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Fei Wang,1 Stefanie Zassman,1 Philip A Goldberg2 1Department of Pharmacy Practice, School of Pharmacy, University of Connecticut, Storrs, CT, USA; 2Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA Background: As the first once-daily basal insulin analog, insulin glargine 100 U/mL (Gla‑100; Lantus®) rapidly evolved into the most commonly prescribed insulin therapy worldwide. However, this insulin has clinical limitations. The approval of new basal insulin analogs in 2015 has already started to alter the prescribing landscape.Objective: To review the available evidence on the clinical efficacy and safety of a more concentrated insulin glargine (recombinant DNA origin) injection 300 U/mL (Gla-300) compared to insulin Gla-100 in patients with type 1 and type 2 diabetes mellitus (T1DM and T2DM).Methods: The following electronic databases were searched: PubMed and MEDLINE (using Ovid platform), Scopus, BIOSIS, and Google Scholar through June 2016. Conference proceedings of the American Diabetes Association (2015–2016) were reviewed. We also manually searched reference lists of pertinent reviews and trials.Results: A total of 6 pivotal Phase III randomized controlled trials known as the EDITION series were reviewed. All of these trials (n=3,500) were head-to-head comparisons evaluating the efficacy and tolerability of Gla-300 vs Gla-100 in a diverse population with T1DM and T2DM. These trials were of 6 months duration with a 6-month safety extension phase.Conclusion: Gla-300 was as effective as Gla-100 for improving glycemic control over 6 months in all studies, with a lower risk of nocturnal hypoglycemia significant only in insulin-experienced patients with T2DM. Overall, patients on Gla-300 required 10%–18% more basal insulin, but with less weight gain compared with Gla-100. Keywords: basal insulin, glargine 300 U/mL, glargine 100 U/mL

Purpose: To extend current knowledge of tobacco use by exploring whether subsets of mothers of infants have unique triggers for smoking relapse during the early stages of becoming a mother. Method: Using data from a study of smoking relapse among mothers of infants (N = 133), comparative analyses were conducted for groups formed on the basis of their intention to be nonsmokers after delivery (yes/no) and their actual smoking behavior during the first 2 weeks of infant life (yes/no). Findings: The identified groups of mothers were found to be significantly different from one another in several ways, including self-reports that their baby's crying episodes caused them to think about smoking and their level of self-confidence to not smoke as response to infant crying. Conclusions: Pediatric nurses in primary and acute care settings are in a unique position to support mothers for whom the challenge of handling infant cry episodes is a trigger for smoking behavior. Interventions that teach mothers how to cope with infant irritability are likely to support the smoking cessation efforts, and consequently, interrupt the intergenerational cycle of tobacco-related maternal and child health morbidities. [ABSTRACT FROM AUTHOR]

In part one of this series Dr. Goldberg discussed the changes in attitudes that have come about regarding microbes and their role in health and disease, due to recent epidemiological studies such as those supporting the 'Hygiene Hypothesis'. In part two, Dr. Goldberg offers suggestions as to how the problems brought about by the western_ lifestyle and western medicine can be addressed by the clinician and their patients. [ABSTRACT FROM AUTHOR]

Introduction: The increase in incidence of colorectal cancer in young patients of African ancestry coupled with increased aggressiveness has warranted investigation of the heritable nature of these cancers. Only a limited number of published reports of hereditary colorectal cancer in indigenous African populations have been reported and no systematic screening of these groups has been performed previously. We aimed to investigate causative germline variants and to establish the incidence of pathogenic/likely pathogenic germline variants in the known colorectal cancer genes in indigenous African colorectal cancer patients using a next-generation sequencing (NGS) multigene panel., Materials and Methods: Patients were selected from two hospitals in Cape Town and Johannesburg, South Africa. Patients with unresolved molecular diagnosis with an age of onset below or at 60 years were selected. Germline DNA samples were analyzed using a 14-gene NGS panel on the Ion Torrent platform. Variant calling and annotation were performed, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Observed variants were verified by Sanger sequencing and/or long-range PCR., Results: Out of 107 patients, 25 (23.4%) presented with a pathogenic/likely pathogenic germline variant (PGV). Fourteen PGVs in at least one mismatch repair (MMR) gene were identified and verified in 12 patients (11.2%). Of these MMR gene variants, five were novel. The remaining 10 PGVs were in the APC, BMPR1A, MUTYH, POLD1, and TP53 genes., Conclusion: The high incidence of PGVs associated with early-onset colorectal cancer in indigenous African patients has important implications for hereditary colorectal cancer risk management. These findings pave the way for personalized genetic screening programs and cascade testing in South Africa. The next step would involve further screening of the unresolved cases using tools to detect copy number variation, methylation, and whole exome sequencing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Yildiz, Musarurwa, Algar, Chambuso, Rebello, Goldberg and Ramesar.)

Background: Colorectal cancer (CRC) is common and often presents with advanced disease in Africa. Multivisceral resection (MVR) improves survival in locally advanced (T4b) CRC. The aim was to describe the management and outcomes of patients with clinical T4b CRC without metastatic disease who underwent MVR., Methods: A retrospective review of patients with T4 CRC who underwent MVR between January 2008 and December 2013., Results: Four hundred and ninety-four patients were included. Of the 158 with suspected T4 cancer, 44 had MVR, of which one was excluded due to metastases. The mean age was 64 years. The male to female ratio was 1:1. The most commonly resected extra-colorectal structure was the abdominal wall (21%). The median survival was 68 months (SD 13.9). The 5-year disease free (DFS) and overall survival (OS) were 46% and 55%, respectively. Survival of patients with colon and rectum cancer was similar. Intraoperative tumour spillage, vascular/perineural invasion, and anastomotic leakage were independent predictors of survival., Conclusion: Multivisceral resection of locally advanced (T4b) CRC is feasible in the African context. Complete resection improves survival and should be the goal., (Copyright© Authors.)

Background: In a previous study we identified 206 patients with colorectal adenocarcinoma in the Northern Cape province of South Africa, diagnosed between January 2002 and February 2009. The age-standardised incidence was 4.2/100 000 per year world standard population. This is 10% of the rate reported in First-World countries. In high-incidence areas, the rate of abnormal mismatch repair gene expression in colorectal cancers is 2 - 7%., Objectives: The aim of this study was to determine the prevalence of hMLH1- and hMSH2-deficient colorectal cancer in the Northern Cape., Methods: Formalin-fixed paraffin wax-embedded tissue blocks from 87 colorectal adenocarcinomas identified in the previous study were retrieved. Standard immunohistochemical staining methods were used to detect the expression of hMLH1 and hMSH2 (i.e. products of the hMLH1 and hMSH2 genes) in the tumours using heat-induced antigen retrieval and diaminobenzidene as a chromogen. Results. In 8 blocks there was insufficient tumour tissue and in 1 case the immunohistochemical staining failed, probably owing to poor fixation, leaving 78 cases for analysis. In 11 cases hMLH1 was deficient and in 6 cases hMSH2 was deficient. Overall, 21.8% of cancers were deficient for hMLH1 or hMSH2., Conclusion: Presuming that 80% of all hMLH1 deficiencies are due to hypermethylation of the gene, we found 10.5% of colorectal cancers in an area with a low incidence of colorectal cancer to be deficient in the product of the mismatch repair gene/s. This is approximately three times the reported rate in high-incidence areas.

Objective: To present 2 challenging cases of patients who request endocrine therapies that their physician considers to be outside of the standard of care., Methods: With these complex cases as a backdrop, we explore the constructs of medicine, malpractice law, and professional ethics that guide physicians' medical decision-making processes., Results: These cases illustrate a common conundrum for clinical endocrinologists, who often find themselves struggling to balance patient satisfaction and well-being with generally accepted standards of medical care. From the perspective of a malpractice lawyer, we review the keys to limiting medicolegal liability, with emphasis on thorough documentation, informed consent, and effective doctor-patient communication. We then review the constructs of professional ethics that guide patient care, with emphasis on virtues of the "good physician," patients' right to self-determination, and paternalism. Finally, we explore some justifications for a compassionate physician to refuse a patient's desired treatment plan., Conclusion: In the end, we hope that this manuscript helps to facilitate best medical, legal, professional, and ethical practices of clinical endocrinology.

Objective: To report our preliminary experience with the revised, more conservative Yale insulin infusion protocol (IIP) that targets blood glucose concentrations of 120 to 160 mg/dL., Methods: We prospectively tracked clinical responses to the new IIP in our medical intensive care unit (ICU) by recording data on the first 115 consecutive insulin infusions that were initiated. All blood glucose values; insulin doses; nutritional support including intravenous dextrose infusions; caloric values for enteral and parenteral nutrition; and use of vasopressors, corticosteroids, and hemodialysis or continuous venovenous hemodialysis were collected from the hospital record., Results: The IIP was used 115 times in 90 patients (mean age, 62 [±14 years]; 51% male; 35% ethnic minorities; 66.1% with history of diabetes). The mean admission Acute Physiology and Chronic Health Evaluation II score was 24.4 (±7.5). The median duration of insulin infusion was 59 hours. The mean baseline blood glucose concentration was 306.1 (±89.8) mg/dL, with the blood glucose target achieved after a median of 7 hours. Once the target was reached, the mean IIP blood glucose concentration was 155.9 (±22.9) mg/dL (median, 150 mg/dL). The median insulin infusion rate required to reach and maintain the target range was 3.5 units/h. Hypoglycemia was rare, with 0.3% of blood glucose values recorded being less than 70 mg/dL and only 0.02% being less than 40 mg/dL. In all cases, hypoglycemia was rapidly corrected using intravenous dextrose with no evident untoward outcomes., Conclusions: The updated Yale IIP provides effective and safe targeted blood glucose control in critically ill patients, in compliance with recent national guidelines. It can be easily implemented by hospitals now using the original Yale IIP.

Aim: The high reported risk of metachronous colon cancer (MCC) in hereditary nonpolyposis colorectal cancer (HNPCC) has led some authors to recommend total colectomy (TC) as the preferred operation for primary colon cancer, but this remains controversial. No previous study has compared survival after TC with segmental colectomy (SC) in HNPCC. The aim of this study was to determine the risk of developing MCC in patients with genetically proven HNPCC after SC or TC for cancer, and to compare their long-term survival., Method: This is a prospective cohort study of all patients referred to our unit between 1995 and 2009 with a proven germline mismatch repair gene defect, who had undergone a resection for adenocarcinoma of the colon with curative intent. All patients were offered annual endoscopic surveillance., Results: Of 60 patients in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years follow up, MCC occurred in eight (21%) SC patients and in none of the TC patients (P = 0.048). The risk of developing MCC after SC was 20% at 5 years. Colorectal cancer-specific survival was better in TC patients (P = 0.048) but overall survival of the two groups was similar (P = 0.29)., Conclusion: Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer., (© 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.)

Aim: The purpose of this study was to determine the incidence of colorectal cancer (CRC) in the Northern Cape province of South Africa, and to identify patients with histological and demographic features suggestive of hereditary non-polyposis colon cancer (HNPCC)., Method: This is a retrospective review of all cases of primary adenocarcinoma of the colon or rectum diagnosed by the two pathology laboratories operating in the Northern Cape between January 2002 and February 2009. Demographic data were collected, as well as pathological staging of the tumours and histological features suggestive of HNPCC (according to the revised Bethesda guidelines for microsatellite instability testing). Population census data for the Northern Cape were obtained from Statistics South Africa., Results: The annual incidence of CRC in the Northern Cape was 3.7/100,000 population (3.5/100,000 for men and 3.9/100,000 for women). The median age at which colorectal cancer was diagnosed was 59 years (range 16-90 years). On pathological and demographic criteria, 75/206 (36%) of the patients met at least one of the criteria of the revised Bethesda guidelines for microsatellite instability testing., Conclusion: CRC is rare in the Northern Cape, and one-third of the patients had demographic or tumour histological features suggestive of HNPCC.

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.

Objective: Previous studies have shown a benefit for surveillance colonoscopy in heterogeneous groups of subjects with suspected or proven hereditary nonpolyposis colon cancer. The aim of this study was to investigate whether surveillance colonoscopy improves the survival in subjects who all carry a single mismatch repair gene defect., Method: This is a prospective cohort study of 178 subjects who carry a mutation of the MLH1 gene in exon 13 (C1528T). They were offered surveillance colonoscopy between 1988 and 2006, and were followed up until September 2007., Results: One hundred and twenty-nine subjects underwent surveillance colonoscopy, and 49 declined. After a median follow up of 5 years, colorectal cancer was diagnosed in 14/129 (11%) subjects in the surveillance group and 13/49 (27%) in the nonsurveillance group (P = 0.019). Cancers in the surveillance group were at an earlier stage than in the nonsurveillance group (P = 0.032). Death from colorectal cancer occurred in three of 129 (2%) subjects in the surveillance group, and six of 49 (12%) in the nonsurveillance group (P = 0.021). The Kaplan-Meyer estimates for median survival from birth were 78 years in the surveillance group, and 55 years in the nonsurveillance group (P = 0.024). The Kaplan-Meyer estimates for median colorectal cancer-free survival from birth were 73 years in the surveillance group and 47 years in the nonsurveillance group (P = 0.0089)., Conclusion: Surveillance colonoscopy was associated with improved overall and colorectal cancer-related survival in subjects carrying a single mismatch repair gene mutation.

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant condition, caused by germline mutations in the mismatch repair genes, that presents with colorectal cancers at a young age, as well as extracolonic tumours. One of the causative mutations is the C1528T (Exon 13) mutation of the MLH1 gene. The purpose of this study is to document the cancer risk for subjects who carry this mutation. This is a prospective cohort study of 200 subjects who carry this mutation. We calculated the risk of developing colorectal cancer only in those subjects who had not undergone surveillance colonoscopy. The incidence of extracolonic cancers (for which surveillance is not routinely offered) was determined for the entire cohort. The results of the study are among the 71 subjects who did not undergo surveillance colonoscopy, colorectal cancers occurred in 36 (51%). They occurred at a median age of 44 years (range 17-73). Using Kaplan-Meier estimates, the risk of developing a colorectal cancer by age 65 was 92%. Eighteen subjects in the cohort of 200 were diagnosed with extracolonic tumours. The most common extracolonic malignancies were breast (6/98 women) and endometrial (3/98 women). Thus this mutation has a high penetrance for colorectal cancer, but is not associated with a high risk of developing extracolonic malignancies.

Background: Hereditary mixed polyposis syndrome is characterised by multiple large-bowel polyps of differing histological types including a mixture of atypical juvenile polyps, hyperplastic polyps and adenomas. Affected individuals are thought to have an increased risk of malignancy, possibly via the juvenile polyposis pathway., Methods: A 51-year-old woman (with a history of a colectomy for polyps during childhood) presented with rectal bleeding. Endoscopy demonstrated small rectal polyps which were hyperplastic on histology. A family tree was drawn up and the three children of the proband underwent flexible sigmoidoscopy., Results: Endoscopic surveillance of the three children revealed one who had a similar phenotype to the mother. This child underwent colectomy and ileorectal anastomosis. The pathological specimen revealed more than 70 polyps, with a combination of juvenile retention, hyperplastic, adenomatous and inflammatory polyps. A second child had multiple small hyperplastic polyps, and the third had a normal colon. Although the gene locus for the disorder has been mapped, neither the gene nor the disease-causing mutation has been defined., Conclusion: A rare inherited polyposis syndrome has been identified in a South African family. Where clinical suspicion of a possible inherited condition exists, investigating at-risk first-degree relatives confirms the inherited nature of the disease. It is possible to use genetic haplotyping (i.e. with a range of markers in the area of the gene) to provide statistical risk to immediate relatives and therefore those at highest risk.

Background: While disorders such as gastro-oesophageal reflux disease, gastrointestinal (GI) cancers and inflammatory bowel disease are prevalent among all racial groups in the Western Cape, there is little knowledge of local GI service provision. The state of equipment, facilities and staffing is largely unrecorded and to date unknown. The aim of this study was to audit the availability of GI facilities in the provincial sector, which provides care for the majority of people in the Western Cape., Method: All hospitals in the Western Cape providing endoscopy were evaluated by means of a hands-on audit, to identify available organisational infrastructure. Data including staffing, details and utilisation of existing equipment, maintenance and disinfection techniques and delays in service provision were collected., Results: Over a period of 12 months, 17 Western Cape hospitals were visited: 3 tertiary, 5 regional and 9 district-level institutions. There are currently 89 GI endoscopes in state service, with an average age of 6.1 years (range 1-23 years). While most institutions utilise video endoscopy, in many instances equipment is near the end of its economic life. A total of 26,434 endoscopic procedures were performed over a 12-month period. Overall at least 60% of all adult endoscopy was undertaken at tertiary institutions. The mean delay from consultation until gastroscopy or colonoscopy was 9.25 weeks (range 0.5-28 weeks) and 8 weeks (range 1-20 weeks), respectively. Only 1 tertiary and 1 regional hospital employed fully trained, registered nurses, and the majority of institutions did not conform to internationally accepted standards for the maintenance and disinfection of endoscopic equipment., Conclusion: While endoscopy equipment is widely distributed throughout the province, it is evident from this study that services in the Western Cape fall short of international standards, with delays in endoscopic provision, lack of adequate equipment, inadequate scope maintenance and disinfection and a shortage of trained staff. As such, much of the population reliant on state facilities has poor access to GI health care. These deficiencies need to be addressed.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, characterized by the occurrence of predominantly colon and endometrial cancer and, less frequently, cancer of the small bowel, stomach, hepatobiliary tract, ureter, renal pelvis, ovaries and brain. The phenotypic diversity may partially be explained by allelic heterogeneity. The aim of this study was to investigate the frequency of extracolonic cancers in a cohort of females sharing the same c.C1528T disease-predisposing mutation in the hMLH1 gene. Data on cancer history were obtained from 87 mutation-positive females and 121 mutation-negative sisters, as a control group. Testing for microsatellite instability (MSI) and expression of the wild-type hMLH1 allele was performed on extra-colonic tumour tissue blocks of mutation-positive individuals. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females vs. 7% (8/121) of mutation-negative females (P = 0.10). Multiple primary cancers occurred at a significantly higher incidence in the first group. Breast cancer, which was the most frequent extra-colonic cancer in mutation positive females (53%), occurred at a young age, and occurred bilaterally in two out of seven cases. Involvement of the hMLH1 gene was confirmed in five out of seven cases of breast cancer, two cases of endometrial cancer, one case of ovarian cancer and one case of renal cell carcinoma, by detecting immunohistochemical compromise of the gene product. Although the study might not have been adequately statistically powered (to provide a significant P value), the noteworthy findings in this study include the confirmation of a range of Lynch II type cancers in a cohort we previously thought was wholly predisposed to Lynch I features, and a confirmation of breast cancer as part of the spectrum of Lynch syndrome cancers affecting women.

Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ and hematopoietic transplantation. This clinically oriented review article briefly summarizes the pathophysiology of PTDM, then presents a comprehensive clinical approach to diagnosis and therapy. Topics include the key clinical aspects of PTDM screening, diagnosis, and management during all phases following transplantation from the intensive care unit, to the inpatient ward, to the outpatient arena.

Background: It is difficult to provide a colonoscopic surveillance service for at-risk family members with hereditary nonpolyposis colorectal carcinoma when many of those family members live in a remote area of South African far from endoscopic services. A mobile surveillance programme was established to service these individuals., Objective: The aim of this study was to compare the quality of the mobile service to that provided in established endoscopy units., Method: Ninety-one asymptomatic subjects with known disease-causing mutations underwent 259 colonoscopies. Of these, 171 colonoscopies were performed by a mobile colonoscopy service in small rural hospitals and 88 in established endoscopy units. The quality of the colonoscopic services was measured by completion rate, the rate of detection of colonoscopic abnormalities, histopathological analyses of biopsies, surgical intervention and colorectal cancer deaths., Results: The caecum was reached in 96% of all colonoscopies. A significant lesion was detected in 8.8% of colonoscopies. There was no difference in the rate of complete colonoscopy and detection rate of lesions in the established units and the mobile service (both P = 0.6). The rate of detection of early adenocarcinomas was similar (P = 0.17). The colonoscopic screening/surveillance programme meets international standards with a high accuracy (95.75%) and negative predictive value (100%)., Conclusion: The mobile service provides access to colonoscopy in remote areas without compromising the quality of service.

Objective: To present an unusual case of amiodarone-induced thyrotoxicosis (AIT) associated with an autonomously functioning thyroid nodule, which was detected by means of a technetium scan; review the existing literature regarding the association of AIT with autonomous thyroid nodules; and explore the use of radioisotope imaging studies in patients with AIT., Methods: We describe a 62-year-old man with paroxysmal atrial fibrillation, receiving long-term amiodarone therapy, who was referred by his cardiologist for evaluation of abnormal thyroid function tests. He was found to have an unusual case of AIT, associated with an autonomously functioning thyroid nodule., Results: Thyroid function studies obtained by the patient's cardiologist had shown a completely suppressed thyrotropin level and a free thyroxine level of 3.5 ng/dL. A 24-hour thyroid iodine 123 uptake and technetium Tc 99m pertechnetate scan revealed a "single, strong focus in the right thyroid lobe, with the rest of the thyroid gland...not well visualized." Thyroid ultrasonography disclosed a single, well-defined 1.5-cm solid nodule. Repeated thyroid function studies revealed a normal thyrotropin level of 2.87 micro IU/mL and a normal free thyroxine level of 2.4 ng/dL. The patient was managed conservatively with follow-up surveillance., Conclusion: Prospective studies should be performed to better ascertain the value of Tc 99m thyroid scanning in determining the cause of AIT. Until such studies have been completed, we suggest that nuclear studies are unlikely to be cost-effective for assessing all patients with AIT. One logical strategy would be to gain experience with scans in only those patients with known thyroid nodules, which have been detected during physical examination or by ultrasonography. The potential clinical utility of such an approach would be of considerable interest.

Studies of the effects of hypoglycemia on the brain using neurocognitive testing have suggested that mainly complex functions subserved by secondary and tertiary cortex are affected by mild to moderate hypoglycemia and that intensively treated patients with Type I diabetes mellitus (T1DM) may have altered sensitivity to the central nervous system effects of hypoglycemia. Functional magnetic resonance imaging provides a sensitive, regionally-specific probe of possible neurophysiologic changes related to hypoglycemia in the brain. Eleven intensively-treated T1DM patients and 11 matched non-diabetic controls took part in a 2-day protocol in which functional magnetic resonance imaging (MRI) was used to measure changes in the patterns of brain activation produced by simple auditory and visual stimuli in different conditions. On one day, participants were euglycemic the entire time. On the other day, an initial 50-min euglycemic period was followed by a 50-min hypoglycemic period. Results indicated that hypoglycemia reduced the amplitude of the blood-oxygenation level dependent response in primary auditory and visual cortex to simple auditory and visual stimuli. The latency and duration of the transient hemodynamic response function were not affected. Responses to hypoglycemia were similar in diabetic and non-diabetic participants. These results suggest that mild to moderate hypoglycemia may alter the balance of blood flow and oxygen extraction when glucose levels are lowered. Intensively-treated T1DM, with its attendant frequent hypoglycemic episodes, did not seem to alter hypoglycemic responses in primary visual and auditory cortex.

Background: Insulin adsorbs to plastics used for intravenous (IV) tubing. As a result, clinical IV insulin infusion procotols advise an initial priming volume of up to 50 mL, which may be wasteful-especially since most institutions use 100-mL IV solution bags. In this brief report, we sought to determine the optimal priming volume required for clinical IV insulin infusions., Methods: One hundred units of regular human insulin was dissolved into 100 mL of 0.9% NaCl. Employing a standard polypropylene infusion set, a priming infusion was started. At 10- mL intervals, from 0 to 50 mL, effluent was collected directly into glass vials. After dilution (1:10,000) using a proprietary buffer, insulin concentrations were then measured using a double antibody radioimmunoassay. Twenty individually prepared insulin bags were tested in this manner., Results: Insulin levels without prime were 15.8% [95% confidence interval (CI), 9.1-22.6%] lower than insulin levels following 50 mL of prime (designated as "maximal values"). After a priming volume of 10 mL, insulin adsorption losses fell to a marginally significant 6.6% (95% CI, 0.1-13.1%). Following 20 mL of prime, insulin concentrations were indistinguishable from maximal values (3.4% loss, 95% CI, -0.2% to 7.1%)., Conclusions: For standard IV insulin infusions, a priming volume of 20 mL is sufficient to minimize the effect of insulin adsorption losses to IV lines. Priming volumes exceeding 20 mL are wasteful, increase costs, and generate unnecessary work for nurses and pharmacists.

Objective: To summarize key metabolic results from use of the Yale Insulin Infusion Protocols (IIPs), as well as the primary barriers to their implementation. To offer practical suggestions for overcoming these barriers, drawing from our experiences "selling root canals" during the successful implementation of our hospital-wide IIPs., Methods: Since 2002, Yale IIPs have been employed to achieve strict glycemic control in our ICU patients. Barriers to protocol implementation were noted, and strategies were designed to overcome these barriers., Results: In 2002, we implemented Version 1 of the Yale IIP, which purposefully targeted conservative blood glucose (BG) levels of 100 to 139 mg/dL. Following extensive hospital-wide experience with Version 1, Version 2 of the IIP (which debuted in 2004) successfully lowered BG targets to 90 to 119 mg/dL, with minimal impact on observed rates of hypoglycemia. These nurse-driven protocols safely and effectively controlled glucose levels in our ICU patients, without the need for ongoing physician supervision., Conclusion: This work describes the successful implementation of an evolving hospital-wide IIP. To be successful, an IIP must account for the following essential elements: (1) the current BG level, (2) the velocity of glycemic change, and (3) the current insulin infusion rate. We have reviewed five "points of emphasis" to consider when implementing an IIP.

Functional magnetic resonance imaging (fMRI) was used to measure the effects of acute hypoglycemia caused by passive sensory stimulation on brain activation. Visual stimulation was used to generate blood-oxygen-level-dependent (BOLD) contrast, which was monitored during hyperinsulinemic hypoglycemic and euglycemic clamp studies. Hypoglycemia (50 +/- 1 mg glucose/dl) decreased the fMRI signal relative to euglycemia in 10 healthy human subjects: the fractional signal change was reduced by 28 +/- 12% (P < .05). These changes were reversed when euglycemia was restored. These data provide a basis of comparison for studies that quantify hypoglycemia-related changes in fMRI activity during cognitive tasks based on visual stimuli and demonstrate that variations in blood glucose levels may modulate BOLD signals in the healthy brain.

Objective: The clinical management of colorectal malignancies that arise via the mismatch repair gene pathway may differ from those that arise from the more common loss of heterozygosity pathway. They respond differently to chemotherapy, have a different prognosis and are associated with a raised incidence of metachronous lesions if a germline mutation is present. Established methods of detecting mismatch repair gene defects require the testing for microsatellite instability. This is expensive and requires specialized molecular biological resources and staff. An immunohistochemical method is attractive because it is far cheaper, and can be performed by most anatomical pathology laboratories. The aim of this study was to determine the incidence of mismatch repair gene defects using immunohistochemistry in a group of patients who were aged < or = 45 years at the time of diagnosis of colorectal cancer and to compare the patient survival and pathological features of tumours with and without mismatch repair gene defects., Methods: One hundred and four patients with colorectal cancer, diagnosed at 45 years or younger between January 1983 and December 2001, who had been managed at Groote Schuur Hospital, were identified from clinical records. Demographic and clinical data was collected from the clinical notes. The pathological reports were reviewed and the original histopathological slides retrieved. New tissue sections were cut from the original paraffin embedded tissue blocks to obtain both normal colonic mucosa and tumour on the same slide. There was insufficient tissue available or poor staining in 11 patients so 93 were available for the study., Results: The mismatch repair status was detected by antibodies to hMLH1 and hMSH2 gene product using a standard immunohistochemical technique. Fifty-six (60%) of 93 tumours demonstrated normal expression of both hMLH1 and hMSH2 protein. Twenty-five (27%) tumours did not express hMLH1 and 12 (13%) hMSH2 proteins. Comparison of the histopathological features revealed that a greater proportion of tumours with absence of either the hMLH1 or hMSH2 product were right sided, mucinous and poorly differentiated when compared to those that expressed the gene product. There was no detectable difference in overall survival or in survival of patients with Duke's C carcinoma when the groups were separated by the presence or absence of gene product., Conclusions: This study found that 40% of patients who were < or = 45 years of age at the time of diagnosis of colorectal cancer seen at Groote Schuur Hospital have tumours which are related to the absence of expression of either hMLH1 or hMSH2 genes.

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone. Our results showed no effect of antecedent hypercortisolemia on epinephrine responses to subsequent hypoglycemia (area under the curve/time 280 +/- 53 vs. 337 +/- 57 pg/ml, P = 0.16). Of particular importance, selective blockade of endogenous cortisol production during antecedent hypoglycemia had no effect on subsequent counterregulatory responses to hypoglycemia. Compared with epinephrine responses following antecedent euglycemia (area under the curve/time 312 +/- 38 pg/ml), epinephrine responses were comparably blunted following antecedent hypoglycemia, regardless of whether concurrent metyrapone blockade was employed (198 +/- 28 vs. 192 +/- 28 pg/ml, P = NS). Similar results were obtained for glucagon and ACTH levels. Considered together, these observations provide strong evidence that hypoglycemia-induced hypercortisolemia is not primarily responsible for the generation of HAAF.

Pheochromocytomas classically present with paroxysms of hypertension and adrenergic symptoms including headaches, palpitations, tremor, and anxiety. However, these tumors can be clinically silent and occasionally present only when catecholamine release is up-regulated by exogenous stimuli. In addition, the clinical presentation of pheochromocytoma can mimic a number of more common medical conditions, including migraine headaches, cardiac arrhythmias, and myocardial infarction, making diagnosis difficult. In this report, we present the case of a young woman who, while receiving oral corticosteroid therapy for presumed migraine headaches, suffered a myocardial infarction and ultimately hemorrhaged into a previously undiagnosed pheochromocytoma. Our patient exhibited severe, labile hypertension after the administration of iv beta-blockade for presumed myocardial ischemia, raising our initial clinical suspicion for pheochromocytoma. In this paper we review some of the key clinical issues related to this complex case, including steroid-induced stimulation of catecholamine synthesis and release, the role of pheochromocytoma in myocardial ischemia and electrocardiographic changes, and the rare complication of tumor hemorrhage. We then briefly review the essential diagnostic and management strategies for this rare but potentially lethal tumor, with specific emphasis on pheochromocytoma-related cardiovascular emergencies and the surgical management of tumor hemorrhage.

Objective: Recent studies suggest that strict perioperative glycemic control improves clinical outcomes after cardiothoracic surgery. However, optimal methods and targets for controlling blood glucose (BG) levels in this setting have not been established. Currently published intensive insulin infusion protocols (IIPs) have important practical limitations, which may affect their utility. In this article, the authors present their experience with a safe, effective, nurse-driven IIP, which was implemented simultaneously in 2 cardiothoracic intensive care units (CTICUs)., Design: Prospective cohort study., Setting: Tertiary referral hospital and community teaching hospital., Participants: CTICU patients., Interventions: A standardized, intensive IIP was used for all patients admitted to both CTICUs. Hourly BG levels, relevant baseline variables, and clinical interventions were collected prospectively from the active hospital chart and CTICU nursing records., Measurements and Main Results: The IIP was used 137 times in 118 patients. The median time required to reach target BG levels (100-139 mg/dL) was 5 hours. Once BG levels decreased below 140 mg/dL, 58% of 2,242 subsequent hourly BG values fell within the narrow target range, 73% within a "clinically desirable" range of 80 to 139 mg/dL, and 94% within a "clinically acceptable" range of 80 to 199 mg/dL. Only 5 (0.2%) BG values were less than 60 mg/dL, with no associated adverse clinical events., Conclusions: The IIP safely and effectively improved glycemic control in 2 CTICUs, with minimal hypoglycemia. Based on prior studies showing the benefits of strict glycemic control, the implementation of this IIP should help to reduce morbidity and mortality in CTICU patients.

Objective: In a recent randomized controlled trial, lowering blood glucose levels to 80-110 mg/dl improved clinical outcomes in critically ill patients. In that study, the insulin infusion protocol (IIP) used to normalize blood glucose levels provided valuable guidelines for adjusting insulin therapy. In our hands, however, ongoing expert supervision was required to effectively manage the insulin infusions. This work describes our early experience with a safe, effective, nurse-implemented IIP that provides detailed insulin dosing instructions and requires minimal physician input., Research Design and Methods: We collected data from 52 medical intensive care unit (MICU) patients who were placed on the IIP. Blood glucose levels were the primary outcome measurement. Relevant clinical variables and insulin requirements were also recorded. MICU nurses were surveyed regarding their experience with the IIP., Results: To date, our IIP has been employed 69 times in 52 patients admitted to an MICU. Using the IIP, the median time to reach target blood glucose levels (100-139 mg/dl) was 9 h. Once blood glucose levels fell below 140 mg/dl, 52% of 5,808 subsequent hourly blood glucose values fell within our narrow target range; 66% within a "clinically desirable" range of 80-139 mg/dl; and 93% within a "clinically acceptable" range of 80-199 mg/dl. Only 20 (0.3%) blood glucose values were <60 mg/dl, none of which resulted in clinically significant adverse events. In general, the IIP was readily accepted by our MICU nursing staff, most of whom rated the protocol as both clinically effective and easy to use., Conclusions: Our nurse-implemented IIP is safe and effective in improving glycemic control in critically ill patients.

Endocrine emergencies are commonly encountered in the ICU. This article focuses on several important endocrine emergencies, including diabetic hyperglycemic states, adrenal insufficiency, myxedema coma, thyroid storm, and pituitary apoplexy. Other endocrine issues that are related to intensive care, such as intensive insulin therapy, relative adrenal insufficiency, and thyroid function test abnormalities are also covered in detail.

Objective: To compare knee-length with thigh-length graduated compression stockings for correct application and rate of compliance when they are prescribed for the prevention of deep-vein thrombosis in surgical patients., Methodology: Patients who were prescribed graduated compression stockings were prospectively studied in three surgical units at Groote Schuur Hospital from February to June 1997. Knee-length stockings were prescribed in the colorectal unit, while the thigh-length variety were prescribed in the hepatobiliary and trauma units. Patients were observed for the correct application and size of stockings, and the presence of compression bands. A total of 72 patients were studied., Results: One patient in the knee-length group and 7 patients in the thigh-length group were not wearing their stockings. Twenty-one of 30 patients (70%) in the knee-length group and 15 of 42 (35.7%) in the thigh-length group had correctly applied stockings (P = 0.009)., Conclusions: Knee-length are more likely to be correctly applied than thigh-length stockings. Knee-length should replace thigh-length stockings in general surgical patients.

Hypothesis: Eradication of esophageal varices by repeated injection sclerotherapy and maintenance of eradication using continued surveillance endoscopy may reduce recurrent variceal bleeding and death from esophageal varices., Design: A prospective study of consecutive adult patients with endoscopically proved esophageal variceal bleeding., Setting: A tertiary care university hospital in a metropolitan area., Patients: Two hundred four patients (127 men and 77 women; mean age, 50.1 years; age range, 16-82 years) underwent 993 emergency and elective variceal endoscopic injection treatments with 5% ethanolamine oleate during 1992 endoscopy sessions. Most (166 [81.4%]) had cirrhosis, mainly due to alcohol abuse (131 [78. 9%]). The number of patients with each modified Pugh-Child risk grade was as follows: A, 30; B, 91; and C, 83. (The modified Pugh-Child classification comprises ascites, encephalopathy, serum albumin and bilirubin levels, and prothrombin time. Each variable is given a value of 1 to 3 with increasing impairment of liver function. Addition of the values leads to the Pugh-Child risk grades for each patient, with 5 and 6 giving grade A; 7 through 9, grade B; and 10 through 15, grade C, respectively.), Results: Ninety-five patients (46.6%) rebled at a median of 17 days (range, 0-2583 days). Seventy-four patients (36.3%) had a total of 112 further bleeding episodes before eradication of varices. Varices were eradicated in 99 (87.6%) of 113 patients who survived longer than 3 months after a median of 5 injections and remained eradicated in 43 (mean follow-up after eradication, 38 months; range, 4-125 months). Rebleeding was markedly reduced after eradication of varices. Varices recurred in 56 patients, of whom only 10 rebled from recurrent esophageal varices. Cumulative survival by life table analysis was 55%, 41%, and 30% at 1, 3, and 5 years, respectively. One hundred thirty-seven patients (67.2%) died during follow-up. Liver failure was the most common cause of death. Minor complications (mucosal ulceration) occurred in 105 patients. Major complications, including a localized injection site leak (n = 9), esophageal stenosis (n = 25), and esophageal perforation (n = 5), occurred in 39 patients., Conclusions: Repeated injection sclerotherapy eradicated esophageal varices in most long-term patients. Complications related to injection sclerotherapy were mostly minor. Complete eradication of varices reduced rebleeding and death from esophageal varices.

Background: The syndrome of hereditary non-polyposis colorectal cancer (HNPCC) can be diagnosed fairly accurately using clinical criteria and a family history. Identifying HNPCC helps to prevent large-bowel cancer, or allows cancer to be treated at an early stage. Once the syndrome has been diagnosed a family member's risk can be judged approximately from a family tree, or it can now be predicted accurately if the causative mutation is known., Objective: This study involved attempts to improve the management of a family with HNPCC over a period of 10 years. Clinical diagnostic criteria, colonoscopic surveillance, surgical treatment, genetic counselling, molecular genetic research, and finally predictive genetic testing were applied as they evolved during this time., Subjects and Methods: A rural general practitioner first noted inherited large-bowel cancer in the family and began screening subjects as they presented, using rigid sigmoidoscopy at the local hospital. At the time that the disorder was recognised as being HNPCC (1987), screening by means of colonoscopy at our university hospital was aimed primarily at first-degree relatives of affected individuals. After realising how many were at risk, screening was brought closer to the family. A team of clinicians and researchers visited the local hospital to identify and counsel those at risk and to perform screening colonoscopy. Family members were recruited for research to find the gene and its mutation that causes the disease, to develop an accurate predictive test and to reduce the number of subjects undergoing surveillance colonoscopies., Results: There are approximately 500 individuals in this family. In the 10 years of this study the number of subjects who have been counselled for increased genetic risk or who have requested colonoscopic surveillance for HNPCC in this kindred has increased from 20 to 140. After the causative mutation was found in the hMLH1 gene on chromosome 3, a test for it has reduced the number of subjects who need screening colonoscopy by over 70%. A protocol has been devised to inform family members, to acquire material for research in order to provide genetic counselling for (pre-test and post-test) risk, and to test for the mutation. Eventually, identifying those with the mutation should focus surveillance accurately., Conclusions: The benefits of restricting screening to subjects with the mutation that causes colorectal cancer and of performing operations to prevent cancer are hard to measure accurately. However, it is likely that at least half the family members will be able to avoid colonoscopic screening, some deaths from cancer should be prevented, and the cost of preventing and treating cancer in the family should fall substantially.

Purpose: The aim of this study was to describe the technique of radical excision of multifocal anal intraepithelial neoplasia and discuss controversial issues surrounding the management of this condition., Method: We describe the case of a 31-year-old female with previous vulval warts, vulval squamous carcinoma, and recent immunosuppression who had widespread anal intraepithelial neoplasia excised, and the resulting defect was split-skin grafted, including the anal canal., Results: Excision and split-skin grafting was successful in removing the disease and left a satisfactory cosmetic and functional result., Conclusion: Diffuse, high-grade, anal intraepithelial neoplasia is rare. Excision of these lesions remains controversial but may be the best option.