John R. Claybaugh

Prospective randomized double blind placebo-controlled evaluation of azithromycin for treatment of cat-scratch disease

OBJECTIVE To determine the efficacy of azithromycin in the treatment of patients with typical cat-scratch disease. DESIGN Prospective, randomized, double blind, placebo-controlled clinical trial. SETTING Large military medical center and its referring clinics. PATIENTS Active duty military members and their dependents with laboratory-confirmed, clinically typical cat-scratch disease. INTERVENTION Study participants assigned by randomization to treatment with oral azithromycin or placebo for 5 days. OUTCOME MEASURES Lymph node volume was calculated using three dimensional ultrasonography at entry and at weekly intervals. The ultrasonographer was blinded to the treatment groups. Endpoint evaluations were predetermined as time in days to 80% resolution of the initial total lymph node volume. RESULTS Demographic and clinical data showed that the azithromycin and placebo treatment groups were comparable at entry although the placebo group tended to be older. Eighty percent decrease of initial lymph node volume was documented in 7 of 14 azithromycin-treated patients compared with 1 of 15 placebo-treated controls during the first 30 days of observation (P = 0.026). After 30 days there was no significant difference in rate or degree of resolution between the two groups. CONCLUSIONS Treatment of patients with typical cat-scratch disease with oral azithromycin for five days affords significant clinical benefit as measured by total decrease in lymph node volume within the first month of treatment.

Effects of Exercise on Atrial Natriuretic Factor: Release Mechanisms and Implications for Fluid Homeostasis

SummaryAtrial natriuretic factor is reported to be elevated during and immediately following exercise and is thought to play a role in fluid homeostasis and cardiovascular regulation. The predominant stimuli for atrial natriuretic factor release during exercise appear to be increases in atrial pressures or atrial distension, both of which are reported to increase with exercise. The intensity and perhaps duration of exercise also influence the magnitude of the atrial natriuretic factor response. It is not clear if the rise in plasma atrial natriuretic factor during exercise plays any role in altering renal function since high intensity exercise is typically associated with an antidiuresis. However, elevations in plasma atrial natriuretic factor may in part be responsible for the increase in urine flow reported when exercise is performed at low or moderate intensities. Atrial natriuretic factor also has vascular effects which may be important in buffering or moderating the blood pressure response to exercise.The atrial natriuretic factor response to exercise and basal levels of the hormone are greatly elevated in patients who suffer from a variety of cardiovascular and pulmonary disease conditions. These elevated plasma atrial natriuretic factor values are associated with increases in atrial pressure and appear to be related to the severity of disease. Although much controversy exists regarding the renal and vascular effects of atrial natriuretic factor, the measurement of this hormone, particularly during exercise, may be of clinical value by providing an additional tool to evaluate patients and determine the effectiveness of various treatment regimens.

Fluid and Electrolyte Homeostasis During and Following Exercise: Hormonal and Non-Hormonal Factors

Precise control of fluid and electrolyte homeostasis is essential for the survival of man. The performance of exercise results in a significant disturbance of water and electrolyte homeostasis. These alterations during exercise are due to the loss of fluids and electrolytes primarily in sweat and to voluntary dehydration associated with an inappropriate suppression of thirst. During the performance of exercise, as well as during recovery, compensatory measures occur to rectify these changes. A variety of hormones are important in the compensatory responses to correct water and electrolyte disturbances. The goal of this chapter is to describe the changes in water and electrolyte homeostasis resulting from exercise and the responses, regulation, and actions of the hormones important in correcting these imbalances.

Renal Functions of the Baikal Seal Pusa sibirica and Ringed Seal Pusa hispida

Various renal functions were studied in the Baikal seal (Pusa sibirica), which inhabits freshwater, and in the ringed seal (P. hispida), its marine counterpart. The urine osmolality progressively increased during dehydration (and fasting), reaching a plateau after 35 h. The average maximum urine osmolality was 2,374±60 and 2,052 ± 100 mOsm/kg in the Baikal and ringed seals, respectively. Urea and electrolytes (Na, K, and Cl) accounted for 82.6% and 9.3%, respectively, of total urine osmolality in the Baikal seal, and for 72.6% and 16.1%, respectively, in the ringed seal. Administration of 500 ml 0.15 M NaCl solution (stomach tubing) during fasting had little effect on the level of urine osmolality; however, the contribution of urea to total urine osmolality decreased (to 60%) while that of electrolytes increased (to 23%). Using the endogenous creatinine clearance as a measure of glomerular filtration rate, it was estimated that about 0.2% of filtered water and 0.05% of filtered Na are excreted during dehydration. There was a significant positive correlation between urine osmolality and urinary excretion of ADH during the 70-h dehydration period; however, there was no significant correlation between urinary Na and aldosterone excretions. Administration of 1 liter water (stomach tubing) resulted in a marked diuresis accompanied by a reduction in urine osmolality. In one seal, a hypotonic urine was obtained. This diuretic response was not accompanied by a parallel change in creatinine clearance, but by a moderate increase in the excretion of solutes. Administration of 500 ml 0.5M NaCl solution (i.v.) resulted in a rapid increase in the excretion of water and Na. The Na (and Cl) concentration of urine increased to 350-500 mEq/1, while that of urea decreased to 800 mM/1. The percentage of excretion of filtered Na also increased to about 2.0. There were no major differences in renal functions between the Baikal and ringed seals. Moreover, the present results are qualitatively similar to those obtained from the harbor seal by previous investigators. It is concluded that the Baikal seal, isolated from seawater and living in freshwater for .5 million years, remarkably retained the renal function they possessed at the time of isolation.

Inappropriate antidiuretic hormone in children with viral meningitis

Urinary excretion rates of antidiuretic hormone were determined by radioimmunoassay in children with bacterial (6) and viral (11) meningitis, and in children with other febrile illnesses (7). These values were compared to normal data obtained from 50 healthy, normally hydrated children ranging in age from 1 week to 9 years. Plasma sodium concentrations were measured in the sick children; urine osmolality and creatinine concentrations were measured in all children. Upon admission, all children with bacterial meningitis and 64% of those with viral meningitis had urinary antidiuretic hormone excretion rates greater than 2 S.D. above values obtained from age-matched controls. Fifty-seven percent of children with other febrile illnesses had similarly elevated antidiuretic hormone values; however, only in the bacterial and viral meningitis groups were antidiuretic hormone excretion rates inappropriate because they occurred when serum sodium concentrations were found to be normal or low normal (i.e., 136 +/- 2 mEq/L and 137 +/- 1 mEq/L, respectively). The average serum sodium in the group with other febrile illnesses was higher (146 +/- 5 mEq/L; p less than 0.05) and could represent an appropriate stimulus for antidiuretic hormone release. In spite of high levels of antidiuretic hormone, most viral meningitis patients did not concentrate their urine, probably because all except 2 were younger than 2 months of age. We conclude that viral meningitis, like bacterial meningitis, frequently is associated with inappropriate antidiuretic hormone secretion; however, most children with viral meningitis may be protected from developing hyponatremia because of their inability to concentrate their urine.

Metabolism of Neurohypophysial Hormonesa

Over the past decade several new routes of neurohypophysial hormone metabolism have been identified. These include nonhepatic splanchnic clearance and renal clearance in addition to filtration that appears to be receptor mediated. The intraluminal degradation of VP in the proximal tubule, and distal tubular secretion, at least in one species, has been identified. The brain has been identified as a site for VP and OT metabolism, and the amniotic sac may be a major site for VP clearance in the guinea pig fetus. There have been generalized findings regarding VP and OT metabolism. First, VP metabolism in the whole body and in the amniotic sac appears to increase with increasing concentrations of hormone; this does not appear to be the case with OT. Also, evidence has been presented that suggests a potential for the formation of biologically active metabolites. There have been several associations of pathophysiological states with altered VP or OT metabolism, sometimes with plasma levels remaining unchanged. Lastly, caution is emphasized when measuring these hormones by RIA, and differences in specificities of antisera toward hormone metabolites must be considered.

Fluid and Electrolyte Balance and Hormonal Response to the Hypoxic Environment

The effect of the hypoxic environment on body fluid regulating systems is influenced by both the direct and indirect effects of hypoxia. Regarding the direct physiological effects, for instance, hypoxemia can directly stimulate the carotid body chemoreceptors with subsequent stimulation of antidiuretic hormone (ADH) release (79), and by mechanisms still unclear, hypoxia reduces the secretion of aldosterone (15,16,39,57,62,81,84,85). In the natural setting, coincident environmental factors such as cold and exercise, discussed elsewhere in this text, and possibly hypobaria, may influence the responses to hypoxia. Additionally, the indirect effects of short-term hypoxia on respiration and cardiovascular reflexes also effect water and electrolyte regulating hormones, and the longer-term effects of decreased appetite impact on electrolyte balances which cause compensatory responses of these hormone systems. Finally, there are the poorly understood indirect consequences of “stress” on various hormonal systems, particularly those of ADH and glucocorticoids, that cannot be excluded from the mechanisms of hypoxia-induced effects on these systems.

Exercise and decompression sickness: a matter of intensity and timing

The paper in this issue of The Journal of Physiology entitled ‘Aerobic exercise before diving reduces venous gas bubble formation in humans’, by Dujic et al. (2004) extends their findings in animals (Wisloff & Brubakk, 2001) to human subjects, and confirms that exercise performed prior to exposure to modest pressures, equivalent to 18 m of sea water depth, can ameliorate venous bubble formation upon decompression. Since bubble formation is associated with decompression sickness (DCS), this article impacts broadly on the field of diving physiology. If confirmed, it potentially affects a large population. First, in addition to pilots and diving professionals who are impacted by profession, there are an estimated 854 000 new certifications for SCUBA divers issued worldwide each year (Professional Association of Diving Instructors, web page). Second, the article provides clarification and changes the commonly accepted view of the effects of exercise on decompression-induced bubble formation. Third, the theoretical explanation for the response whereby a reduction in bubble nuclei may result from the heavy exercise, thereby accounting for the reduced bubble formation upon decompression, represents a plausible and potentially important avenue for more research. The previously held general concepts of exercise and bubble formation resulting from decompression involved the understanding that exercise at depth would increase blood flow and consequently nitrogen uptake. With more nitrogen in the body the time required to unload the additional nitrogen would then be greater. Indeed, studies have shown that if exercise occurred during one dive, and a similar dive was conducted with no exercise, more nitrogen was eliminated while resting at sea level following the dive when exercise was performed (Dick et al. 1984). This is in line with the finding that more bubbles were detected when subjects exercised during or immediately following completion of decompression, and the intravascular bubbles impede the elimination of inert gases. Summarization of prior reports generally led to the conclusion that exercise performed either prior to or during exposure to pressure would increase the risk of DCS (Vann & Thalmann, 1993). Such impressions suggested that otherwise unexplainable cases of DCS might have been due to strenuous exercise performed prior to an incident. This was the case even in a highly controlled US Navy dive (Hughes & Eckenhoff, 1986). On the other hand, more recent reports indicate that if exercise is performed at a modest intensity during decompression, Doppler-detected gas emboli are reduced (Jankowski et al. 1997). The beneficial effects of exercise during decompression are similarly thought to be a consequence of increased blood flow but in this case resulting in increased gas elimination. So the timing of exercise performed at depth and the intensity of the exercise become critical factors in whether or not the effects are harmful or beneficial. The controversy over the impact of exercise on the outcome of decompression is not new. In Haldanes time, both Royal and US Navies routinely imposed exercise on their divers during decompression, believing that the elevated circulatory state would accelerate the elimination of nitrogen. The practice ended when many experiments demonstrated that various exercise regimens before, during and following decompression either from depth or to altitude increased the incidence of DCS. A long period followed where exercise was prohibited during and following decompression. Later, sporadic reports appeared showing beneficial effects of exercise during decompression. So far no definitive conclusion can be drawn regarding the effect of exercise on DCS before, during or after decompression. However, it is apparent that a beneficial effect of exercise performed during decompression is dependent on type and intensity of exercise. The present study stresses the importance of the timing of the pre-dive exercise. In other studies by this group that were conducted in rats, a beneficial effect of pre-dive exercise did not occur if the exercise was done too close to, i.e. within 10 h, or too much in advance of, e.g. 48 h, the dive time (Wisloff et al. 2004). If the mechanism of exercise-induced suppression of bubble formation is related to nitric oxide (NO) production, then the timing of NO administration in relation to its prophylactic effects on bubble formation should be similar. In the same study, Wisloff et al. (2004) reported that administration of an NO-releasing agent reduced bubble formation even when given 30 min prior to hyperbaric exposure. Thus, the timing of the responses to exercise and NO administration were quite different. It is not clear why exercise performed only within a window of time near 24 h prior to the dive can produce the effect if the mechanism is linked to an NO-dependent reduction in bubble nuclei. Whether or not the effect of exercise on bubble formation operates through the formation of NO as the authors hypothesize, or through yet another mechanism, the present study significantly advances our understanding of the effects of pre-dive exercise, and provides another means of ameliorating the formation of bubbles upon decompression in humans. The contribution of this effect will need further standardization and study before pre-dive exercise can be widely adopted as a predictable safeguard against DCS. For instance, better knowledge is needed of how much exercise is necessary to provide a certain degree of protection, and how this can measured. Clarification of the mechanism may be helpful in this regard.

Hormonal and Renal Responses to Hyperbaria

With the advent of a new diving technique “the saturation dive” about three decades ago, human divers are now able to engage in a multi-day dive to a considerable depth. In a dry simulation (chamber) dive carried out at Duke University in 1981, several divers exposed themselves to a depth of 686 m (nearly 70 atmospheres absolute or ATA) for 24 h and then safely returned to sea level. Apparently, human divers seem to be able to cope with such high pressures and can maintain normal activities albeit on a somewhat limited basis.

Prospective Randomized Double-Blind Placebo-Controlled Evaluation of Azithromycin for Treatment of Cat Scratch Disease |[dagger]| 810

OBJECTIVE: To determine the efficacy of azithromycin in the treatment of patients with typical cat scratch disease (CSD).