Corneal Nerve Changes Observed by In Vivo Confocal Microscopy in Patients Receiving Oxaliplatin for Colorectal Cancer: The COCO Study.

An objective method of early identification of people at risk of chemotherapy-induced peripheral neuropathy is needed to minimize long-term toxicity and maximize dose intensity. The aims of the study were to observe corneal nerve microstructure and corneal sensitivity changes and peripheral neuropathy in patients receiving oxaliplatin, and to determine its association with corneal parameters at different stages of treatment and assess utility as non-invasive markers to detect and monitor peripheral neuropathy. Twenty-three patients scheduled to receive oxaliplatin chemotherapy with intravenous 5-FU for gastro-intestinal cancer were recruited and followed up with for 12 months. Ocular examinations including corneal and retinal evaluations, alongside peripheral neuropathy assessment, were performed. The corneal nerve density did not show significant change after chemotherapy when measured with a widely used semi-automated program or an automated analysis technique. Macula and optic nerve function did not change during or after oxaliplatin chemotherapy. However, the corneal nerve density modestly correlated with clinical peripheral neuropathy after 20 weeks of chemotherapy (r = 0.61, p = 0.01) when peripheral neuropathy is typical most profound, and corneal nerve sensitivity correlated with neuropathy at 12 (r = 0.55, p = 0.01) and 20 weeks (r = 0.64, p = 0.006). In conclusion, corneal changes detected on confocal microscopy show moderate association with peripheral neuropathy, indicating their potential to identify the development of oxaliplatin-induced peripheral neuropathy. However, further studies are required to confirm these findings.

Corneal Confocal Microscopy in Type 1 Diabetes Mellitus: A Six-Year Longitudinal Study.

Purpose: The current study describes corneal nerve morphology using in vivo confocal microscopy (IVCM) in patients with type 1 diabetes (T1D) who were followed up for 6 years, and it examines the relationship between corneal parameters and metabolic control of glucose and peripheral neuropathy. Methods: Sixty-two participants (37 with T1D and 25 control participants) were assessed in 2011 and 2017. Participants with bilateral cataract surgery or controls who developed diabetes were excluded. All underwent HbA1c, IVCM, and central corneal sensitivity measurements at both time points in the eye previously examined. A modified total neuropathy score was obtained. Results: Participants were age and sex matched. The mean duration of diabetes was 32.1 ± 12.0 years at the follow-up visit. The sub-basal nerve density in participants with T1D was lower than that of the controls and did not change (mean ± SD, 11.07 ± 4.0 to 11.41 ± 4.1 mm/mm2; P = 0.71), but it showed a marginal change in controls (19.5 ± 3.7 to 21.63 ± 4.03 mm/mm2; P = 0.06). The corneal sensitivity in T1D did not change (1.3 ± 1.5 to 1.4 ± 1.0 mbar; P = 0.8), and it declined in the controls (0.2 ± 0.3 to 0.6 ± 0.3 mbar; P < 0.001). There were no significant changes in HbA1c (60.5 ± 12.5 to 61.6 ± 13.7 mmol/mol) or in modified total neuropathy scores (2.4 ± 3.2 to 3.4 ± 3.8; P = 0.2). Conclusions: The corneal nerve damage and poorer corneal sensitivity reported in the patients with T1D did not change and displayed improvement with good glycemic control. Translational Relevance: The corneal nerve changes may be of more value in those with a shorter duration of diabetes for the timely prediction of at-risk individuals likely to develop peripheral neuropathy, particularly in type 1 diabetes.

Endocrine adverse effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors are increasingly being utilised as an effective therapy for a variety of cancers. However, they have the potential to cause serious autoimmune toxicities in multiple organ systems termed 'immunotherapy-related adverse events'. Endocrine toxicities are common, can occur well after commencement of therapy and can result in significant morbidity and mortality if not recognised. This makes it important for all physicians, in addition to endocrinologists and oncologists, to understand the nature of these reactions and the general approach to their diagnosis and management. This review aims to provide an overview of the epidemiology, pathophysiology, clinical presentation and management of the endocrine adverse events.

Differing protocols of managing adult diabetic ketoacidosis outside of the intensive care unit make no difference to the rate of resolution of hyperglycaemia and acidosis.

AIMS: To compare the outcome of people with type 1 diabetes admitted to the general ward with diabetic ketoacidosis (DKA) to two hospitals in Auckland, using different protocols of care. METHODS: North Shore Hospital uses a UK weight-based, ketone centric protocol while Auckland Hospital uses a protocol based on glucose measurements only. All notes of people over 16 years of age admitted to the general wards with DKA to these hospitals in one year were reviewed and their outcome compared. RESULTS: Forty-one admissions in 35 people with DKA at Auckland Hospital were compared to 30 admissions in 26 people with DKA at North Shore Hospital. The degree of ketoacidosis and hyperglycaemia on admission was similar at the two hospitals. The duration of insulin and 10% dextrose infusions was similar but the total number of units of insulin infused and rate of dextrose given per hour were higher at North Shore, with similar rates of hypokalaemia and hypoglycaemic events at each site. The rate of resolution of hyperglycaemia and acidosis did not differ. The length of stay of patients was similar at the two hospitals. CONCLUSIONS: The frequent measurement of bedside ketones did not result in more rapid resolution of DKA compared to relying on glucose measurements alone.

Fragility fractures at Auckland City Hospital: we can do better.

This study describes in detail the burden of caring for patients aged ≥ 50 years seen in one year with a fragility fracture in a large urban environment and shows that these fractures result in a long length of stay and significant mortality. Intervention to prevent further fracture was poorly done. PURPOSE: To examine the epidemiology of fragility fracture in patients over age 50 years and record the number who received appropriate secondary prevention treatment. METHODS: All patients aged ≥ 50 years presenting with a fracture during the 12 months following July 1st 2011, to Auckland City Hospital or residing in central Auckland at the time of their fracture, were identified from hospital and Accident Compensation Corporation records. A random sample of 55% of these patient's records were reviewed to establish the type of fracture, prior fracture and falls history, and use of bisphosphonates in the 12 months before presentation. Their length of stay (LOS) by type of fracture was recorded. The use of bisphosphonate drugs in the following 12 months was obtained from centralised national records of prescriptions. RESULTS: 2729 patients aged ≥ 50 years presented with a fragility fracture in the central Auckland region in one year. Fifty-six percent of these patients were seen at Auckland Hospital and of these, 82% patients required admission with a mean LOS of 20 days (SD ± 24 days).The remaining 44% of patients were looked after in the private outpatient sector. Approximately 30% of the admissions were for hip fracture. Sixty-four percent of patients with a fragility fracture did not receive a potent bisphosphonate, 12% were considered not appropriate for treatment, and 24% received a potent bisphosphonate during their admission or in the next 12 months. CONCLUSIONS: Approximately 1 in 18 people aged ≥ 50 years presented in one year with a fragility fracture.Secondary prevention strategies were poorly implemented. Additional resources for identifying and initiating secondary fracture prevention care such as a Fracture Liaison Service are urgently needed.

23 years of managing diabetic ketoacidosis at Auckland Hospital

AIMS: To examine the length of stay and need for intensive care of people admitted with diabetic ketoacidosis (DKA) to a single centre between 1988 and 2011. METHODS: Patients aged ≥15 years admitted for the first time with DKA (plasma glucose ≥ 10mmol/L and a bicarbonate concentration ≤15mmol/L and a pH <7.35, and raised plasma or urine ketones or anion gap) to Auckland City Hospital from 1988-2011 were identified retrospectively. The patients were divided into four cohorts (1988-1996; 1997-2001; 2002-2006; 2007-2011). Over this time period there was no significant change to the insulin infusion protocol. RESULTS: There were 576 admissions with DKA in 388 people over the 23 years. The mean age of the patients and glucose concentration at presentation to hospital fell significantly over time. The admission pH and bicarbonate concentration was higher in more recent cohorts. The length of stay and need for intensive care admission fell significantly over time, but the number of patients subsequently readmitted with DKA remained high. In-hospital mortality remained low. CONCLUSIONS: DKA remains an important reason for admission to this hospital, but the severity of DKA at presentation has reduced over time. The need for intensive care admission and length of stay has fallen dramatically.

Impact of diabetes mellitus on the ocular surface: a review.

Although diabetes mellitus is reaching epidemic proportions worldwide, ocular surface complications are still largely believed to be uncommon. Although these complications are not often sight threatening, the general well-being of patients and the cost of their health care can be respectively compromised and added by them. Over the last decade, an association of ocular surface complications (in particular reduced corneal sub-basal nerve density and corneal sensitivity) with peripheral neuropathy has emerged, which could help recognize the development of peripheral complications at an earlier stage and also provide research opportunities for examining new treatment modalities of diabetic neuropathies. The ocular surface complications of diabetes mellitus and their association with peripheral neuropathy are reviewed by this report.

In Vivo Confocal Microscopy of Corneal Nerves: An Ocular Biomarker for Peripheral and Cardiac Autonomic Neuropathy in Type 1 Diabetes Mellitus.

PURPOSE: We investigated the relationship between corneal subbasal nerve (SBN) plexus density, corneal sensitivity, and peripheral and cardiac autonomic neuropathy in patients with type 1 diabetes mellitus. METHODS: We recruited 53 patients with type 1 diabetes mellitus and 40 normal control participants. Corneal in vivo confocal microscopy (IVCM) and sensitivity testing were performed on one eye of each subject. Autonomic function testing was done and an overall neuropathy score obtained from a combination of a symptomatic neuropathy score, clinical assessment, biothesiometry, and nerve conduction tests. RESULTS: The corneal SBN density (P < 0.001) and corneal sensitivity (P < 0.001) were significantly lower in subjects with diabetes compared to controls. A modest negative correlation between total neuropathy score and SBN density was observed (r = -0.33, P = 0.01). A negative correlation between corneal sensitivity and expiration/inspiration component of the autonomic nerve analysis (ANS-EI) also was noted (r = -0.36, P = 0.008). Corneal SBN density was abnormal in 50% of diabetic subjects classified as "Normal" by the clinical and electrophysiological based tests of total neuropathy score. CONCLUSIONS: The correlation of corneal SBN density with total neuropathy score suggests that reduced corneal nerve density reflects peripheral neuropathy in diabetes. Corneal SBN changes precede other clinical and electrophysiology tests of neuropathy supporting a possible role for corneal IVCM and corneal sensitivity testing as surrogate markers in the assessment of diabetic peripheral and cardiac autonomic neuropathy.

Peripheral neuropathy and tear film dysfunction in type 1 diabetes mellitus.

PURPOSE: To compare tear film metrics in patients with type 1 diabetes mellitus (DM) and healthy controls and investigate the association between peripheral neuropathy and ocular surface quality. METHODS: Dry eye symptoms were quantified in 53 patients with type 1 DM and 40 age-matched controls. Ocular examination included tear film lipid layer thickness grading, tear film stability and quantity measurement, and retinal photography. DM individuals additionally underwent a detailed neuropathy assessment. RESULTS: Neither mean age nor dry eye symptom scores differed significantly between the DM and control groups (P = 0.12 and P = 0.33, resp.). Tear lipid thickness (P = 0.02), stability (P < 0.0001), and quantity (P = 0.01) were significantly lower in the DM group. Corneal sensitivity was also reduced in the DM group (P < 0.001) and tear film stability was inversely associated with total neuropathy score (r = -0.29, P = 0.03). CONCLUSION: The DM group exhibited significantly reduced tear film stability, secretion, and lipid layer quality relative to the age-matched control group. The negative correlation between tear film parameters and total neuropathy score suggests that ocular surface abnormalities occur in parallel with diabetic peripheral neuropathy.

The clinical course of patients with type 2 diabetes presenting to the hospital with sulfonylurea-induced hypoglycemia.

BACKGROUND: This study describes the clinical course of adult patients with type 2 diabetes taking a sulfonylurea and presenting to the hospital with severe hypoglycemia. SUBJECTS AND METHODS: This was a retrospective chart review of all patients >15 years of age with type 2 diabetes and taking a sulfonylurea who presented to the emergency services of Auckland City Hospital over a 6-year period with severe hypoglycemia. RESULTS: One hundred eighty-five patients met the inclusion criteria. Their mean ± SD age was 71 ± 11 years, and known duration of diabetes was 14.7 ± 10 years. Of the patients, 167 had micro- and/or macrovascular complications of diabetes, and one-third had had a previous admission with hypoglycemia. Only 61 patients (33%) had a glomerular filtration rate of >60 mL/min. The length of stay was not correlated with admission creatinine level (highest tertile of creatinine, 71 ± 93 h; lowest tertile, 51 ± 79 h). Recurrent in-hospital hypoglycemia occurred in over one-third of patients, and 28 (15%) were re-admitted to the hospital within 28 days of discharge for various reasons, including further hypoglycemia in 13 patients. Two patients died during their admission. CONCLUSIONS: Patients with type 2 diabetes presenting to the hospital with sulfonylurea-associated hypoglycemia have a high burden of comorbidity, require a long hospital stay, and are at risk of subsequent re-admission to hospital. Careful evaluation of their best future treatment strategies must be undertaken taking account of their comorbidities, including their renal function.

A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities.

CONTEXT: Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. The molecular basis of the condition has been ascribed to inactivating mutations in the human glucocorticoid receptor (hGR) gene. OBJECTIVE: The objective of the study was to present three new cases caused by a novel mutation in the hGR gene and to delineate the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. DESIGN AND RESULTS: The index case (father) and his two daughters presented with increased urinary free cortisol excretion and resistance of the hypothalamic-pituitary-adrenal axis to dexamethasone suppression in the absence of clinical manifestations suggestive of Cushing syndrome. All subjects harbored a novel, heterozygous, point mutation (T→G) at nucleotide position 1724 of the hGR gene, which resulted in substitution of valine by glycine at amino acid 575 of the receptor. Compared with the wild-type receptor, the hGRαV575G demonstrated a significant (33%) reduction in its ability to transactivate the mouse mammary tumor virus promoter in response to dexamethasone, a 50% decrease in its affinity for the ligand, and a 2.5-fold delay in nuclear translocation. Although it did not exert a dominant negative effect on the wild-type receptor and preserved its ability to bind to DNA, hGRαV575G displayed significantly enhanced (∼80%) ability to transrepress the nuclear factor-κΒ signaling pathway. Finally, the mutant receptor hGRαV575G demonstrated impaired interaction with the LXXLL motif of the glucocorticoid receptor-interacting protein 1 coactivator in vitro and in computer-based structural simulation via its defective activation function-2 (AF-2) domain. CONCLUSIONS: The natural mutant receptor hGRαV575G causes primary generalized glucocorticoid resistance by affecting multiple steps in the glucocorticoid signaling cascade, including the affinity for the ligand, the time required for nuclear translocation, and the interaction with the glucocorticoid-interacting protein-1 coactivator.

A community-based model of care improves blood pressure control and delays progression of proteinuria, left ventricular hypertrophy and diastolic dysfunction in Maori and Pacific patients with type 2 diabetes and chronic kidney disease: a randomized controlled trial.

BACKGROUND: In this study, our main goal was to determine whether an integrated, community-based model of care using culturally appropriate health-care assistants to manage hypertension in Maori and Pacific patients with diabetes and chronic kidney disease (CKD) is more effective than conventional care in achieving blood pressure (BP) targets and delaying progression of cardiac and renal end-organ damage. METHODS: Sixty-five Maori and Pacific patients (aged 47-75 years) with type 2 diabetes, moderate CKD (>0.5 g proteinuria/day, serum creatinine 130-300 µmol/l) and hypertension were randomized to usual care (n = 32) or community/intervention care (n = 33) for 12 months. Community care patients were visited monthly by a nurse-led health-care assistant for BP measurement. Antihypertensives were adjusted using a stepwise protocol, aiming for a BP <130/80 mmHg. Office BP and renal and echocardiographic parameters were measured at baseline and 12 months. RESULTS: Baseline characteristics including office BP, renal and echocardiographic parameters, and number of antihypertensives were well matched in both groups. By 12 months, the community care patients had achieved a significantly greater reduction in office systolic BP (-21 ± 26 mmHg vs -12 ± 20 mmHg, P = 0.04) and in 24-h urine protein (-1.4 ± 2.6 g vs +0.1 ± 2.8 g, P = 0.04). The number of prescribed antihypertensives was greater in these patients at 12 months (3.4 ± 1.1 vs 2.3 ± 1.0, P < 0.01). Left ventricular (LV) mass and left atrial (LA) volume progressed in the usual care group, but not in the intervention group (P < 0.05). CONCLUSION: This novel model of care is more effective than conventional care in lowering systolic BP and reducing cardiac and renal end-organ damage in these high-risk patients.

Glucagon is absorbed from the rectum but does not hasten recovery from hypoglycaemia in patients with type 1 diabetes.

AIMS: A failure to secrete glucagon during hypoglycaemia is near universal in patients with type 1 diabetes 5 years after disease onset and may contribute to delayed counter-regulation during hypoglycaemia. Rectal glucagon delivery may assist glucose recovery following insulin-induced hypoglycaemia in such patients and has not been previously studied. METHODS: Six male patients (age 21-38 years) with type 1 diabetes (median duration 10 years) without microvascular complications, were studied supine after an overnight fast on two separate occasions at least 14 days apart. After omission of their usual morning insulin and 45 min rest, hypoglycaemia was induced by an intravenous insulin infusion which was terminated when capillary glucose concentration reached 2.5 mmol l(-1). Subjects were randomized to insert a rectal suppository containing 100 mg indomethacin alone (placebo) or 100 mg indomethacin plus 1 mg glucagon at the hypoglycaemic reaction. Serial measurements were made for 120 min. RESULTS: In the two groups, mean (SD) plasma glucose concentrations fell to a similar nadir of 1.8 (0.7) mmol l(-1) (placebo) and 2.1 (1.2) mmol l(-1) (glucagon). Peak plasma glucagon following hypoglycaemia was higher in the glucagon group; 176 (32) ng l(-1)vs. 99 (22) ng l(-1) after placebo (P = 0.006). However, the glucose recovery rate over 120 min after hypoglycaemia did not differ significantly. CONCLUSIONS: Our results provide evidence for the absorption of glucagon from the rectum. They also indicate that 1 mg does not constitute a useful mode of therapy to hasten recovery from hypoglycaemia in patients with type 1 diabetes.

Current and former smoking increases mortality in patients on peritoneal dialysis.

AIMS: There is limited information on the effects of smoking behaviour on mortality in patients with end-stage renal failure (ESRF). This study aimed to assess the interaction of smoking on death rate in patients with renal failure on dialysis. METHODS: All patients (n=1293) commencing peritoneal dialysis between 1985 and 1995 for renal failure in New Zealand were prospectively followed 6 monthly until 1997 and data entered on the National database. Mortality rates were calculated from the national database and rates in patients with diabetes compared with those without diabetes and in those who did or did not smoke. RESULTS: Follow-up data was available on all patients for a range of 20-40 months. 35% of the patients were clinically classified as having diabetic nephropathy as the cause of renal failure (11% type 1, 24% type 2). Seventeen percent of the total cohort were current smokers, 45% former smokers and 38% lifetime non smokers at dialysis commencement. These rates were similar between patients with diabetes (18% current, 51% former, 32% non-smoker) and those without diabetes (17% current, 42% former, 41% non-smoker). At survey end in 1997, 43% of the patients without diabetes had died compared with 59% of patients with type 1 diabetes (p<0.05) and 62% of patients with type 2 diabetes (p<0.05). The age-adjusted mortality of patients with a history of current or former smoking was higher than non-smokers. Those patients with diabetes and a history of smoking had even higher mortality. CONCLUSIONS: Patients with a current or former history of smoking on peritoneal dialysis are at greatly increased risk of death. A strategy of aggressive smoking cessation efforts should be adopted for these patients at the earliest opportunity.