Increased tissue kallikrein levels in type 2 diabetes.

AIMS/HYPOTHESIS: We measured components of the kallikrein- kinin system in human type 2 diabetes mellitus and the effects of statin therapy on the circulating kallikrein-kinin system. METHODS: Circulating levels of bradykinin and kallidin peptides, and high and low molecular weight kininogens, as well as plasma and tissue kallikrein, and kallistatin were measured in non-diabetic and diabetic patients before coronary artery bypass graft surgery. Tissue kallikrein levels in atrial tissue were examined by immunohistochemistry and atrial tissue kallikrein mRNA quantified. RESULTS: Plasma levels of tissue kallikrein were approximately 62% higher in diabetic than in non-diabetic patients (p=0.001), whereas no differences were seen in circulating levels of bradykinin and kallidin peptides, and high and low molecular weight kininogens, or in plasma kallikrein or kallistatin. Immunohistochemistry revealed a twofold increase in tissue kallikrein levels in atrial myocytes (p= 0.015), while tissue kallikrein mRNA levels were increased eightfold in atrial tissue of diabetic patients (p=0.014). Statin therapy did not change any variables of the circulating kallikrein-kinin system. Neither aspirin, calcium antagonists, beta blockers or long-acting nitrate therapies influenced any kallikrein-kinin system variable. CONCLUSIONS/INTERPRETATION: Tissue kallikrein levels are increased in type 2 diabetes, whereas statin therapy does not modify the circulating kallikrein-kinin system. Cardiac tissue kallikrein may play a greater cardioprotective role in type 2 diabetic than in non-diabetic patients and contribute to the benefits of ACE inhibitor therapy in type 2 diabetic patients. However, our findings do not support a role for the kallikrein-kinin system in mediating the effects of statin therapy on endothelial function.

Restoration of normal reflex responses to orthostatic stress during felodipine therapy in congestive heart failure.

The mechanisms underlying the abnormal responses to orthostatic stress in congestive heart failure are ill defined and little is known about the effects of specific therapy. In the present study intravascular pressures and plasma noradrenaline levels were measured in nine patients with heart failure subjected to 45 degrees and 90 degrees upright tilt. Studies were repeated during 4 weeks of vasodilator therapy with felodipine and again after felodipine withdrawal. Before the introduction of vasodilator therapy, tilt did not activate orthostatic reflexes despite significant reductions in left ventricular filling pressure and cardiac output. Thus, plasma noradrenaline, heart rate and systemic vascular resistance were unaffected and blood pressure fell. Felodipine resulted in a rapid and sustained improvement in left ventricular function but restoration of orthostatic reflexes was delayed and could be detected only after 48 h therapy. At this time, and during the subsequent 4 weeks, tilt-induced reductions in ventricular filling and cardiac output produced a normal rise in plasma noradrenaline and heart rate. A postural drop in blood pressure, however, was not averted because the direct action of felodipine on vascular smooth muscle prevented adrenergically-mediated increments in systemic vascular resistance. Felodipine withdrawal led to a prompt deterioration in left ventricular function. Orthostatic reflexes, however, were still intact 48 h later when tilt elicited a completely normal pattern of responses. These observations confirm that the abnormal responses to orthostatic stress in congestive heart failure are due principally to impairment of autonomic control mechanisms and are not related to the absence of venous pooling. Importantly the autonomic dysfunction is reversible with felodipine therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Meningitis due to Haemophilus influenzae type b resistant to both ampicillin and chloramphenicol.

A strain of Haemophilus influenzae type b with considerable resistant to both ampicillin and chloramphenicol was recovered from a South Dakota child with meningitis. There was an initial lack of response to conventional doses but the child improved after a brief period of 200 mg/kg/day of chloramphenicol. The organism showed in vitro resistance to ampicillin, carbenicillin, tetracycline, and chloramphenicol (for each antibiotic the minimal inhibitory concentration (MIC) was 8 micrograms/ml or greater with a bacterial challenge of 10(5) colony-forming units (CFU)/ml), but it was sensitive to both streptomycin and rifampin (MIC 1.6 micrograms/ml, respectively). Isobolograms constructed from the results of testing various concentrations of ampicillin and chloramphenicol showed additive effects with high bacterial inocula (10(5) or 10(7) CFU/ml), but antagonism with low inocula (10(2) or 10(4) CFU/ml).

Retropharyngeal cellulitis: a manifestation of Kawasaki disease in children.

Kawasaki disease (KD) or mucocutaneous lymph node syndrome is an acute febrile illness with prominent vasculitic features. The cause is unknown and the disease is seen most commonly in young children. After its initial description in Japan, the disease was thought to be rare in the United States, but recognition has dramatically increased over the past decade. Common symptoms of the disease for which the otolaryngologist may be initially consulted include inflammation of the lips and oral cavity and acute cervical lymphadenopathy. We present a case of Kawasaki disease initially complicated by retropharyngeal soft tissue swelling. Similar reports are rare in the pediatric literature; however, no such reports appear in the otolaryngology literature.

Meningococcal conjunctivitis in neonates.

Three neonates were admitted with purulent conjunctivitis, and an initial diagnosis of gonococcal ophthalmia was made because gram-negative diplococci were seen on gram stains of conjunctival exudates. Meningococci were grown from eye exudates of all three infants and from the blood of one. Since Neisseria species other than gonococci can sometimes cause neonatal ophthalmia, an etiologic diagnosis should not be made until microbiologic identification is complete. Before the results of definitive bacteriologic studies are known, care should be taken in discussing the cause of the infection with family members and in planning their medical management. Since systemic infections may occur in some infants with ophthalmia due to Neisseria species, blood and spinal fluid in addition to eye exudate cultures may be indicated, and patients should be managed with parenteral antibiotics.

Immunological responsiveness to Escherichia coli during pregnancy.

To determine whether immunological responsiveness to a bacterial antigen is altered during pregnancy and lactation, Swiss mice (gestation, 19 to 21 days) were studied during early, middle, and late pregnancy and in the early postpartum period. Pregnant and nursing mice, each along with a virgin female littermate control, were injected with 2 x 10(6) heat-killed Escherichia coli and sacrificed 4 days later for the enumeration of splenic anti-E. coli plaque-forming cells (PFC). For 72 4- to 10-day pregnant and control mice ranked together, total PFC per spleen ranged from 0 to 312,650, with 61% of the counts from pregnant animals ranking above the median of 12,700. The mean number of PFC for the pregnant animals was greater than for sister controls in 19 of 23 litters studied (P = 0.001). Responsiveness was also increased for 72 mice tested in later pregnancy. Counts of PFC of 72% of mice 11 to 18 days pregnant were above the median when ranked with those of their controls (P < 0.001). In 18 of 21 litters studied, pregnant animals responded better than littermate controls (P = 0.001). Responses of mice at term (19 to 21 days) were depressed when compared with those of controls, but nursing animals 6 to 9 postpartum responded like virgin animals. Previous studies suggested that low concentrations of estradiol stimulate the mitosis of PFC. To determine if progesterone also increases numbers of PFC, concentrations in a range physiological for pregnancy were added to cultures of spleen cells from male mice injected with E. coli 3 days before. After 24 h of incubation, numbers of PFC in these suspensions were compared to those of the same suspensions incubated without hormone. In 19 of 25 and 48 of 68 suspensions tested at concentrations of 500 pg and 50 ng of progesterone per ml, the numbers of PFC were increased over those of the same suspensions without hormone (P < 0.01). Geometric mean number of PFC for progesterone-treated cells was 45% greater than that for the controls. Findings suggest that female sex hormones, important for the normal growth and differentiation of fetal cells, may also enhance division and/or maturation of immunocompetent cells in the mother.

Effect of estradiol on immune competence: in vivo and in vitro studies.

The administration of a single dose of 2.5 mug of microcrystalline estradiol-17 beta from 1 day before and up until 3.5 days after the administration of 3 X 10(5) heat-killed Escherichia coli significantly increased numbers of splenic anti-E. coli antibody-producing cells in male mice sacrificed 4 days after receiving anitgen. Administration early in the proliferative phase of antibody production, i.e., 1 day before or 1 day after the antigen, appeared to increase numbers of antibody-producing cells more than when it was administered at a later time. When given 2 days before the antigen or 2 h before sacrifice no effect was observed. Spleen cells harvested from male animals injected 3 days before with 5 X 10(6) heat-killed E. coli were incubated for 24 h in vitro with estradiol in concentrations ranging from 5 pg to 20 ng/ml. With concentrations of 500 pg to 5,000 pg/ml, significant increases in antibody-producing cells occurred, whereas at concentrations of 20 ng/ml some decrease was observed. The increase in antibody-producing cells was blocked by a mitotic inhibitor. Significant changes in numbers of antibody-producing cells were not observed after a 2-h incubation period. Uptake of titrated thymidine was increased in thymic and spleen cells incubated for 24 h with 500 pg of estradiol per ml; a concentration of 20 ng/ml slightly (but insignificantly) decreased uptake. Findings suggest that estradiol, in concentrations that approximate physiological serum levels in females, enhances mitosis of immunocompetent cells. This phenomenon may have bearing on the better immunological responsiveness of females than males.

Effects of vasodilator treatment with felodipine on haemodynamic responses to treadmill exercise in congestive heart failure.

Treatment with vasodilators in heart failure has not always produced a useful improvement in the haemodynamic responses to exercise, and in many cases early drug tolerance has further limited the potential of this type of treatment. In a study to evaluate the efficacy of felodipine, a new calcium antagonist with selective vasodilator properties, in the management of congestive heart failure 10 patients with congestive heart failure underwent treadmill exercise testing before and during oral treatment with felodipine 30 mg daily. At every level of exercise felodipine lowered the pulmonary capillary wedge pressure, whereas cardiac index and stroke index increased considerably. The haemodynamic improvement was associated with an increase in the duration of exercise to exhaustion. Importantly, these beneficial effects were sustained throughout four weeks of treatment without evidence of drug tolerance. These observations suggest a useful role for felodipine in the long term management of congestive heart failure.

Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal human fetus: a prospective Doppler echocardiographic study.

We used Doppler echocardiography to quantitate the changes in intracardiac blood flow velocities and right and left ventricular stroke volumes in 80 normal human fetuses from 19 to 40 weeks gestation. Blood flow velocity spectra across the aortic, pulmonary, tricuspid, and mitral valves were digitized to obtain peak velocities (m/sec) and flow velocity integrals. Aortic and pulmonary diameters were measured at valve level from two-dimensional echocardiographic images and cross-sectional area was calculated assuming a circular orifice. Ventricular stroke volume was calculated as the product of the cross-sectional area of a great vessel and the flow velocity integral through that vessel. The pulmonary arterial and aortic diameters increased linearly with gestational age (r = .82, r = .84), and pulmonary arterial diameter consistently exceeded aortic diameter. There was a positive relationship between stroke volume and gestational age: stroke volume increased exponentially from 0.7 ml at 20 weeks to 7.6 ml at 40 weeks for the right ventricle (r = .87) and from 0.7 ml at 20 weeks to 5.2 ml at 40 weeks for the left ventricle (r = .91). Similar results were obtained for right and left ventricular and combined cardiac outputs. In 44% of the fetuses it was possible to quantitate both right and left ventricular stroke volumes. There was a close correlation between right and left ventricular stroke volumes in these fetuses (r = .96) and right ventricular stroke volume exceeded left ventricular stroke volume by 28%.(ABSTRACT TRUNCATED AT 250 WORDS)