Respiratory measurements and airway clearance device prescription over one year in amyotrophic lateral sclerosis.

Objective: The rates of decline in respiratory measurements, including Peak Cough Flow (PCF) have not been established in Amyotrophic Lateral Sclerosis (ALS). Additionally, optimal prescription of cough adjuncts which aim to increase cough strength are unknown. The primary aim of this study was to quantify declines in respiratory function in ALS using PCF, Sniff Nasal Inspiratory Pressure (SNIP) and Slow Vital Capacity (SVC). Secondary aims were to measure respiratory morbidity, audit the characteristics of those prescribed cough adjuncts, and compare outcomes between treated and untreated cohorts. Methods: A prospective, longitudinal, observational, cohort study evaluated respiratory measures, morbidity, and physical function in ALS patients at three monthly intervals, over one year. Patient and disease characteristics of those prescribed cough adjuncts were profiled at the time of device prescription. Results: one hundred and eight participants with mean age 62.1 ± 11.5 years participated. PCF declined rapidly at a rate of 124.8L/min/year (p < 0.001). SNIP, SVC (%predicted), and ALSFRS-R also declined significantly at rates of 18.72cmH2O, 17.49%, and 9.62 units per year respectively (p < 0.001). Thirty-two (29.6%) patients reported 56 incidences of chest infection and 21 died. Patients prescribed a cough adjunct (44.4%) had significantly lower average PCF, SNIP, SVC percent predicted, and ALSFRS-R (p < 0.001). Conclusions: This study identified a rapid rate of decline in PCF, a similar decline in SNIP, and slower declines in SVC and ALSFRS-R. Cough adjunct prescription was triggered by declining respiratory measures and recommended PCF thresholds, but also by respiratory symptoms. Chest infections were common in patients regardless of cough adjunct prescription and should be closely monitored.

A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people.

A difference in the inheritance of diabetes has been shown between the families of twenty-six patients with maturity-onset type diabetes of young people (MODY) and families of thirty-five patients with classical juvenile-onset diabetes (JOD). In the families of MODY: 1) twenty-two of twenty-six (85 per cent) propositi had a diabetic parent; 2) 46 per cent of families showed direct vertical transmission of diabetes through three generations; 3) of forty-seven tested siblings twenty-five (53 per cent) had latent diabetes; 4) the diabetic phenotype in the families was consistent, most affected individuals having a noninsulin requiring type of disease. These findings are compatible with autosomal dominant inheritance of MODY, although they do not exclude multifactorial inheritance. In contrast, in the families of JOD: 1) only four (11 per cent) of propositi had a diabetic parent; 2) three generation inheritance was found in only two (6 per cent) of JOD families, and 3) of seventy-four tested siblings eight (11 per cent) were diabetic. This difference provides further evidence of genetic heterogeneity in diabetes mellitus and indicates that there is a need for careful definition of the phenotype of diabetes in populations in which the genetics of diabetes is to be analyzed. Diabetes 24:44-53, January, 1975.

Abnormal thermoregulation in diabetic autonomic neuropathy.

Hypothermia has been reported to be more common in diabetic people than in nondiabetic people, and we have investigated the possibility that autonomic neuropathy may be associated with disordered thermoregulation. After an overnight fast and maintenance of normoglycemia, 12 insulin-treated diabetic patients with and 11 without neuropathy and 12 nondiabetic control subjects, all less than 55 yr, were subjected to external cooling by perfusing water at 16 degrees C through a liquid-conditioned coverall for less than or equal to 45 min. Patients with autonomic neuropathy had impaired vasoconstriction to cooling, particularly in the foot, calf, and forearm. Core temperature rose by 0.2 degrees C in control subjects and by 0.15 degrees C in patients with diabetes but no neuropathy. In contrast, group mean core temperature was unchanged in those with autonomic neuropathy and fell in 3 subjects (P less than .001). Cooling caused shivering in 6 patients with diabetic autonomic neuropathy, but not in those with neuropathy or control subjects (P less than .05). Baseline metabolic rates were similar in all three groups, but the increase after cooling was significantly greater among those who shivered (P less than .05-.02). Thus, young diabetic patients with autonomic neuropathy have impaired thermoregulation to a relatively short period of external cooling, even during metabolic stability, which may predispose to hypothermia.

The various faces of diabetes in the young: changing concepts.

Diabetes included several disorders associated with hyperglycemia. A difference in inheritance between the families of juvenile-onset- and maturity-onset-type diabetics, provides evidence for genetic heterogeneity. Heterogeneity of insulin responses to glucose was foung among nonobese patients with maturity-onset-type diabetes. Prospective studies in young patients have shown that glucose intolerance may not progress for as long as 22 years and that subnormal insulin responses to glucose have not decreased further, up to 12 years. However, patients who progressed to diabetes requiring insulin had insulin responses that were subnormal or below the control mean. None whose insulin responses exceeded this mean have decompensated. Thus, insulin response to glucose has prognostic implications. A tentative classification of diabetes in the young is proposed. There was a significant correlation between muscle capillary basement membrane width and known duration of carbohydrate intolerance.

Group therapy in the treatment of diabetes.

The psychological burden imposed by diabetes is large but is often ignored by health care professionals who concentrate on its technical aspects. In this article we review the need for psychosocial support in the treatment of diabetes. Group psychotherapy, although most widely used in psychiatry, was in fact started by a physician almost 80 yr ago and has been used as an adjunct to the management of many medical conditions. Limited experience of group psychotherapy among diabetic patients has given encouraging results. Issues remain, however, as to which groups of patients might benefit most, who should act as group leader, and how one can best assess outcome.

A new approach to the treatment of nocturnal hypoglycemia using alpha-glucosidase inhibition.

Nocturnal hypoglycemia is common in the diabetic patient on twice-daily regular and intermediate (NPH or lente) insulin regimens because intermediate-acting insulins before the main evening meal produce "unopposed" free insulin peaks around 0300 h, food absorption having been completed much earlier. Fourteen insulin-dependent diabetic patients were treated for 6 wk with the alpha-glucosidase inhibitor, acarbose, in a double-blind crossover study to see whether the drug would delay absorption of the evening meal sufficiently to correct the mismatch and prevent nocturnal hypoglycemia. On 200 mg acarbose (six patients), inhibition of carbohydrate digestion was so profound as to lead to midevening hypoglycemia with severe flatulence and abdominal colic. With a smaller dose of 100 mg before the evening meal (eight patients) there was a significant reduction in MAGE and MBG coupled with a clinically significant reduction in midevening and nocturnal hypoglycemic reactions. Alpha-glucosidase inhibition therefore provides a promising new approach to the problem of nocturnal hypoglycemia although a preparation that is safe for long-term clinical use remains to be found.

A critical evaluation of methods of monitoring diabetic control.

Patients with insulin-treated diabetes need to be actively involved in their own treatment. We have found that measurement of blood rather than urinary glucose by our diabetic patients leads to greater understanding and enthusiasm as well as to better control of blood glucose. Home blood glucose monitoring is complementary to rather than a substitute for measurement of hemoglobin A1. The latter provides an objective index of long-term control that is of more use to the doctor than to the patient. The former gives the patient information that enables him to master his own disease from day to day.

Double-blind evaluation of efficacy and tolerability of metformin in NIDDM.

OBJECTIVE: To test the efficacy and tolerability of metformin. RESEARCH DESIGN AND METHODS: An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily. RESULTS: Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly, and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated. CONCLUSIONS: Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects.

Well-being, cerebral function, and physical fatigue after nocturnal hypoglycemia in IDDM.

OBJECTIVE: This study assessed the effect of nocturnal hypoglycemia on well-being cerebral function, and physical fatigue the next day in 10 subjects with IDDM. RESEARCH DESIGN AND METHODS: After an exercise test to determine work-loads corresponding to 30 and 60% VO2max, volunteers were studied twice, 4 weeks apart. Blood glucose was lowered one night to 2.3-2.7 mmol/l for 1 h, and at the control visit, hypoglycemia was avoided. The next morning, well-being was assessed using the minor symptom evaluation profile (MSEP), and cerebral function was assessed with the paced auditory serial addition test, the digit symbol substitution test, trail making part B, four-choice reaction time, and auditory P300 latency. Subjects then exercised at predetermined workloads corresponding to 30% VO2max for 30 min and 60% VO2max until exhaustion. Fatigue was assessed every 10 min using the Borg scale for rating of perceived exertion. RESULTS: All three components of the MSEP scored higher (indicating more symptoms) after the hypoglycemic night compared with the control night (P < 0.01 contentment, sleep; P < 0.001 vitality). None of the cerebral function tests performed the next day was affected by hypoglycemia. Exercise capacity was similar at both visits, but subjects were more fatigued after the hypoglycemic night (P < 0.01, analysis of variance). There were no differences in potassium, catecholamine, glucose, or lactate concentrations between visits either before or during exercise. CONCLUSIONS: One hour of hypoglycemia at night affects a subject's sense of well-being, but not cerebral function, the next day. The greater fatigue after the hypoglycemic night cannot be explained by the biochemical parameters measured.

Influence of duration of hypoglycemia on the hormonal counterregulatory response in normal subjects.

Glucagon and epinephrine are the most important short term glucose counterregulatory hormones. The epinephrine response in patients with insulin-dependent diabetes mellitus is related to the level of glycemic control, but little is known about the factors influencing counterregulation in normal subjects. We, therefore, conducted hyperinsulinemic glucose clamp studies to examine the counterregulatory response to recurrent and prolonged mild hypoglycemia in normal women. Blood glucose was clamped for 20 min at 3.5 mmol/L. Thereafter, the subjects had their blood glucose maintained at 2.8 mmol/L for 90 min and on another occasion lowered to 2.8 mmol/L and raised to 3.5 mmol/L twice during the 90-min period. Continuous hypoglycemia produced augmented plasma glucagon, cortisol, and pancreatic polypeptide responses (all P less than 0.05) compared to these responses to recurrent hypoglycemia. Plasma GH increased, but the magnitude of the response was not altered by the duration of hypoglycemia. During the recurrent hypoglycemia study plasma epinephrine levels rose and fell in parallel with the fluctuations in blood glucose. The mean peak increase was similar [1.37 +/- 0.25 (+/- SE) nmol/L] to that during the continuous study (1.76 +/- 0.23 nmol/L). There was no change in plasma glucagon levels in response to hypoglycemia of less than 15-min duration. We conclude that 1) the duration of hypoglycemia influences the counterregulatory response, and 2) epinephrine release is under precise control and responds rapidly to fluctuations in blood glucose.

Patient self-monitoring of blood glucose and refinements of conventional insulin treatment.

The compelling evidence that blood glucose control will slow or prevent microvascular complications has stimulated research to find better ways of managing insulin-dependent diabetes. The excellent results obtained with "open loop" insulin infusion systems suggest that the relative failure of conventional treatment is the result of (1) a lack of appropriate feedback to the patient and (2) the use of insulin regimens which do not mimic physiologic insulinemia, particularly in the basal state. Doctors regard blood glucose measurements as an essential part of diabetic management and extension of this technology to patients has added a new dimension, particularly in the assessment of control. Nevertheless, home blood-glucose monitoring will not necessarily improve diabetic control; the best results have been obtained when it has been offered as part of a package deal which includes more investment of time and interest by patients and doctor together with joint discussions of problems and changes in treatment. The biggest problem with conventional twice daily insulin regimens is to sustain constant basal insulin levels during the night. Attempts to obtain fasting normoglycemia with an injection before supper often result in nocturnal hyperinsulinemia and hypoglycemia. This can usually be resolved by changing to a three times daily regimen with an extra injection of NPH insulin at bedtime. Three times daily insulin injections with feedback from home blood-glucose monitoring give as good blood glucose control as infusion systems and are cheaper and more acceptable to patients.

Genetic patterns in diabetes mellitus.

Diabetes comprises many syndromes whose only common feature is a high blood glucose level. Some are entirely genetic, some partially so, and others not at all. Perhaps the most important advance in the past 10 years is proof that insulin dependent diabetes is genetically different from the insulin independent form. Most progress has been made in unraveling the etiology of insulin dependent diabetes, although more information is needed before the mode of inheritance is finally settled. The last few years have produced a plethora of new facts about insulin dependent diabetes mellitus, providing geneticists, clinicians, and epidemiologists with the fascinating challenge of a disease with an apparently genetic susceptibility to external (environmental) triggers. Little progress has been made in the field of insulin independent diabetes, and one might safely predict that the diabetic syndrome will still produce some nightmares for researchers who take up the challenge of trying to unravel its various etiologies and methods of inheritance.

Glucagon secretion in unaffected monozygotic twins of juvenile diabetics.

Glucagon secretion during a 50-g oral glucose tolerance test has been investigated in 16 nondiabetic monozygotic twins of juvenile diabetics and compared with the results in 10 normal controls and 10 untreated, newly diagnosed, maturity-onset diabetics. Normal subjects showed a significant mean fall in glucagon at 15, 30, and 60 min, with a return to the baseline at 120 min. Maturity-onset diabetics showed a significant mean rise 15 min after oral glucose. The mean of the twin group was intermediate between normals and diabetics, although there was considerable individual variation with some showing suppression and others stimulation of glucagon release. When the twins were divided according to the length of discordance it was found that the mean response in the 8 twins who had been discordant for a mean of 19 years was indistinguishable from that of normal subjects, whereas the mean response of twins discordant for a mean of only 4.5 years was similar to that of the diabetic patients. It is possible, therefore, that hypersecretion of glucagon may occur in some subjects predisposed to develop diabetes mellitus, and the finding of lack of suppression of glucagon in the identical twin of a juvenile diabetic may be of prognostic significance. Identical twins who have been discordant for over 10 years are thought on other grounds to be unlikely to develop diabetes, and the finding of a normal glucagon response is further confirmation of their normal metabolic status and reinforces the suggestion that they are not prediabetic.

The effects of 3-hydroxybutyrate and glucose on human T cell responses to Candida albicans.

Diabetic patients are particularly susceptible to mucocutaneous candidosis. T lymphocytes are central to the induction of antigen-specific immune responses and may be sensitive to the biochemical abnormalities associated with poorly controlled diabetes; namely, hyperglycaemia and/or ketonemia. To examine this we have studied the effect of varying concentrations of glucose and 3-hydroxybutyrate (3-HB) in cultures of human T cells stimulated with Candida albicans antigen. Proliferation of T cells from six type 1 diabetic and six non-diabetic control subjects was significantly inhibited (both P < 0.05) in glucose-free medium, and at a glucose concentration of 80 mmol l-1 as compared with cultures containing glucose at physiological concentration (5 mmol l-1). 16 and 32 mmol l-1 3-HB also inhibited T cell proliferation in the presence of 5 mmol l-1 glucose (P < 0.05). The effect of glucose and 3-HB were not additive and the inhibition was not due to cell death. 32 mmol l-1 3-HB had less effect when present solely during antigen pulsing than during subsequent lymphocyte stimulation, and was effective even when added after 72 h of a six day culture. This suggests that ketosis affects T cell proliferation more than antigen processing and presentation. We conclude that human antigen-specific T cell proliferation is inhibited in vitro only by concentrations of 3-HB encountered in moderately severe diabetic ketoacidosis, and by glucose concentrations found in severe hyperosmolar non-ketotic coma. The impairment of T cell function under such extreme conditions could be implicated in the close association of diabetic ketoacidosis with deep fungal infections, particularly invasive mucormycosis.

Targets of therapy for NIDDM.

Non-insulin-dependent diabetes (NIDDM) is a common multimetabolic disorder with potential (and potentially severe) long-term complications affecting large and small blood vessels. Where microvascular complications (retinopathy, nephropathy and neuropathy) are concerned, the Diabetes Control and Complications Trial (DCCT), as well as much circumstantial evidence, suggests that hyperglycaemia is the main aetiological factor and this is likely to apply in NIDDM as well as IDDM. Unfortunately, achieving normoglycaemia in NIDDM is not easy and it is unclear whether insulin has advantages over oral hypoglycaemic agents or vice versa. Turning to macrovascular disease, it is unclear which of the many potentially atherogenic abnormalities-hypertension, hyperinsulinaemia, hyperlipidaemia, etc-are most important. A further problem is that macrovascular disease is already well developed in many patients when NIDDM is diagnosed and we do not know whether secondary prevention is effective. Nevertheless, it is sensible to try to reverse the atherogenic milieu and this should be done in the first instance by lifestyle modification rather than drugs. Even if we cannot manipulate the biochemistry to prevent small or large vessel complications, much can still be done; proactive foot care can prevent ulceration, timely laser treatment can prevent visual loss and thrombolytic therapy is relatively more effective in diabetic patients with myocardial infarction than in their non-diabetic peers. Finally, patients with NIDDM need intensive education and each needs an individualised treatment plan and goals.

Bovine and human NPH insulins as T cell immunogens.

The aim of this study was to assess the immunocompetence of T cells from patients with poorly controlled diabetes with respect to Candida albicans antigen and to compare the relative immunogenicity of human insulin, bovine insulin and protamine at the T-cell level during 6 months treatment with human or bovine NPH insulins. T-cell proliferation was measured in vitro in response to C. albicans, bovine and human insulin, bovine and human NPH and protamine in 17 patients with newly-diagnosed type 1 (insulin-dependent) and 12 with poorly-controlled type 2 (non-insulin-dependent diabetes) before and after 0.5, 1, 3 and 6 months of treatment with either bovine or human NPH insulin. The following results were found: Baseline responses to C. albicans (as a recall antigen) were similar for patients and controls despite marked hyperglycaemia in the patients. No patient had a response greater than mean + 2 S.D. of controls to human or bovine insulin before starting treatment, or had insulin autoantibodies. Treatment with human NPH insulin did not induce T-cell responses to human or bovine insulin, but 3/13 (23%) patients treated with bovine NPH responded to bovine and human insulin after 6 months, of whom one responded exclusively to human. In contrast, 6 (46%) bovine and 3 (19%) human NPH-treated patients responded to protamine. It was concluded that there is no evidence of T-cell immunosuppression in poorly-controlled diabetes or of T-cell autoimmunity to insulin in newly-diagnosed type 1 diabetes. Treatment with bovine NPH insulin immunizes T cells to insulin, but human NPH does not.(ABSTRACT TRUNCATED AT 250 WORDS)

Patient Education 2000: take-home messages from this congress.

A personal review is presented about the conclusions and highlights during the Congress on Patient Education 2000 (14 June 1994, Geneva, Switzerland). Attention is paid to differences between diseases concerning patient education. Further, a summary is presented of the discussion of quality of life, over-optimism, medical information supply, purpose of patient education, the need for discipline and the psychological problems due to wrong patient education.

Diseases the doctor (or autoanalyser) says you have got.

Much of modern medical practice involves treating patients with asymptomatic conditions or risk factors which I call 'diseases the doctors says you've got'. These generally asymptomatic conditions, which are usually discovered by screening, include hypertension, hyperlipidaemia, many cases of type 2 diabetes and the post-menopausal state. My argument is that many doctors do not have the interest or inclination to follow such patients. However, persuading them to take their tablets or modify their diets or lifestyles is arguably more difficult than in the 'proper' diseases on which physicians spend most of their training. I suggest that the only way of doing this is to educate and enthuse the patients and find a way to make them as interesting as the cases of the rare diseases we all find so fascinating.

Does diabetic control matter?

Whether achieving normoglycemia is beneficial or dangerous to the diabetic patient has been a matter of debate. The authors explore such issues as the prevention or reversal of complications with tight metabolic control, and the methods currently available to achieve normoglycemia.

Course of brittle diabetes: 12 year follow up.

OBJECTIVE: To determine the course of brittle diabetes. DESIGN: 12 year follow up of patients identified in 1977-9 as having brittle diabetes; retrospective review of the case notes. SETTING: Nottingham health district. SUBJECTS: 25 brittle diabetic patients were identified in 1979-9; 11 (five men) had three or more admissions with ketoacidosis between June 1977 and 1979 and 14 (eight men) had three or more attendances at the accident and emergency department with hypoglycaemia in 1978. Two controls from our diabetic register were matched to each patient for age, sex, and duration of diabetes. MAIN OUTCOME MEASURES: Frequency of ketoacidosis and severe hypoglycaemia in the 12 years after ascertainment; diabetic control and complications in 1988-90; retrospective attribution of the cause of brittleness. RESULTS: Patients with recurrent ketoacidosis had had a median (range) of 28 (8-67) episodes. One man died of a cerebral tumour but five of the surviving nine patients had not been admitted in the past two years, although diabetic control remained poor (median haemoglobin A1 concentration 14%). Seven patients had pure hypoglycaemic brittleness, and five had also had eight or more admissions with ketoacidosis (mixed brittleness). Two died of uraemia within a year after ascertainment and two others in hypoglycaemic coma seven and 12 years later. Brittle diabetes was in most cases related to a specific situation, usually unhappiness at home or school. CONCLUSIONS: Brittle diabetes is often episodic and almost always related to stressful life circumstances. Once the underlying cause is removed it tends to improve. Recurrent hypoglycaemic brittleness of psychological origin has a poor prognosis.