Donn J. D'Alessio

Minimum infective dose of animal viruses

The potential for spread of viral and other infectious diseases is a function of the dose required to initiate an infection with either clinical or sub‐clinical sequelae. This is especially important for environmental spread where dilution and natural die‐off are generally assumed to play prominent roles in the control of disease. The use of disinfectants and other methods of pathogen destruction are common in certain instances but often a few survivors will eventually find routes back to their hosts. The importance of the minimum infectious dose is, therefore, evident. This report will review studies on the doses of different viruses required to initiate infection in animals and man.

Risk of Diabetes in Siblings and Other Relatives of IDDM Subjects

The risk of insulin-dependent diabetes mellitus (IDDM) was examined in siblings of an unselected population (n = 194) of newly diagnosed diabetic individuals <30 yr old. From 1 July 1984 to 30 June 1987, diabetic subjects (proband) identified within a geographically defined area of southern Wisconsin were studied. IDDM occurred among siblings of probands in 13.5% of families and was associated with proband age at diagnosis. The highest risk was found for diabetic subjects <10 yr old at diagnosis (P = 0.04). We did not find an association between sibling IDDM and proband sex, HLA-DR3/4, duration of symptoms, or ketosis at diagnosis. In addition, the odds ratio (OR) for the association of IDDM in the proband with IDDM in parents and second- and third-degree family members was examined by case-control methodology. Diabetic subjects were matched to two types of control subjects (friends and general population) by age stratum and sex. The OR for IDDM was not increased significantly if parental IDDM or non-insulin-dependent diabetes mellitus (NIDDM) was reported. However, there were very few parents with diabetes among diabetic or control subjects. In 6.4% of diabetic subjects, one parent had IDDM, 54% of whom were fathers. In 4.3% of diabetic subjects, one parent had NIDDM, and 57.1% of these were fathers. The OR for IDDM was significantly increased if second- and/or third-degree relatives had IDDM (OR diabetic subjects vs. general population 2.33 [P < 0.05]) or NIDDM (OR diabetic subjects vs. friends 2.05 [P < 0.01]). We conclude that the increased risk of sibling IDDM for younger probands suggests variation in etiological factors by family.

Relationship of Prospective GHb to Glycated Serum Proteins in Incident Diabetic Retinopathy Implications of the glycation gap for mechanism of risk prediction

When estimating long-term glycemic control, A1C is considered the gold standard (1–3), but patients with seemingly equivalent A1C differ in their risk for microvascular complications (4,5). Recently, the “glycation gap,” defined as the difference between the measured A1C and that which would be predicted from another measure of glycemic control, fructosamine, has been proposed as a means of identifying sources of variance in the apparent risk (6). Because hemoglobin is an intracellular protein and fructosamine reflects extracellular proteins, the glycation gap could result from differences between the ambient glucose concentrations or rates of glycation in the intracellular and extracellular compartments or interindividual differences in the turnover/metabolism of underlying proteins (6). In this study, we sought to determine whether there are differences in the relationship of GHb to fructosamine in diabetic subjects who do or do not develop retinopathy. The present study was completed in collaboration with the Wisconsin Diabetes Registry Study (WDRS), an incident type 1 diabetes cohort followed for complications over 4–14 years’ duration. The WDRS has been described previously (7). New fructosamine testing was completed in 86 subjects who were identified among 290 with fundus photographs at 9 years. Patients with retinopathy ( n = 13), patients with missing photographs indicating no retinopathy ( n = 38) at 4 years or missing GHb or random glucose at 4 and/or 9 years ( n = 118), and patients having insufficient plasma for testing fructosamine at the 4-year exam ( n = 35) were excluded. Of the 86 eligible patients, 2 with fructosamine concentrations >1,000 μmol/l were omitted. …

Long-Term Hyperglycemia Is Related to Peripheral Nerve Changes at a Diabetes Duration of 4 years

OBJECTIVE To examine longitudinal hyperglycemia and peripheral nerve responses in a population-based incident cohort. RESEARCH DESIGN AND METHODS A sample from an incident cohort of young people was comprehensively followed from diagnosis of IDDM. Participants were invited to submit blood samples three times per year for central testing of GHb. During their 4th year of diabetes, nerve conduction studies were performed on the median sensory and motor, peroneal motor, and sural sensory nerves. Relationships between mean GHb and nerve latencies, velocities, and amplitudes were explored. RESULTS GHb was positively related to all nerve latencies and negatively related to all nerve velocities. The relationships between mean GHb and nerve conduction latencies and velocities differed by sex for the peroneal nerve latency (β = 0.17 male subjects, β = −0.01 female subjects; P < 0.001). Pubertal participants had lower velocities and longer latencies than prepubertal participants (β = 0.37; P = 0.05 peroneal latency), after adjustment for GHb, height, and extremity temperature. Sensory and motor nerve amplitudes were related to GHb, and these relationships did not differ by sex. CONCLUSIONS Our study indicates that sustained hyperglycemia is related to functional changes, at the minimum, in peripheral sensory and motor nerve conduction at a diabetes duration of 4 years. Our findings are consistent with a dying-back neuropathy, and there is some suggestion that chronic hyperglycemia may be more detrimental to nerves in male subjects than in female subjects.

Glycemic Control and Peripheral Nerve Conduction in Children and Young Adults After 5–6 Mo of IDDM

Objective A cohort of people (n = 86) was examined in the first few months after insulin-dependent diabetes mellitus (IDDM) diagnosis to evaluate the effect of hyperglycemia on nerve conduction velocities and latencies. Research Design and Methods Unselected cases with IDDM, who were 6–29 yr of age, were identified at diagnosis from a large, geographically defined area of southern Wisconsin. Peripheral nerve conduction was measured on a sample from this cohort. Results Peroneal nerve conduction velocity was significantly inversely related to glycosylated hemoglobin (P <0.05, age and height adjusted). All other nerve conduction velocities and latencies (median motor, median sensory, and sural) showed the same tendency, but the associations were not statistically significant. Twenty-four-hour urine C-peptide and duration of diabetes (3–11 mo) were not consistently related to nerve conduction parameters after controlling for age and height. Conclusions These findings suggest that as early as 5–6 mo after diabetes diagnosis, and at a time frequently characterized by partial remission of IDDM, hyperglycemia has a role in the acute slowing of nerve conduction velocity. Other factors such as residual endogenous insulin production do not appear to influence these early changes.

Glycemic Control in Early IDDM

OBJECTIVE A cohort (n = 277) was followed from diabetes diagnosis to evaluate longitudinal glycemic control, urinary C-peptide levels, and certain features of diabetes self-management. RESEARCH DESIGN AND METHODS Unselected cases with IDDM, who were < 30 yr of age, were identified at diagnosis from a 28-county area in Wisconsin. Subjects were asked to submit blood every 4 mo for GHb testing, to report aspects of diabetes self-management every 6 mo, and to collect a 24-h urine specimen 4 mo after diagnosis. RESULTS In the 1st yr of diabetes, the rate of increase (0.23%/mo) in GHb was significant for the cohort (P < 0.001) and for almost all age and sex subgroups. In the 2nd yr, there was no significant rate of increase for the cohort as a whole (P > 0.10). Adolescent males (10–19 yr of age) had a mean GHb level for year 2 higher than males of other age-groups and higher than female adolescents (P < 0.001). Adolescent males had a significant rate of increase in GHb for year 2 (P = 0.02), unlike all other age and sex subgroups. Adolescents had higher initial 24-h urine C-peptide levels than children < 10 yr of age (P < 0.01). During the 2nd yr of diabetes, the percentage of adolescent males reporting three or more insulin injections/day was lower than any other subgroup. CONCLUSIONS These data-suggest that glycemic control stabilizes during the 2nd yr of IDDM, except in adolescent males, and that this may be due partly to aspects of self-management.

The Relationship of Prospective Glycated Hemoglobin to Glycated Serum Proteins in Incident Diabetic Retinopathy: Implications of the Glycation Gap for Mechanism of Risk Prediction

When estimating long-term glycemic control, A1C is considered the gold standard (1–3), but patients with seemingly equivalent A1C differ in their risk for microvascular complications (4,5). Recently, the “glycation gap,” defined as the difference between the measured A1C and that which would be predicted from another measure of glycemic control, fructosamine, has been proposed as a means of identifying sources of variance in the apparent risk (6). Because hemoglobin is an intracellular protein and fructosamine reflects extracellular proteins, the glycation gap could result from differences between the ambient glucose concentrations or rates of glycation in the intracellular and extracellular compartments or interindividual differences in the turnover/metabolism of underlying proteins (6). In this study, we sought to determine whether there are differences in the relationship of GHb to fructosamine in diabetic subjects who do or do not develop retinopathy. The present study was completed in collaboration with the Wisconsin Diabetes Registry Study (WDRS), an incident type 1 diabetes cohort followed for complications over 4–14 years’ duration. The WDRS has been described previously (7). New fructosamine testing was completed in 86 subjects who were identified among 290 with fundus photographs at 9 years. Patients with retinopathy ( n = 13), patients with missing photographs indicating no retinopathy ( n = 38) at 4 years or missing GHb or random glucose at 4 and/or 9 years ( n = 118), and patients having insufficient plasma for testing fructosamine at the 4-year exam ( n = 35) were excluded. Of the 86 eligible patients, 2 with fructosamine concentrations >1,000 μmol/l were omitted. …

PROGRESS IN RHINOVIRUS CHEMOTHERAPY

Prospects for adequate control of acute viral upper respiratory disease Because of their potential usefullby use of vaccines are not encouraging. ness, however, we have sought compounds having activity against the principle etiologic agents of this disease. prophylaxis and even have therapeutic potential. been devoted to evaluating compounds having activity against rhinovirus infections since this group of viruses is a frequent cause of upper respiratory disease. Appropriate compounds may be useful for Particular attention has