Plasma exchange-A useful adjunct therapy to red cell exchange in patients with sickle cell disease and multiorgan dysfunction.

BACKGROUND: Urgent red cell exchange (RBCx) is indicated for many complications of sickle cell disease (SCD), including acute chest syndrome, stroke, and hepatic/splenic sequestration. Many who receive RBCx remain hospitalized and develop further complications, including multiple organ dysfunction syndrome (MODS), a leading cause of death in intensive care units. Therapeutic plasma exchange (TPE) has been advocated as an effective treatment of MODS, but its role in SCD compared with RBCx alone is not well studied. METHODS: We identified all ICU encounters from 2013 to 2019 involving RBCx procedures for MODS or SCD crisis that progressed to MODS, a total of 12 encounters. Data regarding hospital length of stay (LOS), survival, number of TPE procedures following RBCx, and procedure characteristics were collected. Surrogate laboratory markers of end-organ damage and disease severity scores were recorded at the time of admission, post-RBCx, post-TPE, and at discharge. RESULTS: Eight encounters involved RBCx followed by TPE (TPE group) while four involved RBCx alone (RBCx group). The TPE group had a higher SOFA score at ICU admission (9.5 vs. 7.0), greater predicted mortality, and a statistical trend toward higher disease severity scores following RBCx relative to the RBCx group (p = 0.10). The TPE group showed a significantly greater decrease in SOFA score between RBCx and discharge (p = 0.04). No significant difference in mortality or hospital LOS was observed between the groups. CONCLUSION: The findings suggest TPE may be considered as an adjunct treatment for patients with acute complications of SCD that progress to MODS, especially in cases where there is no significant improvement following RBCx.

Prospective evaluation of a change in dietary therapy in dogs with steroid-resistant protein-losing enteropathy.

OBJECTIVE: To describe the clinical effect of dietary alteration as a sole change to therapy in dogs with steroid-resistant protein-losing enteropathy. MATERIALS AND METHODS: Prospective study. Eligible enrolled dogs received dietary alteration as sole change to their therapeutic plan. Canine Chronic Enteropathy Clinical Activity Index and serum albumin were monitored for the 3-month study period. Long-term follow-up data were also available for some of the study participants. RESULTS: Fifteen dogs were eligible for enrollment over the study period. Twelve were enrolled, 10 remained in the study at 30 days, nine completed the 3-month study period. Following dietary alteration, eight of 10 dogs achieved complete remission, one dog achieved partial remission and one dog had no response. Seven of eight dogs achieving complete remission have remained in remission up to 4 years following study. In dogs with complete remission, median Canine Chronic Enteropathy Clinical Activity Index score was 11.5 and 4, and median serum albumin concentration was 15 g/L and 26 g/L at 0 and 14-28 days, respectively. CLINICAL SIGNIFICANCE: Dogs with protein-losing enteropathy with previous lack of response to a combination of dietary therapies, glucocorticoids and immunosuppressive medications can achieve remission following a dietary change. Improvement is likely to be seen within 14 to 30 days. A change in dietary approach may be an alternative to further immunosuppression or anti-inflammatory strategies in some dogs with difficult to treat protein-losing enteropathy.

Histopathologic Characteristics of Intestinal Biopsy Samples from Dogs With Chronic Inflammatory Enteropathy With and Without Hypoalbuminemia.

BACKGROUND: Previous studies have identified hypoalbuminemia as a risk factor for negative outcome in dogs with chronic enteropathy (CE), but it has not been determined whether histopathology differs between CE dogs with and without hypoalbuminemia. OBJECTIVE: To compare histopathologic findings in dogs with biopsy-diagnosed inflammatory CE with and without hypoalbuminemia. ANIMALS: 83 dogs that had intestinal biopsy performed between January 2010-July 2015. Dogs had signs compatible with CE of at least 3-weeks' duration and no evidence of clinically relevant extra-gastrointestinal (GI) disease or potential non-GI causes of hypoalbuminemia. Dogs had primary diagnosis of inflammatory enteritis based on histopathology. METHODS: Dogs were grouped into CE with normoalbuminemia (CEN; serum albumin concentration ≥3.0 g/dL, N = 46) or chronic enteropathy with hypoalbuminemia (CEH; serum albumin concentration <3.0 g/dL, N = 37). A pathologist (SLP) blinded to the groups reviewed biopsy samples and applied the World Small Animal Veterinary Association scoring system to all samples. RESULTS: Intestinal biopsy samples from dogs in the CEH group were significantly more likely to display villous stunting, epithelial injury, crypt distension, and lacteal dilatation, and were more likely to have intraepithelial lymphocytes and lamina propria neutrophils than biopsy samples from dogs in the CEN group. Additionally, higher scores for each of the above listed histopathologic criteria were associated with a lower serum albumin concentration. CONCLUSIONS AND CLINICAL IMPORTANCE: Histopathologic features of chronic inflammatory enteropathy differ between dogs that are hypo- versus normoalbuminemic. Additional work is needed to elucidate the clinical relevance of these differences.

Oxidative stress and neutrophil function in cats with chronic renal failure.

BACKGROUND: Oxidative stress is an important component in the progression of chronic renal failure (CRF) and neutrophil function may be impaired by oxidative stress. HYPOTHESIS: Cats with CRF have increased oxidative stress and decreased neutrophil function compared with control cats. ANIMALS: Twenty cats with previously diagnosed renal failure were compared with 10 age-matched control cats. METHODS: A biochemical profile, CBC, urinalysis, antioxidant capacity, superoxide dismutase (SOD) enzyme activity, reduced to oxidized glutathione ratio (GSH : GSSG), and neutrophil phagocytosis and oxidative burst were measured. Statistical comparisons (2-tailed t-test) were reported as mean +/- standard deviation. RESULTS: The CRF cats had significantly higher serum blood urea nitrogen, creatinine, and phosphorus concentrations than control cats, and significantly lower PCV and urine specific gravity than control cats. The GSH : GSSG ratio was significantly higher in the CRF group (177.6 +/- 197, 61.7 +/- 33; P < .02) whereas the antioxidant capacity was significantly less in the CRF group (0.56 +/- 0.21, 0.81 +/- 0.13 Trolox units; P < .005). SOD activity was the same in control and CRF cats. Neutrophil oxidative burst after Escherichia coli phagocytosis, measured as an increase in mean fluorescence intensity, was significantly higher in CRF cats than controls (732 +/- 253, 524 +/- 54; P < .05). CONCLUSIONS: The higher GSH : GSSG ratio and lower antioxidant capacity in CRF cats is consistent with activation of antioxidant defense mechanisms. It remains to be determined if supplementation with antioxidants such as SOD beyond the level of control cats would be of benefit in cats with CRF.

Laparoscopic diagnosis of pancreatic disease in dogs and cats.

BACKGROUND: Histopathology is the gold standard for the diagnosis of pancreatic disease. Laparoscopy offers a minimally invasive route by which to obtain pancreatic biopsies. HYPOTHESIS: Laparoscopy is a safe and effective technique for evaluating the pancreas in small animal patients. ANIMALS: Medical records of 18 dogs and 13 cats examined between 1999 and 2007 that underwent laparoscopy during which observation or biopsy of the pancreas was recorded. METHODS: The database for the Laparoscopy Laboratory at Colorado State University was searched for records that contained "pancreatitis,""pancreas," or "pancreatic." The presenting complaints, imaging studies, and histopathologic findings of animals were recorded. All hospital admissions were searched for animals with the same presenting complaints and of those it was determined which animals had exploratory surgery and their pancreas biopsied. RESULTS: Thirteen cats and 18 dogs underwent laparoscopy for presumptive pancreatic disease or had the appearance of the pancreas described, pancreatic biopsies obtained, or both. In 14 animals a laparoscopic biopsy of the pancreas resulted in a histopathologic diagnosis when the sonographic findings or the gross assessment failed to do so. In 35% of the animals a biopsy of the pancreas was not obtained despite findings consistent with pancreatic disease. Those animals examined for vomiting or anorexia were significantly more likely to have a biopsy of the pancreas obtained through laparoscopy versus surgery (P < .0001). CONCLUSIONS AND CLINICAL IMPORTANCE: Laparoscopy and pancreatic biopsy is useful for evaluation of pancreatic disease.

Leucocytoclastic vasculitis associated with Staphylococcus intermedius in the pastern of a horse.

A pregnant quarterhorse mare became acutely lame as a result of severe swelling of its right hind leg, thought to have been caused by a fracture or a muscle tear. Diagnostic procedures ruled out a traumatic musculoskeletal cause and a physical examination revealed chronic pastern dermatitis ('scratches'/'grease heel'). Histopathological evaluation of biopsy samples from the right hind leg was consistent with a leucocytoclastic vasculitis, and culture yielded Staphylococcus intermedius. The treatment and infectious causes of pastern dermatitis are discussed.

S-adenosylmethionine (SAMe) in a feline acetaminophen model of oxidative injury.

S-adenosylmethionine (SAMe) is reported to have hepatoprotective and antioxidant functions. Acetaminophen (paracetamol) was used to induce oxidative damage in cats, and to then determine the effect of SAMe treatment on erythrocyte morphology, PCV, liver histopathology, thiobarbituate reacting substances (TBARS), reduced glutathione (GSH), and oxidised glutathione (GSSG). Cats receiving acetaminophen had a significant increase in methemoglobin and Heinz body production. A significant effect for the interaction of time and treatment was found for Heinz body production and changes in PCV. No significant changes were found in blood or hepatic TBARS. Blood GSH increased significantly in all cats, while the blood GSH:GSSG ratio tended to increase the most in cats given acetaminophen only. The hepatic GSH:GSSG ratio tended to increase in cats given SAMe and decrease in cats given acetaminophen, but this effect was not significant. SAMe protected erythrocytes from oxidative damage by limiting Heinz body formation and erythrocyte destruction and maybe useful in treating acetaminophen toxicity.

Influence of synaptic identity on single-Ia-afferent connectivity and EPSP amplitude in the adult cat: homonymous versus heteronymous connections.

1. This study makes use of the pattern of synaptic connections between motoneurons and Ia afferents of triceps surae muscles in the cat to test the relative importance of synaptic identity, neuronal size, and neuronal topography as determinants of Ia-afferent connectivity and excitatory postsynaptic potential (EPSP) amplitude. 2. The synaptic actions of single-Ia medial gastrocnemius (MG) afferents were measured by intracellular recording in MG and lateral gastrocnemius (LG) motoneurons. The spike-triggered averaging technique was used to measure EPSPs generated by homonymous or heteronymous Ia afferents and motoneurons, i.e., neurons supplying the same or different muscles, respectively. In agreement with earlier studies, the pooled sample showed that the number of functional connections and the size of EPSPs were both significantly greater for homonymous than for heteronymous neurons. 3. Afferent conduction velocity, motoneuron conduction velocity, rheobase current, and position of the motoneuron relative to the spinal cord afferent entry were all correlated with EPSP amplitude, but the amplitude difference between homonymous and heteronymous connections remained significant after the statistical removal analysis of covariance (ANCOVA) of the contribution of these variables. Stepwise multiple-regression analysis showed that synaptic identity explained the greatest fraction of the variance in EPSP amplitude (9%), with significant but smaller fractions accounted for by rheobase current or motoneuron conduction velocity. 4. In a separate experiment, the monosynaptic affects from both homonymous and heteronymous single-Ia afferents were examined in each of 88 MG or LG motoneurons. The single-Ia afferents used in this portion of the study were sampled from both MG and LG muscles and selected for similar conduction velocities and spinal cord entry points.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of la EPSP amplitude: the effects of chronic synaptic inactivity.

In this study, we test the hypothesis that monosynaptic connections between la afferents and spinal motoneurons are strengthened by chronic disuse. Impulse activity along the medial gastrocnemius (MG) nerve was blocked for 2 weeks using TTX delivered by an osmotic minipump to a Silastic cuff placed around the nerve. The duration and specificity of this block were confirmed by chronic EMG recordings from several triceps surae muscles. The effect of TTX-induced inactivity of presynaptic elements on EPSP amplitude was distinguished from the effect of treating the postsynaptic target by comparing the results from heteronymous synaptic connections, where only one or the other element was treated. After 2 weeks of synaptic inactivity, the heteronymous EPSPs generated by MG la afferents in lateral gastrocnemius/soleus (LG-Sol) motoneurons were significantly (p less than 0.005) larger than control values (48%). Sample differences in rheobase current and half-afterhyperpolarization, both of which may covary with EPSP amplitude, did not account for the differences between groups. Segregation of the two samples of motoneurons by rheobase current identified the increase as being confined to those LG-Sol cells whose rheobase fell below 10 nA. In addition, EPSPs generated by untreated LG-Sol la afferents in treated MG motoneurons were significantly enhanced (39%, p less than 0.05). Thus, TTX treatment of either presynaptic or postsynaptic elements increases synaptic strength. This increase in monosynaptic EPSP amplitude following TTX-induced inactivity may reflect an alteration intrinsic to the la afferent to motoneuron synapse, but influences from extrinsic sources cannot be discounted.

Nonuniform fatigue characteristics of slow-twitch motor units activated at a fixed percentage of their maximum tetanic tension.

1. The endurance of slow-twitch motor units from the soleus (SOL) and medial gastrocnemius (MG) muscles of the cat were tested by determining the length of time (endurance time, Et) that a unit could maintain its tension output at 85% of maximum. Motor-unit tension was clamped at the target level by altering the stimulation rate of a unit's motor axon through computer feedback control. Tested in this way, units of both muscles displayed a wide range of Ets, approximately 40- to 50-fold. 2. Electromyographic (EMG) waveforms of motor units subjected to force-clamp contractions were analyzed to access whether any activity-dependent changes in their waveform shape might predict Et. Three measurements of waveform shape were determined: baseline-to-baseline duration, peak-to-peak amplitude, and area. Typically, amplitude decreased and duration increased as a contraction proceeded, whereas area remained fairly constant. Because changes in each measure were very similar for units of widely different Ets, it was concluded that neuromuscular junction failure and changes in the excitability of the sarcolemma (excluding the t-tubule system) play a minor role in determining Et. 3. Et was highly correlated with the mean stimulation rate (Et/number of stimuli) used during the force-clamp contractions. Mean rate was seen to progressively decrease with increasing Et. This correlation could not be explained by measures of isometric contractile speed or relaxation (e.g., twitch contraction time or half-relaxation time) measured before the force-clamp contractions. Both contraction time and half-relaxation time were found to be unrelated to both Et and the rate used to stimulate the unit during the force-clamp contraction. 4. Among type S units of SOL and MG, maximum tetanic tension and Et were not related. A significant relation (r = -0.49) was found between axonal conduction velocity and Et for SOL units (n = 38). In addition, a significant correlation (r = 0.47) was found between conduction velocity and tetanic tension for SOL units. Perhaps because of the small sample of type S units from MG (n = 10), conduction velocity was found not be related to either Et or tetanic tension. 5. Others have shown that a motor unit's maximum tetanic tension and axonal conduction velocity are correlated with its order of recruitment among motoneurons innervating a muscle. Recent work has further shown that among type F units the order in which a motoneuron is recruited is highly correlated with the fatigue resistance of its muscle unit.(ABSTRACT TRUNCATED AT 400 WORDS)

Control of motor-unit tension by rate modulation during sustained contractions in reinnervated cat muscle.

1. The aim of this study was to describe the control of tension by rate modulation of single motor units in reinnervated muscle. 2. Single fast-twitch motor units were isolated from medial gastrocnemius (MG) muscles in two groups of anesthetized adult cats: one in which the MG nerve was left untreated and another in which that nerve was sectioned and immediately sutured together 10-33 mo before study. Together with conventional measures of isometric contractile properties, units were tested with the use of computer-controlled feedback regulation of stimulation rate to maintain tension during continuous isometric contraction at a constant submaximal level [25% of maximal tension (Pmax)]. 3. For motor units from both groups, stimulation rate began to decline after target tension was attained and then settled at lower values for variable durations before rapidly increasing, usually within the last 5% of the contraction's duration, until reaching the experimentally selected limit of 100 pulses/s (pps). 4. Measures of the declining phase in stimulation rate occurring at the beginning of sustained contraction were not significantly different in comparison of untreated versus reinnervated muscles. These measures included 1) the magnitude of the decrease in rate, 2) the minimum rate attained, and 3) the time taken to reach minimum stimulation rate expressed as a fraction of endurance time (Et, total duration of the sustained contraction). 5. Most fast-twitch units from reinnervated muscles fell within normal limits for both endurance time and the number of stimuli applied over that period.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma growth hormone responses to constant infusions of human pancreatic growth hormone releasing factor. Intermittent secretion or response attenuation.

Administration of human pancreatic tumor growth hormone (GH) releasing factor (hpGRF[1-40]) as a single injection to normal human subjects stimulates the secretion of GH in a dose-responsive manner. In the present studies, hpGRF(1-40) was infused in a graded stepwise manner over a 6-h period in order to determine whether the GH secretory response would be sustained. Normal adult males received four consecutive 90-min infusions of hpGRF(1-40) at doses of 1, 3.3, 10, and 33 ng/kg per min, preceded and followed by a 90-min saline infusion; and the plasma GH responses were compared with those during a separate control infusion. Plasma GH levels were significantly elevated by each hpGRF(1-40) infusion; and dose responsiveness was evident for the lowest three doses. Mean integrated GH secretory rates for the four doses were 1.95, 3.29, 4.29, and 3.65 times those of the respective control study. Plasma GH responses exhibited considerable variability, frequently decreasing during the latter part of each infusion; and at the highest dose, they decreased continuously beginning shortly after the onset of infusion. Episodic GH secretion occurred in individual subjects during each of the infusion periods. The possible contribution of hypothalamic somatostatin secretion to the diminished GH responsiveness was evaluated by determining plasma thyroid stimulating hormone (TSH) levels during the infusions and the TSH responses to thyrotropin-releasing hormone (500 micrograms i.v.) during a separate hpGRF(1-40) infusion of 2 ng/kg per min. Neither basal nor stimulated TSH levels differed between GRF-infused and control groups. The results indicate that GH secretion is dose responsive to hpGRF(1-40) infusions, though the response to hpGRF(1-40) infusions, though the response is complex. The absence of impaired TSH secretion provides evidence against a mediating role of somatostatin. The explanation for the loss of GH responsiveness remains undetermined but could include GRF-induced receptor down-regulation, a postreceptor effect, or, in spite of our negative results, a somatostatin-mediated inhibition.

Metabolic clearance and plasma disappearance rates of human pancreatic tumor growth hormone releasing factor in man.

The metabolic clearance rate (MCR) and plasma disappearance rate (t1/2) of human pancreatic tumor growth hormone releasing factor [hpGRF(1-40)] was determined in normal adult male subjects by single injection and constant infusion techniques. Single injections of 1, 3.3, and 10 micrograms/kg hpGRF(1-40) were administered intravenously, plasma immunoreactive (IR) GRF levels were measured during the subsequent 180 min, and biexponential curve analysis was performed. Graded, dose-constant infusions of hpGRF(1-40) at rates of 1, 3.3, 10, and 33 ng/kg per min were administered and the MCR was calculated from measurement of steady state plasma IR-GRF levels at each infusion rate. The postinfusion disappearance rate was determined by linear regression analysis of plasma IR-GRF levels during the 120-min period after cessation of the infusion. The calculated MCR during the single injection study was 194 +/- 17.5 liters/m2 per d and was not significantly different from the calculated value during the constant infusion study (202 +/- 16 liters/m2 per d). The disappearance rate during the single injection study was subdivided into two linear phases: an initial equilibration phase (7.6 +/- 1.2 min) and a subsequent elimination phase (51.8 +/- 5.4 min). The latter was similar to the linear disappearance rate observed (41.3 +/- 3.0 min) after cessation of the constant infusion. The chromatographic and biologic characteristics of plasma IR-GRF, 30 min after injection, were similar to those of synthetic hpGRF(1-40). The results have been discussed in relation to the MCR of other hypothalamic hormones and have been used to extrapolate secretion rates of GRF in patients with ectopic GRF production.

Ectopic growth hormone-releasing factor and dibutyryl cyclic adenosine monophosphate-stimulated growth hormone release in vitro: effects of corticosterone and estradiol.

Glucocorticoids and estrogens each affect GH secretion in vivo. The effects of corticosterone and estradiol (E2) were studied singly and in combination on GH secretion and cell content of primary cultures of rat adenohypophyseal cells grown in media containing intact or hormone-deficient serum. Secretion was measured under basal conditions and in response to maximally stimulatory doses of ectopic GH-releasing factor (E-GHRF) derived from a carcinoid tumor and dibutyryl cAMP [(DBcAMP) 10(-3) M]. Basal GH release measured over a 4-h period was suppressed by 40% (P less than 0.001) when hormone-deficient serum was substituted for normal serum in the growth media, and the stimulatory responses to DBcAMP and E-GHRF were markedly attenuated (P less than 0.001). The GH content of unstimulated cells was also decreased [29 +/- (SE) 7%, P less than 0.001]. The addition of corticosterone, 3 X 10(-8) M to 3 X 10(-6) M, to the 4-day growth media resulted in dose-related increases in basal and DBcAMP-stimulated GH release during the 4-h test period which was proportional to the increases in total cellular GH content. In contrast, corticosterone exposure caused a dose-related enhancement of E-GHRF-stimulated release above that accounted for by the increase in total GH content alone. Concomitant exposure to the releasing stimuli and corticosterone during a 4-h incubation, however, reduced the effects of the releasing stimuli. The addition of E2, 10(-10) M to 10(-8) M, during the 4-day growth period and/or the 4-h stimulation period did not affect the secretion of GH either basally or in response to the stimuli. E2 did increase the cell content of GH, but the effects were not additive to those of corticosterone. These studies indicate that long term (4-day) exposure to corticosterone increases net GH synthesis and E-GHRF-stimulated release, but that acute (4 h) exposure inhibits stimulated release. Although E2 also increases cellular content of GH, it exhibits no demonstrable direct effects on GH secretion or content in the presence of corticosterone.

Evidence for lactotroph dopamine resistance in idiopathic hyperprolactinemia.

Previous studies in patients with idiopathic hyperprolactinemia (IH) that have suggested the presence of decreased central dopaminergic tone have assumed normal responsiveness of lactotrophs to dopamine (DA). We have examined DA sensitivity in 17 women with IH and 19 female controls by evaluating the plasma PRL responses to successive infusions of increasing concentrations of DA (4, 40, and 400 ng/kg . min) as well as to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic receptor blocker, domperidone (2 mg, iv). PRL levels in controls were unchanged during a saline infusion, but decreased by 34 +/- 7% (mean +/- SE) at the end of the lowest DA infusion (P less than 0.05 vs. saline). Progressive PRL suppression was produced with each increasing dose. In contrast, in patients with IH, the lowest dose produced no significant suppression from basal PRL levels (P less than 0.001 vs. controls); at 40 ng/kg . min DA, fractional suppression was evident but was less than that in controls (P less than 0.01); at 400 ng/kg . min, fractional PRL suppression in IH patients was indistinguishable from that in controls (70 +/- 6% vs. 73 +/- 4%). Patients with IH also exhibited markedly reduced and delayed PRL response to domperidone (P less than 0.02 vs. controls). Significant impairment of the PRL-lowering effect of bromocriptine was observed in the IH patients between 1 and 2 h (P less than 0.02 vs. controls), and their responses to bromocriptine were again delayed. The results indicate the presence of a relative resistance to DA in patients with IH. This resistance is compatible with a decrease in the number or affinity of lactotroph DA receptors.

Ectopic growth hormone releasing factor stimulates growth hormone release from human somatotroph adenomas in vitro.

The effects of an ectopic growth hormone releasing factor (E-GHRF) from a carcinoid tumor were studied in three human GH-secreting pituitary adenomas in monolayer culture. GH release by the adenomas was stimulated by 55 +/- 10%, 57 +/- 8%, and 59 +/- 17% during a 4 h exposure to E-GHRF at concentrations of 3, 0.8, and 24 Units/ml, respectively. Two of the tumors also secreted prolactin (PRL) and in one, E-GHRF (0.8 Units/ml) stimulated PRL release by 48 +/- 8%. GH and PRL release were both suppressed by somatostatin (10(-8)M) in two of the adenomas. These results 1) demonstrate for the first time E-GHRF stimulation of GH release from human pituitary tissue in vitro, 2) support an etiologic role for E-GHRF in the development of acromegaly, and 3) indicate that GH-secreting adenomas retain the capability of responding to GHRF.