering p53 activation and cell cycle block. Consequently, Ccn1(dm/dm) mice exhibit diminished p53 activation and elevated compensatory hepatocyte proliferation, resulting in increased HCC. Furthermore, we show that a single dose of the EGFR inhibitor erlotinib delivered prior to DEN-induced injury was sufficient to block compensatory proliferation and annihilate development of HCC nodules observed 8 months later, suggesting potential chemoprevention by targeting CCN1-inhibitable EGFR-dependent hepatocyte proliferation. Together, these results show that CCN1 is an injury response protein that functions not only to restrict fibrosis in the liver, but also to suppress hepatocarcinogenesis by inhibiting EGFR-dependent hepatocyte compensatory proliferation.

The matricellular protein CCN1 promotes mucosal healing in murine colitis through IL-6.

The matricellular protein CCN1 (CYR61) is known to function in wound healing and is upregulated in colons of patients with Crohn's disease and ulcerative colitis, yet its specific role in colitis is unknown. Here we have used Ccn1(dm/dm) knockin mice expressing a CCN1 mutant unable to bind integrins α6ß1 and αMß2 as a model to probe CCN1 function in dextran sodium sulfate (DSS)-induced colitis. Ccn1(dm/dm) mice exhibited high mortality, impaired mucosal healing, and diminished interleukin-6 (IL-6) expression during the repair phase of DSS-induced colitis compared with wild-type mice, despite having comparable severity of initial inflammation and tissue injury. CCN1-induced IL-6 expression in macrophages through integrin αMß2 and in fibroblasts through α6ß1, and IL-6 promoted intestinal epithelial cell (IEC) proliferation. Administration of purified CCN1 protein fully rescued Ccn1(dm/dm) mice from DSS-induced mortality, restored IEC proliferation and enhanced mucosal healing, whereas delivery of IL-6 partially rectified these defects. CCN1 therapy accelerated mucosal healing and recovery from DSS-induced colitis even in wild-type mice. These findings reveal a critical role for CCN1 in restoring mucosal homeostasis after intestinal injury in part through integrin-mediated induction of IL-6 expression, and suggest a therapeutic potential for activating the CCN1/IL-6 axis for treating inflammatory bowel disease.

The clinical utility of conventional karyotyping in the detection of cytogenetic abnormalities in soft tissue tumours: an Asian institutional experience.

OBJECTIVES: To assess the clinical utility of conventional karyotyping as a diagnostic tool in soft tissue tumours amidst the increasing use of molecular cytogenetics. DESIGN: Case series. SETTING: Singapore General Hospital, an Asian institution. PARTICIPANTS: A total of 35 participants (18 male and 17 female) aged 15 to 81 years were included in this study. Conventional karyotyping of 35 consecutive fresh soft tissue tumour specimens was performed over 4 years and the results were analysed. RESULTS: Of the 35 cases of soft tissue tumours reviewed, chromosome abnormalities were detected in 22 (63%) cases, 11 (31%) showed a normal karyotype, and 2 (6%) had culture failure. Of the 22 cases with abnormal karyotype, nine (41%) cases showed recurring aberrations: Ewing's sarcomas (n=2), desmoplastic small round cell tumour (n=1), synovial sarcomas (n=3), myxoid liposarcomas (n=2), and lipoma (n=1). One lipoma case had a t(2;12)(q23;q15) in which 2q23 breakpoint was not reported before. Chromosomal aberration involving 12q15 breakpoint has been shown in a previous study to be indicative of a lipoma-like liposarcoma. Another lipoma case had addition of 5q15 and 9p13 together with a balanced aberration of t(12;13) (q13;q12) which were novel aberrations. One synovial sarcoma case showed t(3;7)(q21;p13) which was an uncharacteristic aberration. CONCLUSION: Conventional karyotyping demonstrated utility as a genome-wide screening tool for soft tissue tumours and an adjunct diagnostic tool in the event histopathology results were doubtful. With the more widespread use of karyotyping, novel recurring chromosomal aberrations may be discovered.

The impact of endovascular repair of ruptured abdominal aortic aneurysm on the gastrointestinal and renal function.

Introduction. Systemic effects of ruptured abdominal aortic aneurysm (rAAA) may be altered by the mode of surgery. This study aimed to determine systemic effects of endovascular aneurysm repair (EVAR) compared to open repair (OR). Patients and Methods. Consecutive patients with rAAA were repaired by OR or EVAR according to computerised tomographic (CT) findings. Renal function was monitored by estimated glomerular filtration rate (eGFR), serum urea and creatinine, and urinary albumin creatinine ratio (ACR). Hepatic function was assessed postoperatively for 5 days. Intestinal function was determined by the paracetamol absorption test. Intestinal permeability was assessed by urinary lactulose/mannitol ratio. Results. 30 rAAA patients were included. Fourteen had eEVAR and sixteen eOR. Serum urea were higher in eOR, while creatinine was similar between groups. Hepatic function showed no intergroup difference. Paracetamol absorption was increased in eEVAR group at day 3 compared to day 1 (P = 0.03), with no similar result in eOR (P = 0.24). Peak lactulose/mannitol ratio was higher in eOR (P = 0.03), with higher urinary L/M ratio in eOR at day 3 (P = 0.02). Clinical intestinal function returned quicker in eEVAR (P = 0.02). Conclusion. EVAR attenuated the organ dysfunction compared to open repair. However, a larger comparative trial would be required to validate this. The clinical trial is registered with reference number EUDRACT: 2013-003373-12.

Possibility of inhibition of calcium-activated chloride channel rescuing erectile failures in diabetes.

Although calcium-activated chloride channel (CaCC) blockers, niflumic acid (NFA) and anthracene-9-carboxylic acid (A9C), have been shown as potential erectogenic agents in healthy corpus cavernosum (CC) tissues, the pharmacological characteristics of CaCC blockers in diabetic state are relatively unknown. This study compares the direct muscle relaxant property of NFA and A9C with their influence on contraction and nitrergic relaxation as elicited by electrical field stimulation in normal and 16-week-old diabetic rabbit CC (n=8). Mean blood glucose level in alloxan-treated rabbits was elevated threefold (21.9±0.5 mmol l(-1) vs 7.1±0.2 mmol l(-1) in untreated rabbits; P<0.05). There was no significant alteration in the efficacies of NFA and A9C in eliciting a concentration-dependent relaxation of noradrenaline-induced cavernosum tone and in inhibiting neurogenic contraction of CC from diabetic rabbits. The capability of NFA (100 µM) and A9C (1 mM) in augmenting nitrergic transmission was also not adversely affected by diabetes. However, in CC from diabetic rabbits, A9C markedly increased nitrergic relaxation response to 1-10 Hz by 10.6-36.6% (vs -5.1-0.8% in nondiabetic control). CaCC sensitivity to A9C appears to be enhanced in diabetic CC tissue. Inhibiting the CaCC activity in diabetes-related ED may tip the balance between proerectile/relaxant and antierectile/contractile mechanisms in favor of cavernosum relaxation.