Pathology of grey seals Halichoerus grypus in southwest England including pups in early rehabilitation.

Few investigations have examined the pathology of grey seals Halichoerus grypus in southwest England, where it is the most abundant marine mammal. Here, primary pathological findings are presented from 107 post-mortem examinations of grey seals in southwest England between 2013 and 2020. Over three-quarters were pups in their first year of life; the origins of the carcasses reflected the known breeding season and breeding sites of grey seals in the region. Trauma was the most common primary pathological finding (n = 49), followed by infectious disease (n = 36). Traumatic findings included fisheries-related trauma (n = 15), other acute physical traumas (n = 15) and other chronic traumas (n = 19). Infectious disease findings included respiratory infections (n = 21) and gastrointestinal infections (n = 9). There was no difference in the primary pathological findings for seals found dead or that died or were euthanased on the day they were found compared to those dying in early rehabilitation, suggesting that it is appropriate to include findings from seals in early rehabilitation in studies of wild grey seal pathology. Seals that had not been frozen before post-mortem examination were nearly twice as likely to have a primary pathological finding of infectious disease or trauma than those that had been frozen, highlighting the need, wherever possible, to avoid freezing seals prior to post-mortem examination.

Immunologic enhancement of tumor xenografts by pepsin-degraded immunoglobulin.

The serums from guinea pigs previously injected with mouse Ehrlich ascites tumor cells were fractionated to obtain gamma(2)-immunoglobulin. This immunoglobulin was degraded with pepsin to obtain an F(ab')(2) fragment. Fresh tumor cells were incubated with immunoglobulin or the fragment and injected into normal guinea pigs. The growth of these cells as tumor xenografts was inhibited by the gamma(2)-immunoglobulin and enhanced by the F(ab')(2) fragment. Similar incubation of tumor cells with normal guinea pig gamma(2)-globulin or its derived F(ab')(2) fragment did not alter subsequent tumor growth.

Bone loss and bone turnover in diabetes.

There have been conflicting reports about the effect of diabetes on bone density. In 1978, we studied 109 patients, 46 with type I and 63 with type II diabetes; approximately 12 years later we restudied 35 of the 66 surviving patients. In the original study, radial bone density did not differ significantly between patients with either type of diabetes but was significantly lower than in nondiabetic control subjects. In eight osteopenic patients, bone formation rate and other histological indexes of osteoblast recruitment and function were markedly depressed compared with those in nondiabetic control subjects. In patients remeasured approximately 2.5 years (41 patients) and approximately 12.5 years (35 patients) after baseline, bone loss had continued at the expected rate in patients with type I diabetes, with maintenance of the same deficit, but was slower than expected in patients with type II diabetes, such that the initial deficit had been completely corrected. In six of the eight patients who had undergone bone biopsy, one with type I and five with type II diabetes, the mean bone mineral density z-score of the spine and femoral neck approximately 12 years later was > 0 and in one subject was significantly higher than normal at both sites. Based on these data and on previous studies, we propose that in patients with diabetes, low bone formation retards bone accumulation during growth, metabolic effects of poor glycemic control lead to increased bone resorption and bone loss in young adults, and low bone turnover retards age-related bone loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets.

AIMS: In long-term clinical trials in patients with type 1 diabetes spanning a wide range of HbA1c, addition of pramlintide to existing insulin regimens led to reductions in HbA1c that were accompanied by weight loss and no increase in overall severe hypoglycemia event rates. Given that weight gain and increased hypoglycemia risk contribute to the difficulty of attaining HbA1c targets (<7 %), the question arose whether pramlintide could benefit patients approaching, but not reaching glycemic targets with insulin alone. To address this question, we conducted a pooled analysis from 3 long-term clinical trials, including all patients with an entry HbA1c between 7.0 % and 8.5 %. METHODS: Within the subset of patients with an entry HbA1c between 7.0 % and 8.5 % (approximately 28 % of all patients enrolled in the 3 studies), 196 were treated with placebo + insulin (baseline HbA1c 7.9+/-0.4 %, body weight 76.0+/-14.3 kg [mean+/-SD]) and 281 with pramlintide+insulin (baseline HbA1c 7.9+/-0.4 %, body weight 75.4+/-13.1 kg). Endpoints included placebo-corrected changes from baseline to week 26 in HbA1c, body weight, and the event rate of severe hypoglycemia. RESULTS: Adjunctive therapy with pramlintide resulted in significant reductions in HbA1c and body weight from baseline to week 26 (0.3 % and 1.8 kg, placebo-corrected treatment differences, respectively, both p

Microalbuminuria in clinical practice.

Albumin excretion rate measured by new immunoassays and semiquantitative tests is advocated as a means for early detection of diabetic nephropathy. We determined albumin excretion rate in 276 patients. Albumin excretion rate was normal in 66%, within the microalbuminuric range in 27%, and within the macroproteinuric range in 7%. Significant predictors of albumin excretion rate included presence of hypertension and glycosylated hemoglobin level in type I diabetes mellitus, and years since diagnosis in type II diabetes mellitus. A semiquantitative test was deemed to be of limited diagnostic value. We conclude that testing for early diabetic nephropathy in routine clinical practice gives valuable information and that determination by a quantitative immunoassay based on a single 24-hour urine sample is preferable. The optimal frequency of screening and the levels that determine progressive renal disease have yet to be established.

Motor vehicles, hypoglycemia, and diabetic drivers.

Individuals with diabetes are increasingly persuing employment in fields previously restricted as a result of the development of chronic complications. Improved glycemic control resulting from use of sophisticated insulin delivery and monitoring systems has also led to the recognition of recurrent hypoglycemia as a potential major clinical and occupational hazard. No data concerning the occupational safety of individuals with insulin-treated diabetes mellitus (ITDM) are available. We review the literature on diabetic drivers in an effort to examine the impact of certification of ITDMs as commercial drivers. In the absence of significant worldwide experience with ITDMs as commercial drivers, the discussion is necessarily based on projected accident rates derived from data on frequency of hypoglycemia. These studies are universally flawed by variable definitions of hypoglycemia, ascertainment bias, and patient selection. They do, however, provide a worst-case/best-case scenario for discussion. It is imperative that any expansion of employment opportunities for ITDMs be followed carefully with prospective studies to assess the impact on public safety.

On diabetic osteopathy: a radiographic study of 21 patients.

Twenty-one diabetic patients with anesthetic peripheral neuropathy who never suffered a foot infection or local ulceration had roentgenograms of both feet to seek whether osseous changes characteristic of diabetic osteopathy were present. We found nine patients with vascular calcification (all 21 patients had palpable pedal pulses); four patients with ancient fractures; one patient with two phalangeal erosions; and two patients with equivocal osseous cystic lesions. No patient had findings typical of diabetic osteopathy. From this study, plus experience with other diabetic patients who had infected, ulcerated feet, we conclude that diabetic osteopathy represents healing or healed lesions of local osteomyelitis.

Effect of glyburide on metabolic control and insulin binding in insulin-dependent diabetes mellitus.

The extrapancreatic effects of the sulfonylurea drug glyburide in insulin-dependent diabetes mellitus were examined in a double-blind, prospective study involving 28 patients. Administration of glyburide in addition to the usual diet and insulin dose for 6 mo led to a minimal and transient decrease in hemoglobin A1c and total glycosylated hemoglobin. Insulin receptors of peripheral monocytes were initially normal in both number and affinity in this group of insulin-dependent diabetic patients, but, after 6 mo of glyburide therapy, binding to insulin receptors declined at the lower insulin concentration range without falling out of the normal range. No changes could be demonstrated in plasma triglycerides, cholesterol, or lipoprotein-cholesterol fractions. We conclude that the extrapancreatic effects of the sulfonylurea glyburide in insulin-deficient diabetic subjects are small. These effects may be mediated through a postinsulin receptor mechanism.

Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group.

OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.

Evaluation of the insulin jet injector as a potential source of infection.

In recent years jet injection of insulin has been widely used by patients with diabetes mellitus. Jet injectors may become contaminated by bacteria because of repeated use without cleaning; cleansing every 2 weeks is recommended. We investigated the occurrence of bacterial contamination by culturing jet injectors in everyday use by 19 patients with diabetes. Swabs from the interior chambers were cultured on blood agar plates. Only one of 20 cultures yielded bacterial growth, and the organism recovered was a presumed contaminant that could not be identified as any common pathogen. No study patient, nor any of more than 70 patients whom we instructed in jet injection, showed any clinical evidence of infection attributable to jet injector use. Jet injectors are unlikely to become colonized by bacteria or to cause infection in patients using them for insulin administration. The low rate of colonization may be due to the antibacterial preservatives added to commercial preparations of insulin. Additional data based on larger numbers of patients would be useful in further clarifying the risk of infection associated with jet injectors.

The diagnosis of diabetes: how to determine which patients to treat.

The diagnosis of diabetes depends on identifying a compatible clinical picture with confirmation by demonstrable abnormalities in blood glucose levels. In florid diabetes, classical symptoms of diabetes and high glucose in blood and urine make the diagnosis easy. For asymptomatic diabetes; if confirmed fasting blood glucose measures over 125 mg per 100 ml, the diagnosis is accepted. When the fasting blood glucose measures under 125 mg per 100 ml, I recommend an oral glucose tolerance test and apply suitable criteria for interpretation. The United States Public Health Service criteria represent a reasonable, moderate approach when one modifies the interpretation by cognizance of environmental factors in the patient and by identifying interfering influences as drugs, physical inactivity, fever or starvation. Indeed, one should postpone a glucose tolerance test until these interfering factors abate. Management of the patient with an abnormal glucose tolerance test includes sharing the prognostic dilemma with the patient regarding the likelihood of deterioration in glucose tolerance to florid diabetes. In this situation the term, abnormal glucose tolerance test, is preferred over chemical diabetes. The physician and the patient must develop some degree of comfort with a clinical state that often remains nebulous. Though the writings of authorities occasionally sound dogmatic, rigid, and conflicting, they reflect a viewpoint which opines that no clear answers are available; that the clinician and his patient must accept this posture; and that together they must develop the best therapeutic program for the individual in question.

Classification and pathogenesis of the diabetes syndrome: a historical perspective.

Once thought to be solely a disease of insulin deficiency, diabetes mellitus now is recognized as a disorder with multiple pathogenetic mechanisms. Newer terminology identifies those uncommon patients with true insulin deficiency as having insulin-dependent diabetes (IDDM), while the majority of patients with diabetes have some residual insulin secretion but may have a disorder of insulin receptor number or affinity. These patients have non-insulin dependent diabetes (NIDDM). Other patients may have gestational diabetes, impaired glucose tolerance, a potential for glucose intolerance, or a previous history of diabetes. A few patients will have diabetes secondary to a known cause, such as pancreatitis or Cushing's syndrome. Understanding this nosological approach to diabetes should enhance the clinician's decisions regarding therapy.