Development and validation of a semi-automated surveillance system-lowering the fruit for non-ventilator-associated hospital-acquired pneumonia (nvHAP) prevention.

OBJECTIVES: Conducting manual surveillance of non-ventilator-associated hospital-acquired pneumonia (nvHAP) using ECDC (European Centre for Disease Prevention and Control) surveillance criteria is very resource intensive. We developed and validated a semi-automated surveillance system for nvHAP, and describe nvHAP incidence and aetiology at our hospital. METHODS: We applied an automated classification algorithm mirroring ECDC definition criteria to distinguish patients 'not at risk' from patients 'at risk' for suffering from nvHAP. 'At risk'-patients were manually screened for nvHAP. For validation, we applied the reference standard of full manual evaluation to three validation samples comprising 2091 patients. RESULTS: Among the 39 519 University Hospital Zurich inpatient discharges in 2017, the algorithm identified 2454 'at-risk' patients, reducing the number of medical records to be manually screened by 93.8%. From this subset, nvHAP was identified in 251 patients (0.64%, 95%CI: 0.57-0.73). Sensitivity, negative predictive value, and accuracy of semi-automated surveillance versus full manual surveillance were lowest in the validation sample consisting of patients with HAP according to the International Classification of Diseases (ICD-10) discharge diagnostic codes, with 97.5% (CI: 93.7-99.3%), 99.2% (CI: 97.9-99.8%), and 99.4% (CI: 98.4-99.8%), respectively. The overall incidence rate of nvHAP was 0.83/1000 patient days (95%CI: 0.73-0.94), with highest rates in haematology/oncology, cardiac and thoracic surgery, and internal medicine including subspecialties. CONCLUSIONS: The semi-automated surveillance demonstrated a very high sensitivity, negative predictive value, and accuracy. This approach significantly reduces manual surveillance workload, thus making continuous nvHAP surveillance feasible as a pivotal element for successful prevention efforts.

Should International Classification of Diseases codes be used to survey hospital-acquired pneumonia?

As surveillance of hospital-acquired pneumonia (HAP) is very resource intensive, alternatives for HAP surveillance are needed urgently. This study compared HAP rates according to routine discharge diagnostic codes of the International Classification of Diseases, 10th Revision (ICD-10; ICD-HAP) with HAP rates according to the validated surveillance definitions of the Hospitals in Europe Link for Infection Control through Surveillance (HELICS/IPSE; HELICS-HAP) by manual retrospective re-evaluation of patient records. The positive predictive value of ICD-HAP for HELICS-HAP was 0.35, and sensitivity was 0.59. Therefore, the currently available ICD-10-based routine discharge data do not allow reliable identification of patients with HAP.

Cancer survivors' preference for follow-up care providers: a cross-sectional study from the population-based PROFILES-registry.

BACKGROUND: The best practice for the organization of follow-up care in oncology is under debate, due to growing numbers of cancer survivors. Understanding survivors' preferences for follow-up care is elementary for designing patient-centred care. Based on data from prostate cancer and melanoma survivors, this study aims to identify: 1) preferences for follow-up care providers, for instance the medical specialist, the oncology nurse or the general practitioner; 2) characteristics associated with these preferences and 3) the preferred care provider to discuss cancer-related problems. MATERIAL AND METHODS: Survivors diagnosed with prostate cancer (N = 535) and melanoma (N = 232) between 2007 and 2013 as registered in The Netherlands Cancer Registry returned a questionnaire (response rate was 71% and 69%, respectively). A latent class cluster model analysis was used to define preferences and a multinomial logistic regression analysis was used to identify survivor-related characteristics associated with these preferences. RESULTS: Of all survivors, 29% reported no preference, 40% reported a preference for the medical specialist, 20% reported a preference for both the medical specialist and the general practitioner and 11% reported a preference for both the medical specialist and the oncology nurse. Survivors who were older, lower/intermediate educated and women were more likely to have a preference for the medical specialist. Lower educated survivors were less likely to have a preference for both the medical specialist and the general practitioner. Overall, survivors prefer to discuss diet, physical fitness and fatigue with the general practitioner, and hereditary and recurrence with the medical specialist. Only a small minority favored to discuss cancer-related problems with the oncology nurse. CONCLUSION: Survivors reported different preferences for follow-up care providers based on age, education level, gender and satisfaction with the general practitioner, showing a need for tailored follow-up care in oncology. The results indicate an urgency to educate patients about transitions in follow-up care.

Rational treatment of empyema in children.

HYPOTHESIS: Efficacious and cost-effective treatment of pediatric empyema can be accomplished following a protocol based on its radiographic appearance. Therapeutic modalities include thoracostomy tube drainage (TTD) with or without fibrinolytic therapy (FT) and video-assisted thoracoscopic debridement (VATD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. RESULTS: From 1995 through 1999, 31 children were treated ranging in age from 11 months to 18 years (mean age, 5.1 years). Twenty-seven (87.1%) underwent TTD; of these, 22 (81.5%) received FT with urokinase. The TTD failed in 4 children (14.8%) who required salvage VATD. Primary VATD was performed in another 4 children (12.9%). The mean length of stay was 14.6 days (TTD, 14.1 days; salvage VATD, 20. 0 days; primary VATD, 11.5 days), ranging from 8.0 to 30.0 days. Complications included readmission for fever (2 patients [6.5%]) and gastrointestinal bleeding (1 patient [3.2%]). There were no anaphylactic reactions or bleeding episodes due to urokinase. Two patients (7.4%) treated with TTD and FT developed an air leak that resolved spontaneously. The mean hospital charges were $78,832 (TTD with or without FT, $75,450; salvage VATD, $107,476; primary VATD, $69,634). The procedural charges were highest for salvage VATD. CONCLUSIONS: Most cases of pediatric empyema can be treated by TTD with or without FT. This therapy is safe and effective for children with nascent disease. Primary VATD is preferred in children with advanced disease. Cost-effectiveness could be further improved through better prediction of those patients likely to fail TTD and require salvage VATD. An algorithmic approach based on findings from computed tomography or (better) ultrasonography of the chest may be the best way to make this distinction and rationalize care.

Computer-assisted training and learning in surgery.

The teaching and learning of surgery is a time-honored tradition based upon the "see one, do one, teach one" apprenticeship model. Recent improvement of this model has centered upon incremental change in skills teaching and testing and curricular development. Economic pressures have strained the resources of academic health centers and faculty responsible for teaching surgery, even as information technology has opened new avenues for obtaining and benefitting from relevant information. Combining the tools of simulation theory, virtual reality, and the principles of adult education offers new opportunities to optimize surgical education as we enter a more highly connected and interdependent era, where the boundaries between teacher and student blur as the modern surgeon truly becomes a lifelong learner.

Salvage laparotomy for failure of peritoneal drainage in necrotizing enterocolitis in infants with extremely low birth weight.

BACKGROUND/PURPOSE: Peritoneal drainage is a temporizing procedure for infants with extremely low birth weight (ELBW) who have perforated necrotizing enterocolitis (NEC). "Salvage" laparotomy is advocated when patients worsen after drainage. Some patients have survived with intact gastrointestinal functional after drainage alone. The purpose of this study is to determine if these salvage laparotomies are beneficial. METHODS: The authors reviewed the records of ELBW infants treated at Stanford University with perforated NEC from 1993 through 1998. Data collected included demographic makeup, type of operation, survival rate, postoperative complications, length of stay (LOS), and cost. RESULTS: The authors treated 26 patients, 9 with laparotomy and 17 with peritoneal drainage. The peritoneal drainage group had lower birth weight and more comorbid conditions. Survival rate was similar between laparotomy and drainage: 55.6% versus 41.2%. Four patients in the drainage group underwent salvage laparotomy for perceived clinical deterioration. All of these patients died. The clinical status of patients who had salvage laparotomy and died was similar to those who did not and lived. Seven of 13 patients treated with drainage followed only by supportive care and antibiotics survived. Cost and LOS for patients undergoing salvage laparotomy were much greater than for nonsurviving patients undergoing only peritoneal drainage: 84 +/- 20 days and $660,000 compared with 34 +/- 11 days and $306,000. CONCLUSIONS: Both primary peritoneal drainage and laparotomy should be considered primary therapy for perforated NEC. Patients undergoing peritoneal drainage typically experience clinical deterioration after operation. In this limited experience, salvage laparotomy did not appear beneficial.

The future of medical education is no longer blood and guts, it is bits and bytes.

In the United States, medical care consumes approximately $1.2 trillion annually (14% of the gross domestic product) and involves 250,000 physicians, almost 1 million nurses, and countless other providers. While the Information Age has changed virtually every other facet of our life, the education of these healthcare professionals, both present and future, is largely mired in the 100-year-old apprenticeship model best exemplified by the phase "see one, do one, teach one." Continuing medical education is even less advanced. While the half-life of medical information is less than 5 years, the average physician practices 30 years and the average nurse 40 years. Moreover, as medical care has become increasingly complex, medical error has become a substantial problem. The current convulsive climate in academic health centers provides an opportunity to rethink the way medical education is delivered across a continuum of professional lifetimes. If this is well executed, it will truly make medical education better, safer, and cheaper, and provide real benefits to patient care, with instantaneous access to learning modules. At the Center for Advanced Technology in Surgery at Stanford we envision this future: within the next 10 years we will select, train, credential, remediate, and recredential physicians and surgeons using simulation, virtual reality, and Web-based electronic learning. Future physicians will be able to rehearse an operation on a projectable palpable hologram derived from patient-specific data, and deliver the data set of that operation with robotic assistance the next day.

Simulation and virtual reality in surgical education: real or unreal?

Rapid change is under way on several fronts in medicine and surgery. Advances in computing power have enabled continued growth in virtual reality, visualization, and simulation technologies. The ideal learning opportunities afforded by simulated and virtual environments have prompted their exploration as learning modalities for surgical education and training. Ongoing improvements in this technology suggest an important future role for virtual reality and simulation in surgical education and training.

Timed daily administration of prolactin and corticosteroid hormone reduces murine tumor growth and enhances immune reactivity.

In the present study, we investigated the time-dependent interactive effects of daily injections of prolactin (PRL) and corticosterone (CORT) on the activation of lymphocyte function and inhibition of tumor growth in vivo in mice. BALB/c mice were injected subcutaneously with EMT-6 fibrosarcoma cells (a murine connective tissue tumor cell derived from mammary gland), and then different groups of animals were treated with PRL (1 microg/g body weight [BW] ip) at Oh, 4h, 8h, 12h, 16h, or 20h after CRT (1 microg/g BW ip) daily for 10 days. Different control groups were vehicle treated or treated with either hormone alone. Mice were kept in constant light 1 week before and during injections and in a 14:10 light-dark cycle thereafter. Tumor progression was monitored for up to 21 days after the cessation of treatment, and thereafter spleen lymphocytes were harvested and tested for mitogen-triggered proliferation. Prolactin administration at 8h or 16-20h after corticosteroid treatment reduced tumor volume by 77% and 49%, respectively, relative to vehicle-treated controls. Other time relations of hormone treatment were ineffectual. Further studies indicated that the immunosuppressant cyclosporin A (CSA) substantially stimulated tumor growth; this effect was completely abrogated by a simultaneous 8h related hormone treatment. How ever, the 8h hormone treatment was ineffective in inhibiting tumor growth in T-cell-deficient nude mice. Spleen lymphocytes from tumor-bearing (TB) mice showed an elevated basal proliferative capacity stimulated by concanavalin A (ConA; a stimulus for T-cell proliferation) and lipopolysaccharide (LPS; a stimulus for B-cell proliferation) compared to non-TB mice. Spleen lymphocytes from TB mice treated with CORT and PRL at 8h intervals exhibited an increased spontaneous (as well as LPS- and ConA- triggered) proliferation (by 104%, 48%, and 70%, respectively) compared with vehicle control TB mice. Fluorescence-activated cell sorting (FACS) analysis of splenocytes from hormone-treated animals indicated a 34-100% increase in the CD4+ (e.g., T helper cell) population. Treatment of animals with either hormone alone did not inhibit tumor growth or stimulate immune function relative to vehicle controls. The daily rhythms of plasma PRL, CORT, and thyroxine were all substantially altered by the presence of tumor in these mice. These results indicate that appropriately timed daily treatment of PRL and CORT can attenuate tumor growth, in part, via activation of antitumor immune mechanisms. Collectively, these data suggest that circadian neuroendocrine activities must be temporally organized appropriately to inhibit tumor growth.

Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes.

Bromocriptine, a potent dopamine D(2) receptor agonist, has been shown to reduce insulin resistance, glucose intolerance and hyperlipidaemia in both numerous animal studies and in Phase II studies. Bromocriptine has been used worldwide for over 20 years to treat Parkinson's disease, macroprolactinoma and other disorders; it has been found to be generally safe. We therefore investigated the possible beneficial effects of Ergoset(R) (Ergo Science Corp.), a new quick release formulation of bromocriptine, on glycaemic control and serum lipid profile in obese Type 2 diabetic subjects in two large Phase III studies. A large, randomised, double-blind placebo-controlled study was conducted in which Ergoset was given once daily at 8 am. (4.8 mg maximum dose) for 24 weeks as adjunctive therapy to sulphonylurea (485 subjects) to obese Type 2 diabetics held on a weight- maintaining diet. Treatment efficacy parameters included change from baseline in glycated haemoglobin A(1c) (HbA(1c)), fasting and post-prandial serum glucose, insulin, triglyceride and free fatty acid levels. Baseline glycated haemoglobin, fasting glucose, insulin, triglyceride and free fatty acid levels did not differ between treatment groups. and on average were 9.4 +/- 0.05%, 222 +/- 2 mg/dl, 24 +/- 1 µU/ml, 248 +/- 11 mg/dl, and 850 +/- 32 µEq/l, respectively. A similarly designed study of Ergoset as monotherapy in Type 2 diabetics (154 subjects) with similar baseline clinical characteristics was conducted. Addition of Ergoset treatment to sulphonylurea reduced percent glycated HbA(1c) by 0.55 (P < 0.0001) (approximately 1.0 for responders, 65% of population), fasting and post-prandial glucose by 23 and 26 mg/dl (P < 0.0002), fasting and post-prandial triglycerides by 72 and 63 mg/dl (P < 0.005) and fasting and post-prandial free fatty acids by 150 and 165 µEq/l (P < 0.05), relative to placebo. Twelve percent of all Ergoset subjects, compared to 3% of placebo subjects, withdrew from the study due to adverse events. The most common events causing withdrawal were nausea, dizziness, asthenia, and rhinitis (representing 4.5, 3.3, 2.0, and 0.8% of the total Ergoset populations, respectively). The incidence of serious adverse events did not differ between Ergoset- (3.4%) and placebo- (4.3%) treated subjects. Ergoset as monotherapy also improved glycaemic control (0.56 HbA(1c) decrease relative to placebo after 24 weeks of treatment; P < 0.02). Once daily Ergoset treatment improves glycaemic control and serum lipid profile and is well-tolerated in obese Type 2 diabetics.

Bromocriptine reduces obesity, glucose intolerance and extracellular monoamine metabolite levels in the ventromedial hypothalamus of Syrian hamsters.

We examined whether reductions in body fat stores and insulin resistance in Syrian hamsters induced by bromocriptine are associated with reductions in daily norepinephrine (NE) and serotonin activities as indicated by their extracellular metabolite levels in the ventromedial hypothalamus (VMH). High levels of these monoamines within the VMH have been suspected to induce obesity and insulin resistance. Microdialysate samples from the VMH of freely moving obese male hamsters (BW: 208 +/- 5 g) were collected hourly over a 25-hour period before bromocriptine treatment, during the first day of and after 2 weeks of bromocriptine treatment (800 microg/animal daily, i.p.), and body composition and glucose tolerance analyses were conducted before and after 2 weeks of treatments. The microdialysate samples were analyzed by HPLC for metabolites of serotonin: 5-hydroxy-indoleacetic acid (5-HIAA), NE: 3-methoxy-4-hydroxy-phenylglycol (MHPG), and dopamine: homovanillic acid (HVA). Bromocriptine treatment for 14 days significantly reduced body fat by 60% and areas under the glucose and insulin curves during a glucose tolerance test by 50 and 46%, respectively. Concurrently, extracellular VMH contents of 5-HIAA, MHPG, and HVA were reduced by 50, 29 and 66%, respectively (p < 0.05). Similarly, VMH 5-HIAA and MHPG contents were 48 and 44% less, respectively (p < 0.05), in naturally glucose-tolerant hamsters compared with naturally glucose-intolerant hamsters. Bromocriptine induced reductions of body fat, and improvements in glucose intolerance may result in part from its ability to decrease serotonin and NE activities in the VMH.

Bromocriptine/SKF38393 ameliorates islet dysfunction in the diabetic (db/db) mouse.

Dysfunction of pancreatic islets plays a crucial role in the etiology of type II diabetes. Chronic hyperglycaemia or hyperlipidaemia may impair islet function. Previous studies by our laboratory have demonstrated that dopaminergic agonists ameliorated hyperglycaemia and hyperlipidaemia in obese and diabetic rodents. In the present study, we investigated the effect of a treatment with the dopamine D2/D1 receptor agonists (bromocriptine/SKF38393, BC/SKF) on islet dysfunction in db/db mice. Our results show that a 2-week BC/SKF treatment markedly reduced hyperglycaemia and hyperlipidaemia, and significantly improved islet dysfunction demonstrated by an increase of secretagogue-stimulated insulin release from islets of db/db mice to levels observed in islets from lean mice. There was also a fourfold increase of insulin content in the pancreas of BC/SKF-treated db/db mice compared with that in untreated controls. The effect of BC/SKF on islet function cannot be mimicked in pair-fed animals. BC/SKF had no direct stimulatory effect on islet insulin secretion, suggesting BC/SKF treatment improved islet function via an indirect mechanism. This treatment markedly improved the abnormally elevated daily levels of corticosterone, blood glucose and plasma lipids, supporting the view that BC/SKF may affect the neuroendocrine system that in turn regulates peripheral metabolism and thereby improves islet function.

Dopaminergic neurotoxin administration to the area of the suprachiasmatic nuclei induces insulin resistance.

Dopaminergic neuron neurotoxin (6-hydroxydopamine; 6-OHDA) administration directed to the hypothalamic area of the mammalian pacemaker, the suprachiasmatic nuclei (SCN), was carried out on lean, glucose tolerant hamsters to investigate the possibility that dopaminergic input to the vicinity of the SCN is necessary to maintain this metabolic condition. Glucose tolerance tests (GTT, 3 g glucose/kg) were performed 4 days prior to and 16 days after neurotoxin lesioning. 6-OHDA administration to the area of the SCN resulted in both a significant 58% increase in daily food consumption by the 16th day post-lesioning, and a 85% increase in weight gain 4 and 8 weeks after lesioning relative to controls. Such treatment also significantly increased the total areas under the GTT glucose and insulin curves by 48% and 400% respectively, compared with controls. These findings indicate that body weight gain, glucose intolerance and insulin resistance result from decreased dopaminergic input to the area of the SCN.

Ambulatory urodynamics: extramural testing of the lower and upper urinary tract by Holter monitoring of cystometrogram, uroflowmetry, and renal pelvic pressures.

This article elucidates the clinical applicability and state of the art of ambulatory urodynamics. Ambulatory urodynamics have evolved into practical investigations like EAC, HFM, and EAC combined with renal pelvimetry. EAC has been shown to be the method of preference if detrusor overactivity is involved. Conventional filling cystometry has proved to be an unreliable way to exclude detrusor instability. De novo instability after suspension surgery often indicates that an existing detrusor overactivity was not identified preoperatively. EAC including flowmetry has shown considerable variance in obstructive and contractility parameters in males with LUTS indicative for BPH. This raises doubt whether the clinical flow analysis is the suitable "gold standard" as advocated by the ICS. For a real break through of EAC, less complex automatic analysis is necessary. HFM is a newer method within the range of ambulatory urodynamic tests. It has not yet been completely evaluated. But, because the technique is analogous to the office flowmetry, noninvasive and very well accepted by the patients, it is expected to be widely used. This expectation is strengthened by the fact that HFM seems to show individual therapeutic efficacy of drugs, such as alpha-blockers. As a research tool to evaluate efficacy, it is far more powerful than conventional methods because of the reduction of within-patient standard deviation to about 10%. Finally, EAC combined with pelvimetry offers a promising method for the clinical evaluation of a combined dysfunction of upper and lower urinary tract.

Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects.

OBJECTIVE: A double-blind placebo controlled study investigated long-term effects of Ergoset, a new quick release formulation of bromocriptine, on body weight, body fat, and glucose tolerance in a group (n = 17) of obese subjects who were instructed to follow a moderate hypocaloric diet. RESEARCH DESIGN AND METHODS: Obese individuals (> 25% body fat for men and > 30% body fat for women) were instructed to follow a calorie-restricted diet (70% of weight maintaining based on study entry weight) and were randomized to daily treatment with Ergoset (1.6-2.4 mg/day) or placebo at 0800 over an 18-week treatment period. Oral glucose tolerance tests were performed on subjects before initiation and again at termination of treatment. Body weight and body fat (determined by skinfold measurements) were quantified every 2 weeks during the course of treatment. RESULTS: Ergoset treatment for 18 weeks significantly reduced body weight and body fat versus placebo (6.3 +/- 1.5 and 5.4 +/- 1.1 kg vs. 0.9 +/- 1.0 and 1.5 +/- 0.6 kg. respectively, P < 0.01). Ergoset, but not placebo, also improved glucose tolerance (P < 0.02); the stimulated area under the oral glucose tolerance curve was reduced by 46% (from 121 +/- 23 to 64 +/- 32 mg.h-1.dl-1), while the stimulated area under the insulin curve was reduced by 30%. CONCLUSIONS: When combined with instruction to follow a moderate hypocaloric diet, Ergoset, but not placebo, improves glucose tolerance and promotes significant weight and body fat loss in obese subjects over an 18- week treatment period.

Bromocriptine inhibits in vivo free fatty acid oxidation and hepatic glucose output in seasonally obese hamsters (Mesocricetus auratus).

Seasonally obese hyperinsulinemic hamsters were treated for 5 weeks with bromocriptine (500 to 600 micrograms per animal) and tested for drug effects on energy balance, body fat stores, nocturnal whole-body free fatty acid (FFA) metabolism and hepatic glucose output, and diurnal glucose tolerance. After 5 weeks, bromocriptine treatment reduced retroperitoneal fat pad weight by 45% without altering either daily food consumption or end-treatment total daily energy expenditure. Also, 5 weeks of treatment improved the diurnal glucose tolerance, resulting in a 47% and 33% decrease in the area under glucose and insulin curves, respectively. After 4 weeks, bromocriptine treatment reduced nocturnal lipolysis by 28%, palmitate rate of appearance into plasma by 30%, palmitate oxidation by 33%, and hepatic glucose output by 28%. Moreover, these reductions were accompanied by a 75% reduction in plasma insulin concentration. The data suggest that bromocriptine may improve diurnal glucose tolerance in part by inhibiting the preceding nocturnal lipolysis and FFA oxidation. Reductions in nocturnal FFA oxidation and hepatic glucose production may result from bromocriptine's influences on circadian organization of hypothalamic centers known to regulate these activities. Available evidence suggests that bromocriptine may impact this neuroendocrine organization of metabolism by increasing the dopamine to noradrenaline activity ratio in central (hypothalamic) and peripheral (eg, liver and adipose) target tissues.

The immunoregulatory effects of prolactin in mice are time of day dependent.

The effects of timed administration of PRL on immune activities were investigated in male BALB/c mice. Ten daily injections of PRL (1 mg/kg) were made 0/24, 4, 8, 12, 16, or 20 h after light onset (HALO). On day 11, spleen cells were harvested between 1-3 HALO and cocultured with gamma-irradiated C57BL/6 spleen cells for 5 days, and proliferative responses to alloantigen were assayed (mixed lymphocyte reaction). When given in vivo at 4-12 HALO, PRL strongly stimulated proliferation by more than 2-fold, whereas PRL injections when given at 24 HALO substantially inhibited proliferation and had no effect when given at 16-20 HALO. When endogenous PRL secretion was stimulated for 7 days with injections of domperidone or 5-hydroxytryptophan, the splenocyte response increased by 48% and 64%, respectively, when injections were given at 9-10 HALO, but did not increase when they were given at 23-0 HALO. Inhibition of endogenous PRL secretion for 7 days with bromocriptine (2.5 mg/kg.day) inhibited splenocyte responsiveness by 40% when injected at 9 HALO, but had no effect when administered at 0 HALO. Furthermore, such bromocriptine treatment inhibited T- and B-cell mitogenic responses to Concanavalin-A (by 48%) and lipopolysaccharide (38%) when administered at 10, but not 0, HALO. In a manner similar to mixed lymphocyte reaction responses, daily PRL injections for 10 days at 11 HALO stimulated (40%) the in vivo delayed-type hypersensitivity response to antigen (azobenzenearsonate), whereas injections at 0 HALO were nonstimulatory. Bromocriptine treatment (1.5 mg/kg.day) suppressed the delayed-type hypersensitivity response (43% less than the control value) when administered at 10-12 HALO, but had no effect when administered at light onset. Timed PRL injections for 28 days in adult mice increased (42%) the total thymic cell number when administered at 11 HALO, but had no effect when injected at 0 HALO. Together, these results show that immunocyte responsiveness to PRL is time of day dependent. Thus, these findings support an essential and heretofore unrecognized circadian role in PRL regulation of immunity.

In vitro incorporation of [14C]glycine into muscle protein of gulf killifish (Fundulus grandis) in response to insulin-like growth factor-I.

The effect of recombinant human insulin-like growth factor I (rhIGF-I) on protein synthesis was studied in vitro in the muscle of a teleost fish. Protein synthesis was assessed by the incorporation of [14C]glycine into protein. rhIGF-I stimulated [14C]glycine incorporation in a dose-dependent manner. The minimal effective dose was 0.1 ng/ml and maximal stimulation was obtained with 1 ng/ml. A high concentration (100 ng/ml) was ineffective. Treatment with 1 ng/ml rhIGF-I produced a significant response after 3 hr of incubation and the greatest stimulation was observed after 6 hr. Responsiveness of muscle tissue to IGF-I examined at three different times (0, 6, and 12 hr after light onset, LD 12:12) was greatest at light onset. These results provide evidence that IGF-I may have a role in the regulation of growth in fish and that its activities are dose and time-of-day dependent.