Variation in the clinical management of self-harm by area-level socio-economic deprivation: findings from the multicenter study of self-harm in England.

BACKGROUND: We investigated disparities in the clinical management of self-harm following hospital presentation with self-harm according to level of socio-economic deprivation (SED) in England. METHODS: 108 092 presentations to hospitals (by 57 306 individuals) after self-harm in the Multicenter Study of Self-harm spanning 17 years. Area-level SED was based on the English Index of Multiple Deprivation. Information about indicators of clinical care was obtained from each hospital's self-harm monitoring systems. We assessed the associations of SED with indicators of care using mixed effect models. RESULTS: Controlling for confounders, psychosocial assessment and admission to a general medical ward were less likely for presentations by patients living in more deprived areas relative to presentations by patients from the least deprived areas. Referral for outpatient mental health care was less likely for presentations by patients from the two most deprived localities (most deprived: adjusted odd ratio [aOR] 0.77, 95% CI 0.71-0.83, p < 0.0001; 2nd most deprived: aOR 0.80, 95% CI 0.74-0.87, p < 0.0001). Referral to substance use services and 'other' services increased with increased SED. Overall, referral for aftercare was less likely following presentations by patients living in the two most deprived areas (most deprived: aOR 0.85, 95% CI 0.78-0.92, p < 0.0001; 2nd most deprived: aOR 0.86, 95% CI 0.79-0.94, p = 0.001). CONCLUSIONS: SED is associated with differential care for patients who self-harm in England. Inequalities in care may exacerbate the risk of adverse outcomes in this disadvantaged population. Further work is needed to understand the reasons for these differences and ways of providing more equitable care.

MAdCAM-1 does not play a central role in the early pathophysiology of autoimmune hepatitis.

INTRODUCTION: CD4+ T cells are thought to have a central role in the pathogenesis of autoimmune hepatitis (AIH). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs homing of CD4+ T cells in the alimentary tract and is a therapeutic target in inflammatory bowel diseases. Here we assessed MAdCAM-1 expression in AIH and viral hepatitis and related its expression with immune infiltrate analysis and histopathological key features. METHODS: Hepatic portal areas of pretreatment biopsies (n=10) and follow-up biopsies (n=9) of patients with a confirmed diagnosis of AIH were assessed for MAdCAM-1 expression and infiltrate composition using immunohistochemistry and multispectral imaging (Vectra® Polaris™). Controls consisted of biopsies of patients with untreated chronic viral hepatitis B or C (n=22). RESULTS: MAdCAM-1 expression on endothelium was sparsely present in portal fields of two treatment-naïve AIH patients. Three patients showed MAdCAM-1 expression within lymphoid aggregates. No expression of significance (including single-cell expression) was observed in the remaining 6 patients. In contrast, viral hepatitis C biopsies showed endothelial MAdCAM-1 expression in 8 of 13 untreated patients. Densities of both B-cells (CD20+) and CD4+ T-cells (CD3+ CD8-) were increased in AIH and viral hepatitis patients with MAdCAM-1 expression. CONCLUSION: MAdCAM-1 was detected in liver biopsies in a minority of patients with AIH at the time of diagnosis suggesting no central role in its pathophysiology. Lymphoid or reticular MAdCAM-1 pattern expression was associated with more dense infiltrates of both B-cells and CD4+ T-cells, and may be related to the formation of secondary lymphoid follicles.

The effect of financial incentives on top of behavioral support on quit rates in tobacco smoking employees: study protocol of a cluster-randomized trial.

BACKGROUND: Stimulating successful tobacco cessation among employees has multiple benefits. Employees who quit tobacco are healthier, more productive, less absent from work, and longer employable than employees who continue to use tobacco. Despite the evidence for these benefits of tobacco cessation, a successful method to stimulate employees to quit tobacco is lacking. The aim of this study is to evaluate whether adding a financial incentive to behavioral support (compared with no additional incentive) is effective and cost-effective in increasing abstinence rates in tobacco smoking employees participating in a smoking cessation group training. METHODS/DESIGN: In this cluster-randomized trial employees in the intervention and control group both participate in a smoking cessation group training consisting of seven weekly counseling sessions of ninety minutes each. In addition to the training, employees in the intervention group receive a voucher as an incentive for being abstinent from smoking at the end of the training (€50), after three months (€50), after six months (€50), and after one year (€200). The control group does not receive any incentive. The primary outcome is carbon monoxide validated 12-month continuous abstinence from smoking (Russel's standard). Additionally, an economic evaluation is performed from a societal and an employer perspective. DISCUSSION: The present paper describes the methods and design of this cluster-randomized trial in detail. We hypothesize that the financial incentive for abstinence in the form of vouchers increases abstinence rates over and above the group training. The results of this study can provide important recommendations for enhancement of employee tobacco cessation. TRIAL REGISTRATION: Dutch Trial Register: NTR5657 . First received 27-01-2016.

Risk factors and treatment for recurrent vulvar squamous cell carcinoma.

Recurrent disease occurs in 12-37% of patients with vulvar squamous cell carcinoma (VSCC). Decisions about treatment of recurrent VSCC mainly depend on the location of the recurrence and previous treatment, resulting in individualized and consensus-based approaches. Most recurrences (40-80%) occur within 2 years after initial treatment. Currently, wide local excision is the treatment of choice for local recurrences. Isolated local recurrence of VSCC has a good prognosis, with reported 5-year survival rates of up to 60%. Groin recurrences and distant recurrences are less common and have an extremely poor prognosis. For groin recurrences, surgery with or without (chemo) radiotherapy is a treatment option, depending on prior treatment. For distant recurrences, there are only palliative treatment options. In this review, we give an overview of the available literature and discuss epidemiology, risk factors, and prognostic factors for the different types of recurrent VSCC and we describe treatment options and clinical outcome.

Low prevalence of chronic hepatitis C, but high prevalence of elevated aminotransferases in a cohort of 2026 patients referred for orthopaedic surgery in the eastern part of Germany.

INTRODUCTION: The prevalence of chronic hepatitis C in Germany is about 0.2 - 0.4 %. However, there seems to be regional differences between western and eastern states of the country. Thus, the present study analysed the prevalence of chronic hepatitis C in a cohort of orthopaedic patients in Thuringia. METHODS: Tests for antibodies against hepatitis C virus (anti-HCV) were performed on serum samples of 2026 patients (1183 females, 843 males) admitted for orthopaedic surgery to a university hospital in Thuringia. If anti-HCV was positive, serum was tested for HCV-RNA by polymerase chain reaction (PCR). For the sake of anonymity only age and gender were reported in all patients. In 1465 cases, values of alanine (ALT) and aspartate (AST) aminotransferases were additionally available. The low HCV prevalence was confirmed in a second cohort of orthopaedic patients (n = 929, 599 females, 330 males) investigated at a university hospital in Saxonia. RESULTS: In the Thuringian cohort, anti-HCV was detectable in 12/2026 (0.6 %) individuals (10 females (0.85 %) and 2 males (0.24 %: p = 0.14 %). HCV-RNA was positive in 3/10 of anti-HCV positive females (0.15 % of the study cohort). HCV infection was already known in two cases. Anti-HCV positive patients seemed to be older than anti-HCV negative individuals (64.25 vs. 59.48 years; p = 0.17), as well as HCV-RNA positive cases compared to non-viraemic patients (66.3 vs. 63.6 years; p = 0.32). All HCV-RNA positive females had elevated ALT values. However, ALT and AST were also elevated in 18.2 % and 11.7 % of anti-HCV negative individuals. There was no significant difference between males and females (p = 0.32). In the Saxonian cohort none of 929 individuals were HCV positive. CONCLUSION: The prevalence of chronic hepatitis C is low in the investigated cohorts of orthopaedic patients in Thuringia and Saxonia. However, elevation of aminotransferases occurs surprisingly often. The reasons for elevated aminotransferases and a reliable analysis of the HCV prevalence in different subgroups of the Eastern German population require further evaluation.

Mechanism of antinociceptive action of clonidine in nonmyelinated nerve fibres.

Despite a large body of clinical evidence in favour of a local anesthetic effect of clonidine, the underlying mechanism has not yet been elucidated. In this study we have used the sucrose-gap method to measure the effects of clonidine on the electrophysiological properties of nonmyelinated nerve fibers in the rabbit vagus nerve. The results showed that clonidine enhanced the hyperpolarizing and reduced the depolarizing afterpotential that follow compound action potentials during electrical activity. We showed that summation of these afterpotentials shifts the membrane potential toward more negative values, thus creating a region of low safety conduction, where the local circuit currents might fail to depolarize the axonal membrane to the threshold value needed to open voltage-dependent Na(+) channels. Yohimbine did not reverse the inhibitory effects of clonidine on impulse propagation, indicating that the observed effects of clonidine relies on mechanisms not mediated by alpha(2)-adrenoceptors.

Correlation of the exposure to a pollutant with a task-related action or workplace: the CAPTIV system.

Usually, measurement of pollution at the workplace is performed by air sampling on solid absorbents and filters. The information obtained is the mean value of worker exposure over the sampling period. The use of specific sensors for chemicals can give complementary information, namely continuous exposure information. The CAPTIV system permits one to centralize and store this information along with a video system which restores the images of the workplace. Also, the stored video sequences, correlated to specified exposures, can be found automatically. This gives a rich information resource. In particular it allows one to correlate the occupational activity with the exposure level. The analysis of collected information may lead to advice on good practice at the workplace or even to proposals for modification of existing equipment and processes. A huge quantity of information to be processed is obtained with this new approach. The best use of it can only be made with the help of a high capacity processing tool. That is the reason why CAPTIV has been equipped with a data processor support system. At the end of this paper, we present an example of using CAPTIV to study a stone-cutting work station.

Different factors influencing the expression of Raynaud's phenomenon in men and women.

OBJECTIVE: To determine whether the risk profile for Raynaud's phenomenon (RP) is different between men and women. METHODS: In this cross-sectional study of 800 women and 725 men participating in the Framingham Offspring Study, the association of age, marital status, smoking, alcohol use, diabetes, hypertension, and hypercholesterolemia with prevalent RP was examined in men and women separately, after adjusting for relevant confounders. RESULTS: The prevalence of RP was 9.6% (n = 77) in women and 5.8% (n = 42) in men. In women, marital status and alcohol use were each associated with prevalent RP (for marital status adjusted odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4-3.9; for alcohol use OR 2.2, 95% CI 1.0-5.2), whereas these factors were not associated with RP in men (marital status OR 1.4, 95% CI 0.6-3.5; alcohol use OR 1.0, 95% CI 0.2-4.4). In men, older age (OR 2.3, 95% CI 1.0-5.2) and smoking (OR 2.6, 95% CI 1.1-6.3) were associated with prevalent RP; these factors were not associated with RP in women (older age OR 0.8, 95% CI 0.4-1.6; smoking OR 0.7, 95% CI 0.4-1.1). Diabetes, hypertension, and hypercholesterolemia were not associated with RP in either sex. CONCLUSION: The results indicate that risk factors for RP differ between men and women. Age and smoking were associated with RP in men only, while the associations of marital status and alcohol use with RP were observed in women only. These findings suggest that different mechanisms influence the expression of RP in men and women.

Glucose intolerance, physical signs of peripheral artery disease, and risk of cardiovascular events: the Framingham Study.

BACKGROUND: Diabetes and peripheral artery disease (PAD) are acknowledged hallmarks of development of atherosclerotic cardiovascular disease (CVD). The prognostic implications of physical indicators of PAD, compared with and in conjunction with glucose intolerance based on population based data, are not well documented. METHODS AND RESULTS: The influence of carotid and femoral bruits and nonpalpable pedal pulses, with and without glucose intolerance, on development of coronary disease (CHD), congestive heart failure (CHF), and stroke (CVA) was investigated in a cohort of 1672 men and 2264 women ages 47 to 99 years participating in the Framingham Study. Cross-sectional pooling yielded 29,063 2-year person-examination units based on the sample of whom 440 men and 484 women had glucose intolerance develop. Over the 26 years of follow-up, 210 men and 199 women had 1 or more of the specified CVD events. Logistic regression analysis was used to estimate age-adjusted odds ratios comparing incidence of CVD events in subjects with glucose intolerance, signs of PAD, or both conditions with those with neither condition. Glucose intolerance was associated with a 2-fold excess occurrence of physical signs of PAD (P< .01 ). Femoral and carotid bruits were generally associated with greater increased risk of CHD, CHF, and CVA than was glucose intolerance alone. Particularly in women, the concomitant presence of bruits augmented the CVD risk of glucose intolerance. Nonpalpable pedal pulses were a stronger risk factor for CVD end points than glucose intolerance; particularly in men and in both sexes, those with both conditions were at substantially greater risk of CVD events than those with either alone. CONCLUSIONS: Physical findings of PAD appear to signify a compromised arterial circulation to the heart and brain as well as the limbs in persons with glucose intolerance. Persons with the combination are candidates at high risk for CHD, CHF, and CVA.

The occurrence of Raynaud's phenomenon in a general population: the Framingham Study.

The prevalence and predisposing conditions for primary and secondary Raynaud's phenomenon (RP) were examined in The Framingham Study based on 16 years of follow-up of a cohort of 4182 men and women. The association with atypical chest pain and migraine headache was also investigated. Over the 16 years of follow-up there were 130 men and 171 women who developed primary RP. The prevalence in women (9.6%) was somewhat higher than in men (8.1%) and 81.4% of the RP was primary. Secondary RP was equally prevalent in men (18.6%) and women (19.7%). The most common causes of secondary RP were beta-blocker use (34.2%), carpal tunnel syndrome (10.5%) and rheumatoid arthritis (7.2%). Primary RP cases differed from noncases by having lower systolic blood pressure (p < or = 0.001) and diastolic blood pressure (p < 0.0001), and more coronary disease (p = 0.009), smoking (p < or = 0.01) and higher blood sugars (p < or = 0.009). Atypical chest pain was present more often than noted previously in The Framingham Study general population survey, and was equally prevalent in primary and secondary RP and in the two sexes. Associated migraine was more prevalent in women (14.4%) than men (5.0%). Vibrating tool use with associated RP occurred in 14.6%.

A clinical measure of the posterior epidural space depth.

BACKGROUND AND OBJECTIVES: The object of this study was to measure the clinically relevant depth of the posterior epidural space (ES) while placing subarachnoid catheters. METHODS: "Hanging drop" technique was used to locate the ES via a midline approach in the lumbar area. The distance from the skin to the ES was measured, and the needle was advanced until free flow of cerebrospinal fluid was observed. The distance between entry into the ES and the subarachnoid space-the posterior ES depth-was then measured. Regression analysis was used to investigate relationships between skin-to-ES distance, posterior ES depth, and patient characteristics (height, weight, body surface area [BSA] and age). RESULTS: The 55 patients studied had a mean skin-to-ES distance of 50.9 +/- 12 mm (range, 27-94) and a mean posterior ES depth of 6.9 +/- 4 mm (range 2-25). Skin-to-ES distance was related to BSA (r = .597, P < .0001) and weight (r = .572 P < .0001). No correlation was found between posterior ES depth and any other variable. CONCLUSIONS: The posterior ES has been found to be somewhat larger and more variable than previously described. The findings provide clinical confirmation of recent radiologic and cadaveric studies, which portray a posterior ES of variable size and complex shape. These findings have implications for cannulation and use of epidural therapy as well as for the combined catheter epidural and single-dose spinal technique.

Epidemiologic assessment of angina before and after myocardial infarction: The Framingham study.

Angina pectoris before and after MI was evaluated in a sample of 729 men and women from a general population in whom MI developed during a 36-year period of follow-up. Relations of AP to subsequent CHD events and mortality after initial MI were analyzed by proportional hazards regression models and were adjusted for covariates (age, sex, blood pressure, serum cholesterol, body mass index, glucose intolerance, cigarette smoking, and antihypertensive medications) obtained from routine biennial examinations preceding the initial MI. Comparisons of the influence of angina were made between pre-MI angina, post-MI angina, and absence of AP. The sample had 484 men and 245 women (mean ages, 63 and 69, respectively) who survived greater than / equal to 30 days after MI. The initial MI was clinically unrecognized in 165 (34%) men and 115 (47%) women. Data on covariates were complete for 622 subjects, among whom 30% had pre-Ml angina, 18% had post-MI angina, and 52% did not have AP. Angina was half as common in persons with unrecognized MIs as in those with clinically recognized MIs. During an average of 8.7 years of follow-up, 57% of subjects developed subsequent CHD events, including recognized and unrecognized MI, coronary insufficiency, and CHD death, and 74% died. Both pre-MI angina (hazard ratio, 1.49; 95% CI, 1.17 to 1.91) and post-MI angina (hazard ratio, 1.43; 95% CI, 1.06 to 1.94) adjusted for accompanying risk factors were associated with increased risk for subsequent CHD events compared with those without AP. Neither pre-MI nor post-MI angina was associated with excess overall mortality.

Temporal patterns of stroke onset. The Framingham Study.

BACKGROUND AND PURPOSE: Several studies have shown stroke onset to vary by season, day of the week, and time of day. These temporal patterns, which may provide insights into pathogenesis, were found mainly in clinical series, which can be subject to selection bias. To obtain a less distorted picture of stroke onset, we examined the month and season, day of the week, time, and place stroke occurred in a community-based cohort. METHODS: Over a 40-year period of surveillance of the Framingham Study cohort of 5070 people aged 30 to 62 years and free of stroke and cardiovascular disease at entry, 637 completed initial strokes occurred. Month, season, day of the week, time of day, and place of occurrence of stroke were ascertained systematically and related prospectively to stroke incidence, subtype, and gender. RESULTS: Winter was the peak season for cerebral embolic strokes. Significantly more stroke events occurred on Mondays than any other day, particularly for working men. For intracerebral hemorrhages, a third happened on Mondays in both genders. The time of day when strokes most frequently occurred was between 8 AM and noon. This pattern was true for all stroke subtypes. This pattern persisted when individuals whose onset occurred while sleeping or on awakening were excluded. Stroke in general occurred more at home, with hemorrhagic strokes occurring outside the home and cerebral embolisms in the hospital more than other subtypes. CONCLUSIONS: Temporal patterns of stroke onset were observed for season, day of the week, time of day, and place in a community-based population. These findings suggest that there are periods of increased risk of stroke that may be amenable to preventive strategies.

Hematocrit and the risk of cardiovascular disease--the Framingham study: a 34-year follow-up.

We examined the relationship between the risk of CVD mortality and morbidity and HCT over a period of 34 years of follow-up in the 5209 men and women in the Framingham cohort. There was an increased risk of all-cause death as well as morbidity and mortality due to CVD in subjects with HCT values in the highest quintile. There was no evidence of a decrease risk of CVD in men with lower than median HCT values, and women actually showed increased risk of CVD events with lower HCT values, indicating a J- or U-shaped relationship between HCT and CVD events. The impact of HCT on CVD events appears to differ for different age groups and by sex. HCT is significantly related to the incidence of CVD, including CHD, MI, angina pectoris, stroke, and IC in younger men. In younger women, HCT is related to the incidence of CVD, CHD, MI and mortality from CVD and CHD. A negative association with CHF incidence and stroke death is noted in elderly women. These results support the hypothesis that HCT is an important risk factor for some CVD events, an association that merits further investigation.

Family patterns of coronary heart disease mortality: the Framingham Longevity Study.

Family patterns for age at death were examined in a 40 year follow-up of 5209 men and women (2900 deceased, 2309 living) in the Framingham Study and their parents. Age at death of both mothers and fathers was significantly older for surviving offspring when compared to decreased offspring (p less than 0.0001). When longevity was assessed according to cause of death in the offspring, parental age at death was a significant predictor of death by coronary heart disease (CHD), but not for stroke or cancer. Multiple regression analysis for offspring with sudden CHD death revealed that mother's age at death was a significant predictor of age at sudden CHD death (p less than 0.0003) whereas father's age at death was a significant predictor of age at death in non-sudden CHD death (p less than 0.004). Life table analysis showed longest survival rates associated with both parents surviving to age 75 or older followed by mother only surviving to age 75 or older, then father only, and shortest survival with neither parent surviving to age 75. Longevity appears to be more strongly associated with maternal death age than parental death age. Proportional hazards analysis of risk factors associated with CHD revealed that systolic blood pressure, sex of the individual, and cigarette smoking were the most significant predictors of death age. These findings suggest that familial similarities for death age may be mediated primarily through shared CHD risk factors within families, either genetic or non-genetic.

Antibiotic use in the nursing home. Physician practice patterns.

Antibiotic usage patterns were studied in two nonproprietary nursing homes that included 720 intermediate care and skilled nursing home beds. Medical records of residents receiving antibiotics were reviewed every fourth month for 1 year. Of 181 antibiotic prescriptions written for indications other than prophylaxis, 41% were for presumed urinary tract infections, 35% for respiratory tract infections, and 14% for skin/soft-tissue infections. The majority of antibiotic prescriptions (54%) were made by telephone order. Cultures were obtained in 60% of suspected infections; two thirds of cultures were of the urine. Antibiotics were changed during the course of therapy in only 12% of cases. Eighty-one percent of residents treated with antibiotics improved or were cured, 9.5% were hospitalized or died, and an additional 9.5% failed to improve but remained in the nursing home. Fever was present in 48% of cases prior to treatment, but had no predictive value for patient outcome. We conclude that antibiotic treatment in the nursing home is often initiated in the absence of fever, culture information, or examination of the patient. Empiric prescription of antibiotics in this setting generally is associated with favorable clinical course.

Epidemiology of some peripheral arterial findings in diabetic men and women: experiences from the Framingham Study.

PURPOSE AND PATIENTS AND METHODS: The purpose of this study was to determine the relationship between diabetes and the development of some peripheral arterial findings--carotid and femoral bruits and nonpalpable pedal pulse--and acute cardiovascular events in 1,196 men and 1,582 women based on 20-year follow-up data in the Framingham Study. RESULTS: For both men and women without diabetes, the incidence of carotid bruits and nonpalapble pedal pulses increased significantly with age (p less than 0.05) without any apparent male predominance. In contrast, diabetic men and women were at an elevated risk of each peripheral arterial condition that was not appreciably different across age groups. Compared with women without diabetes, those with diabetes experienced nearly a twofold excess of femoral bruits (p less than 0.05) and a 50% excess of nonpalpable pedal pulses (p less than 0.01). Among men, diabetes nearly doubled the risk of carotid bruits (p less than 0.05). Those who had both diabetes and symptoms of peripheral arterial disease were at especially high risk of incident cardiovascular events. In particular, nonpalpable pedal pulses were associated with more than a twofold excess of coronary heart disease (p less than 0.05) and stroke (p less than 0.01) in diabetic women and more than a twofold excess of coronary heart disease and cardiac failure in diabetic men (p less than 0.01). Femoral bruits doubled the risk of coronary heart disease in diabetic men (p less than 0.05). CONCLUSION: We conclude that while diabetes predisposes to various forms and locations of peripheral arterial disease, the enhanced risk of acute cardiovascular events experienced by diabetic patients is increased further when diabetes is accompanied by indications of a peripheral arterial condition. Since signs of peripheral arterial disease may suggest an impending or coexistent atherosclerotic process, careful examination of arterial circulation by evaluating peripheral pulses and assessing whether bruits are present is important.

Diabetes, intermittent claudication, and risk of cardiovascular events. The Framingham Study.

The impact of diabetes on intermittent claudication was examined in 1813 men and 2504 women with 34-yr follow-up data in the Framingham study. For both sexes, diabetes was associated with a two- to threefold excess risk of intermittent claudication compared with its absence. A pronounced excess risk was also observed in subjects on oral hypoglycemic therapy and in women receiving insulin. Although diabetes was often associated with an atherogenic-risk profile, controlling for age and several concomitant risk factors failed to eliminate the association with intermittent claudication. Those who developed both intermittent claudication and diabetes were at an especially high risk of incident cardiovascular events. In women, the risk of coronary heart disease, stroke, and cardiac failure was increased 3-4 times when diabetes and intermittent claudication occurred together compared with when either condition existed alone. In diabetic men, the presence of intermittent claudication doubled the risk of stroke, and cardiac failure was approximately 3 times more likely in subjects with both conditions compared with either alone. We conclude that diabetes is an important risk factor for intermittent claudication, which in turn confers a serious prognosis for subsequent cardiovascular outcomes in the patient with diabetes.

Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition.

1. In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2. With a half-maximal inhibitory concentration of 5 microM, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3. Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 microM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4. Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N-acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5. DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6. The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan.