Evaluation of a new Perinatal Mental Health Service in a University Maternity Hospital.

OBJECTIVES: Specialist Perinatal Mental Health Services (SPMHS) are a new development in Ireland. This service evaluation examined the impact of the introduction of a SPMHS multidisciplinary team (MDT) on prescribing practices and treatment pathways in an Irish maternity hospital. METHODS: Clinical charts were reviewed to collect data on all referrals, diagnoses, pharmacological and non-pharmacological interventions delivered in a SPMHS over a 3-week period in 2019. The findings were compared to the same 3-week period in 2020 following the expansion of the SPMHS MDT. RESULTS: In 2019 (n = 32) and 2020 (n = 47), most (75 and 79%, respectively) assessments were antenatal. The proportion of patients prescribed psychotropic medication within the SPMHS was not significantly different from 2019 (31%) to 2020 (23%), though more patients were already prescribed psychotropic medications at the time of referral (22% in 2019 v. 36% in 2020). There was an increase in MDT interventions in 2020 with more input from psychology, clinical nurse specialist (CNS), and social work intervention. Adherence to prescribing standards improved from 2019 to 2020. CONCLUSION: Prescribing patterns remained unchanged between 2019 and 2020. Improvement was observed in adherence to prescribing standards and there was increased provision of MDT interventions in 2020. Broader diagnostic categories were also used in 2020, possibly suggesting that the service is now providing more individualized care.

Complications and outcomes of swine that underwent cesarean section for resolution of dystocia: 110 cases (2013-2018).

OBJECTIVE: To report the surgical survival of dams and piglets and follow-up survival and future breeding potential of swine that underwent cesarean section for correction of dystocia. STUDY DESIGN: Retrospective study. ANIMALS: One hundred ten client-owned, female swine. All swine included in this study were breeding stock for market pigs to be used for exhibition purposes. METHODS: Medical records of swine that underwent cesarean section at The Ohio State University Hospital for Farm Animals for resolution of dystocia between January of 2013 and July of 2018 were reviewed. Signalment, history, number of piglets per litter, treatments, and surgical procedure were recorded. Follow-up information (survival, complications, and additional pregnancies) was obtained via telephone interview. RESULTS: A fetus was not palpable in 77 of 110 (70%) cases at presentation. The median litter size was eight piglets (range, 1-14), with medians of five (range, 0-13) live and one dead (range, 0-11) piglets per litter. Follow-up was available for 52 dams, of which 39 (75%) survived. Complications were recorded in 20 of 52 (38.46%) cases and included incisional seroma formation, lethargy, and anorexia. Twenty-three dams became pregnant and farrowed after the cesarean section, with no reported complication in 13 of these. CONCLUSION: Cesarean section in swine is associated with a good prognosis for recovery from the procedure and a fair to guarded prognosis for future breeding. CLINICAL SIGNIFICANCE: Cesarean section may be considered for resolution of dystocia in swine. However, owners should be advised that nearly half of sows require assistance in subsequent deliveries.

Closing wedge ostectomy with transfixation pin-cast stabilization for correction of angular limb deformities of the metatarsophalangeal region in four cattle.

CASE DESCRIPTION: 4 calves were evaluated because of lameness and an angular limb deformity of the metatarsophalangeal region. CLINICAL FINDINGS: 3 calves (ages, 5 days, 10 days, and 1 month) had a congenital varus deformity of the metatarsophalangeal region characterized by medial subluxation of the first phalanx of digits 3 and 4 at the metatarsophalangeal joints. A 6-month-old heifer had a valgus deformity of the metatarsophalangeal region secondary to a malunion of a Salter-Harris type II fracture. The degree of deformity angulation ranged from 16° to 54° for the 4 patients. TREATMENT AND OUTCOME: A closing wedge ostectomy with transfixation pin-cast application was performed on the affected limb of all 4 patients. The ostectomy healed with only minor complications (disuse osteopenia distal to the transfixation pins [n = 4] and cast sores [1]) that were easily resolved with no long-term adverse effects. Duration of follow-up for the 4 patients ranged from 6 to 17 months, and the owners reported satisfactory ambulation with no (n = 2) or only mild (2) residual lameness in the affected limb. CLINICAL RELEVANCE: Results suggested that a closing wedge ostectomy with transfixation pin-cast stabilization is an alternative for management of angular limb deformities of the metatarsophalangeal region in cattle. Such treatment improved the quality of life for all 4 patients. However, 2 of the 4 patients had congenital deformities confirmed to be heritable. There are ethical concerns associated with treating animals with heritable disorders, and exhibition and breeding of such animals should be avoided.

Investigation of a novel prosthesis technique for extracapsular stabilization of cranial cruciate ligament-deficient stifle joints in adult cattle.

OBJECTIVE: To evaluate a novel prosthesis technique for extracapsular stabilization of cranial cruciate ligament (CCL)-deficient stifle joints in adult cattle. SAMPLE: 13 cadaveric bovine stifle joint specimens. PROCEDURES: In the first of 3 study phases, the most isometric points on the distal aspect of the femur (distal femur) and proximal aspect of the tibia (proximal tibia) were determined from measurements obtained from lateromedial radiographs of a stifle joint specimen maintained at angles of 135°, 90°, 65°, and 35°. During phase 2, 800-lb-test monofilament nylon leader line was cut into 73-cm-long segments. Each segment was secured in a loop by use of 2, 3, or 4 crimping sleeves such that there were 12 replicates for each construct. Each loop was distracted to failure at a constant rate of 1 mm/s. Mean force at failure and elongation and mode of failure were compared among the 3 constructs. During phase 3, bone tunnels were created in the distal femur and proximal tibia at the isometric points identified during phase 1 in each of 12 CCL-deficient stifle joint specimens. The 3-sleeve construct was applied to each specimen. Specimens were distracted to failure at a constant rate of 1 mm/s. RESULTS: Among the 3 constructs evaluated, the 3-sleeve construct was considered optimal in terms of strength and amount of foreign material. In phase 3, all replicates failed because of suture slippage. CONCLUSIONS AND CLINICAL RELEVANCE: Use of 800-lb-test monofilament nylon leader line as a prosthesis might be a viable alternative for extracapsular stabilization of CCL-deficient stifle joints in adult cattle. Further in vivo studies are necessary.

Safety and serologic response to a Haemonchus contortus vaccine in alpacas.

Haemonchosis in camelids remains a challenging disease to treat, and prevention has become increasingly problematic due to widespread anthelmintic resistance. Barbervax®is an adjuvanted vaccine containing natural H-11, H-gal-GP antigens obtained from Haemonchus contortus adults via a proprietary process and solubilized in Quil A. This vaccine is approved for use in Australia, after demonstrating its safety and efficacy in sheep and goats. There are no published studies evaluating Barbervax in other ruminants/pseudoruminants such as camelids which can be parasitized with H. contortus. The vaccine utilizes a mixture of the parasite gut mucosal membrane enzymes including H-gal-GP and H11, involved in digesting a blood meal from the host. This study monitored the safety profile of the Barbervax® vaccine in a group of adolescent alpacas. Although designed into the original study of vaccine efficacy, the experimental infection with viable H. contortus third stage larvae could not be completed due to lack of detectable significant variation of infection following experimental challenge. Twelve alpacas (158 + 15 days) were randomized to vaccination with Barbervax® or no treatment. Three doses of Barbervax® were administered at 3 week intervals and investigators involved in animal monitoring and sample collection were blinded to the groupings. Clinical pathologic parameters were evaluated 7 days before vaccination, and 1 and 2 months post-vaccination. Daily clinical observations were made and specific observations regarding the injection site and rectal temperatures were monitored in each alpaca twice daily for 1 week following vaccination. Fecal egg counts, packed cell volume, and total protein were monitored following challenge with 1500 H. contortus larvae on days 42, 46, and 50. An increase in rectal temperature for a duration of 2 days (range 2-4 days) was observed post-vaccination. Vaccinated alpacas were lethargic for 2-3 days following vaccination; however, they maintained an appetite and no visible or palpable injection site reactions were observed. Following the first vaccination, all animals maintained normal clinical pathologic parameters throughout the study period. The vaccinated animals did develop titers to the H. contortus antigen as measured by ELISA. In conclusion, the Barbervax® vaccine demonstrated safety in this small group of young, healthy alpacas, but additional studies are required to evaluate the efficacy of the vaccine under field conditions in protecting alpacas against infection with H. contortus.

Biochemical and genetic predictors and correlates of response to lamotrigine and folic acid in bipolar depression: Analysis of the CEQUEL clinical trial.

OBJECTIVES: CEQUEL (Comparative Evaluation of QUEtiapine plus Lamotrigine combination versus quetiapine monotherapy [and folic acid versus placebo] in bipolar depression) was a double-blind, randomized, placebo-controlled, parallel group, 2×2 factorial trial that examined the effect of adding lamotrigine and/or folic acid (FA) to quetiapine in bipolar depression. Lamotrigine improved depression, but its effectiveness was reduced by FA. We investigated the baseline predictors and correlates of clinical response, and the possible basis of the interaction. METHODS: The main outcome was change in depressive symptoms at 12 weeks, measured using the Quick Inventory for Depressive Symptoms-self report version 16 (QIDS-SR16). We examined the relationship between symptoms and lamotrigine levels, and biochemical measures of one-carbon metabolism and functional polymorphisms in catechol-O-methyltransferase (COMT), methylene tetrahydrofolate reductase (MTHFR) and folate hydrolase 1 (FOLH1). RESULTS: Lamotrigine levels were unaffected by FA and did not differ between those participants who achieved remission and those with persisting symptoms. When participants with subtherapeutic serum levels were excluded, there was a main effect of lamotrigine on the main outcome, although this remained limited to those randomized to FA placebo. None of the biochemical measures correlated with clinical outcome. The negative impact of FA on lamotrigine response was limited to COMT Met carriers. FOLH1 and MTHFR had no effect. CONCLUSIONS: Our results clarify that FA's inhibition of lamotrigine's efficacy is not a pharmacokinetic effect, and that low serum lamotrigine levels contributed to lamotrigine's lack of a main effect at 12 weeks. We were unable to explain the lamotrigine-FA interaction, but our finding that it is modulated by the COMT genotype provides a starting point for follow-on neurobiological investigations. More broadly, our results highlight the value of including biochemical and genetic indices in randomized clinical trials.

Dynamic preload markers to predict fluid responsiveness during and after major gastrointestinal surgery: an observational substudy of the OPTIMISE trial.

BACKGROUND: Stroke volume variation (SVV) and pulse pressure variation (PPV), termed dynamic markers of preload responsiveness, may predict the response to i.v. fluid in critically ill patients. However, the predictive accuracy of these variables during gastrointestinal surgery remains uncertain. METHODS: Observational study of patients aged ≥50 yr undergoing major gastrointestinal surgery, enrolled in the OPTIMISE trial. Patients received six 250 ml fluid challenges with i.v. colloid solution (three during and three after surgery), while SVV and PPV were measured using the LiDCOrapid monitor (LiDCO Ltd, UK). Fluid responsiveness was defined as a stroke volume increase ≥10%. Area under the receiver operating characteristic curve was calculated with 95% confidence intervals. Adjustment for covariates was performed by regression modelling and a clustering method was used to adjust for intra-patient correlation. RESULTS: One hundred patients were recruited between August 2010 and October 2012. Five hundred and fifty-six fluid challenges were administered and 159 (28.6%) were associated with increased stroke volume. The predictive value of both variables was poor during surgery [SVV 0.69 (0.63-0.77); PPV 0.70 (0.62-0.77)], and also after surgery [SVV 0.69 (0.63-0.78); PPV 0.64 (0.56-0.73)]. The findings were similar when analysed according to whether patients were mechanically ventilated [SVV 0.68 (0.63-0.77); PPV 0.69 (0.61-0.77)] or breathing spontaneously [SVV 0.69 (0.61-0.77); PPV 0.63 (0.56-0.72)]. Predictive value improved slightly in a sensitivity analysis excluding outlier values of SVV and PPV. CONCLUSIONS: In this study, the predictive accuracy of SVV and PPV for fluid responsiveness was insufficient to recommend for routine clinical use during or after major gastrointestinal surgery.

Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort.

INTRODUCTION: Faecal peritonitis (FP) is a common cause of sepsis and admission to the intensive care unit (ICU). The Genetics of Sepsis and Septic Shock in Europe (GenOSept) project is investigating the influence of genetic variation on the host response and outcomes in a large cohort of patients with sepsis admitted to ICUs across Europe. Here we report an epidemiological survey of the subset of patients with FP. OBJECTIVES: To define the clinical characteristics, outcomes and risk factors for mortality in patients with FP admitted to ICUs across Europe. METHODS: Data was extracted from electronic case report forms. Phenotypic data was recorded using a detailed, quality-assured clinical database. The primary outcome measure was 6-month mortality. Patients were followed for 6 months. Kaplan-Meier analysis was used to determine mortality rates. Cox proportional hazards regression analysis was employed to identify independent risk factors for mortality. RESULTS: Data for 977 FP patients admitted to 102 centres across 16 countries between 29 September 2005 and 5 January 2011 was extracted. The median age was 69.2 years (IQR 58.3-77.1), with a male preponderance (54.3%). The most common causes of FP were perforated diverticular disease (32.1%) and surgical anastomotic breakdown (31.1%). The ICU mortality rate at 28 days was 19.1%, increasing to 31.6% at 6 months. The cause of FP, pre-existing co-morbidities and time from estimated onset of symptoms to surgery did not impact on survival. The strongest independent risk factors associated with an increased rate of death at 6 months included age, higher APACHE II score, acute renal and cardiovascular dysfunction within 1 week of admission to ICU, hypothermia, lower haematocrit and bradycardia on day 1 of ICU stay. CONCLUSIONS: In this large cohort of patients admitted to European ICUs with FP the 6 month mortality was 31.6%. The most consistent predictors of mortality across all time points were increased age, development of acute renal dysfunction during the first week of admission, lower haematocrit and hypothermia on day 1 of ICU admission.

Serum haptoglobin-matrix metalloproteinase 9 (Hp-MMP 9) complex as a biomarker of systemic inflammation in cattle.

A reliable and specific test that discriminates between acute neutrophil activation and chronic inflammatory disease may be useful in clinical decision making in a variety of conditions encountered in veterinary medical practice. An ELISA specific for neutrophil-derived haptoglobin-matrix metalloproteinase 9 (Hp-MMP 9) complexes was used to determine serum concentrations of Hp-MMP 9 and was compared to ELISA assays for Haptoglobin (Hp) and matrix metalloproteinase 9 (MMP 9) in 15 animals with acute sepsis, 10 animals with chronic inflammatory or metabolic disease and 10 healthy cows. Animal disease classifications were completed prior to the determination of serum concentrations of the 3 proteins. Duration of illness, disease process and lesions observed at necropsy were used to place animals into a specific classification. The serum MMP 9 concentrations in healthy cows differed significantly from those measured in sera of acutely septic and chronically ill animals. Serum haptoglobin concentrations in healthy cows were negligible when compared to animals with acute septic or chronic diseases. There was substantial overlap in MMP 9 and Hp concentrations between acute and chronic disease animals. In contrast, serum concentrations of Hp-MMP 9 complexes found almost exclusively in sera from acutely septic animals but not in chronically ill and normal cattle. The Hp-MMP 9 ELISA may be the serological test of choice in the determination of systemic inflammation associated with bacterial sepsis.

Mortality and utilisation of critical care resources amongst high-risk surgical patients in a large NHS trust.

Previous reports describe a population of non-cardiac surgical patients at high risk of complications and death. Outcomes are sub-optimal for such patients, perhaps in part related to inadequate provision or ineffective utilisation of critical care resources. In this study, data describing 26,051 in-patient non-cardiac surgical procedures performed in a large NHS Trust between April 2002 and March 2005 were extracted from local databases. Of these procedures, 2 414 (9.3%) were high risk with an overall mortality rate of 12.2% and a prolonged hospital stay (high-risk population median (IQR) 16 (9-30) days vs standard risk 3 (2-6) days). Mortality rates for specific procedures were consistent with UK averages. However, only 852 (35.3%) high-risk patients were admitted to a critical care unit at any stage after surgery. Of 294 high-risk patients who died, only 144 (49.0%) were admitted to a critical care unit at any time and only 75 (25.6%) of these deaths occurred within a critical care area. Mortality rates were high amongst patients discharged and readmitted to critical care (37.7%) and amongst those admitted to critical care following initial postoperative care on a standard ward (29.9%). These data suggest that the outcome of high-risk general surgical patients could be improved by adequate provision and more effective utilisation of critical care resources.

Peptidoglycan of Staphylococcus aureus upregulates monocyte expression of CD14, Toll-like receptor 2 (TLR2), and TLR4 in human blood: possible implications for priming of lipopolysaccharide signaling.

Previous studies have indicated that peptidoglycan (PepG) from gram-positive bacteria can exert a priming effect on the innate immune response to lipopolysaccharide (LPS) from gram-negative bacteria. Here, we hypothesized that this priming effect may be preceded by enhanced expression of monocyte CD14, Toll-like receptor 2 (TLR2), and TLR4. In an ex vivo whole human blood model, we observed a substantial synergy between LPS and PepG in the release of tumor necrosis factor alpha and interleukin-1beta (IL-1beta) over the 24-h experimental period, whereas the effect on IL-8 and IL-10 release was more time dependent. The priming effect of PepG on cytokine release was preceded by a rapid upregulation of CD14, TLR2, and TLR4 expression on monocytes: at 3 hours there was a twofold increase in CD14 expression (P < 0.03), a fivefold increase in TLR2 expression (P < 0.03), and a twofold increase in TLR4 expression (P < 0.03). CD14 and TLR2 remained upregulated throughout the experimental period following exposure to PepG (P < 0.05). Only a transient upregulation of these monocyte receptors was observed following treatment with LPS or LPS plus PepG. In conclusion, the synergistic effect of LPS and PepG on cytokine release is preceded by a reciprocal upregulation of TLR2 and TLR4 by both bacterial cell wall components.

Incidence and outcome of critical illness amongst hospitalised patients with haematological malignancy: a prospective observational study of ward and intensive care unit based care.

To determine the incidence and outcome of critical illness amongst the total population of hospital patients with haematological malignancy (including patients treated on the ward as well as those admitted to the intensive care unit), consecutive patients with haematological malignancy were prospectively studied. One hundred and one of the 1437 haemato-oncology admissions (7%) in 2001 were complicated by critical illness (26% of all new referrals). Fifty-four (53%) of these critically ill patients survived to leave hospital and 33 (34%) were still alive after 6 months. The majority (77/101) were not admitted to the intensive care unit but were managed on the ward, often with the assistance of the intensive care team. Independent risk factors for dying in hospital included hepatic failure (odds ratio 5.3, 95% confidence intervals 1.3-21.2) and central nervous system failure (odds ratio 14.5, 95% confidence intervals 1.7-120.5). No patient with four or more organ failures or a Simplified Acute Physiology Score II >/= 65 survived to leave hospital. There was close agreement between actual and predicted mortality with increasing Simplified Acute Physiology Score II for all patients, including those not admitted to intensive care.

TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study.

Tumour necrosis factor (TNF) is an important pro-inflammatory cytokine produced in sepsis. Studies examining the association of individual TNF single nucleotide polymorphisms with sepsis have produced conflicting results. This study investigated whether common polymorphisms of the TNF locus and the two receptor genes, TNFRSF1A and TNFRSF1B, influence circulating levels of encoded proteins, and whether individual polymorphisms or extended haplotypes of these genes are associated with susceptibility, severity of illness or outcome in adult patients with severe sepsis or septic shock. A total of 213 Caucasian patients were recruited from eight intensive care units (ICU) in the UK and Australia. Plasma levels of TNF (P = 0.02), sTNFRSF1A (P = 0.005) and sTNFRSF1B (P = 0.01) were significantly higher in those who died on ICU compared to those who survived. There was a positive correlation between increasing soluble receptor levels and organ dysfunction (increasing SOFA score) (sTNFRSF1A R = 0.51, P < 0.001; sTNFRSF1B R = 0.53, P < 0.001), and in particular with the degree of renal dysfunction. In this study, there were no significant associations between the selected candidate TNF or TNF receptor polymorphisms, or their haplotypes, and susceptibility to sepsis, illness severity or outcome. The influence of polymorphisms of the TNF locus on susceptibility to, and outcome from sepsis remains uncertain.

Sequential changes in in vivo muscle and liver protein synthesis and plasma and tissue glutamine levels in sepsis in the rat.

We have investigated sequential changes in skeletal muscle and hepatic protein synthesis following sepsis, and their relationship to changes in circulating and tissue glutamine concentrations. Male Wistar rats underwent caecal ligation and puncture (CLP) or sham operation, with starvation, and were killed 24, 72 or 96 h later. A group of non-operated animals were killed at the time of surgery. Protein synthesis was determined using a flooding dose of L-[4-(3)H] phenylalanine, and glutamine concentrations were measured by an enzymic fluorimetric assay. Protein synthesis in gastrocnemius muscle fell in all groups. Gastrocnemius total protein content was reduced after CLP and at 72 and 96 h after sham operation. After CLP, protein synthesis was lower at 24 h, and total protein content was lower at 72 and 96 h, than in sham-operated animals. CLP was associated with increased liver protein synthesis at all time points, whereas there was no change after sham operation. Liver protein content did not change after CLP, but was lower at 72 and 96 h after sham operation than in non-operated animals. Plasma glutamine concentrations were reduced at 24 h after sham operation, and at 72 and 96 h after CLP. Muscle glutamine concentrations were reduced in all groups, with the decrease being greater following CLP than after sham operation. In the liver, glutamine concentrations were unchanged after CLP, but increased after sham operation. In rats with sepsis, decreases in muscle protein synthesis and content are associated with markedly reduced muscle glutamine concentrations. Plasma glutamine concentrations are initially maintained, but fall later. In liver, protein synthesis is increased, while glutamine concentrations are preserved. These results support a peripheral-to-splanchnic glutamine flux in sepsis.

Differential expression of suppressors of cytokine signalling genes in response to nutrition and growth hormone in the septic rat.

GH treatment during critical illness and sepsis may increase mortality. A family of negative regulators of cytokine signalling, the suppressors of cytokine signalling (SOCS), have been characterised. SOCS provide a mechanism for cross-talk between the cytokine receptors, including GH. Here, we have investigated the impact of nutrition and GH treatment on GH receptor, SOCS1, SOCS-2, SOCS-3 and cytokine-inducible SH2-containing protein (CIS) hepatic mRNA expression in a rat model of sepsis, caecal ligation and puncture (CLP). Four groups of rats were studied: control (food given ad libitum, n=7), CLP only (n=8), CLP and total parenteral nutrition (TPN) (n=9), and CLP, TPN and GH (n=10). CLP rats underwent surgery and 18 h later received saline or TPN or TPN+GH for 6 h before they were killed. Serum IGF-I levels were lower in all CLP groups (P<0.001). The combination of TPN and GH treatment increased IGF-I levels compared with the saline-treated CLP rats (P<0.01), but IGF-I levels remained lower than control animals (P<0.001). GH receptor and GH-binding protein expression in liver was reduced in animals subjected to CLP and was unaffected by nutrition or GH treatment. Hepatic SOCS-1 was detectable in normal rats, induced in all CLP animals but was unaffected by nutrition and GH. Hepatic SOCS-2 expression was difficult to detect in normal and CLP rats but was greatly induced in CLP rats treated with GH. Hepatic SOCS-3 expression was only just detectable in the control group but was elevated in all CLP groups and unaffected by nutrition and GH. Hepatic CIS expression was difficult to detect in normal rats, was not induced by CLP but was induced by both nutrition and GH. In conclusion, CLP induced low IGF-I levels associated with increased expression of SOCS-1 and SOCS-3, both of which are known to inhibit GH receptor signalling. GH induced SOCS-2 and CIS in the CLP rat despite resistance with respect to IGF-I generation, and parenteral feeding induced CIS in the CLP rat. Thus, there is potential for a complex interaction between GH and cytokine signalling at the level of SOCS expression whereby the inflammatory response may alter GH signalling and GH may influence the inflammatory response.

A cell wall component from pathogenic and non-pathogenic gram-positive bacteria (peptidoglycan) synergises with endotoxin to cause the release of tumour necrosis factor-alpha, nitric oxide production, shock, and multiple organ injury/dysfunction in the rat.

The incidence of sepsis and septic shock due to gram-positive organisms has increased dramatically over the last two decades. Interestingly, many patients with sepsis/septic shock have both gram-positive and gram-negative bacteria present in the bloodstream and these polymicrobial or "mixed" infections often have a higher mortality than infection due to a single organism. The reason for this observation is unclear. The aim of this study was to investigate whether cell wall fragments from gram-positive and gram-negative bacteria could synergise to cause the release of cytokines, shock, and organ injury/ dysfunction in vivo. Male Wistar rats were anaesthetised and received an intravenous bolus of vehicle (saline), lipopolysaccharide (LPS) from Escherichia coli (0.1 mg/kg), peptidoglycan (Pep G) from Staphylococcus aureus (S10 mg/kg), co-administration of LPS (0.1 mg/kg) and PepG from S. aureus (10 mg/kg), LPS (10 mg/kg), PepG from Bacillus subtilis, or co-administration of LPS and PepG from B. subtilis. Blood pressure and heart rate were monitored for 6 h before plasma samples were taken for the measurement of TNF-alpha, total nitrite, and biochemical indices of organ injury. Peptidoglycan from both pathogenic (S. aureus) and non-pathogenic (B. subtilis) gram-positive bacteria synergised with endotoxin to cause formation of TNF-alpha, nitrite, shock, and organ injury. Synergism between PepG and LPS may partly explain the high mortality associated with mixed bacterial infections, as well as the deleterious effects of translocation of bacteria, or their cell wall components from the gut lumen in patients with sepsis.

In rats with sepsis, the acute fall in IGF-I is associated with an increase in circulating growth hormone-binding protein levels.

OBJECTIVE: Growth hormone (GH) given to reverse muscle catabolism in critical illness increased mortality, illustrating the need for better understanding of the pathophysiology of the GH axis. We describe the relationship between changes in plasma insulin-like growth factor-I (IGF-I) and growth hormone-binding protein (GHBP) levels and hepatic growth hormone-binding in rats with sepsis. DESIGN: Randomised, controlled study. SETTING: University research laboratory. SUBJECTS: One hundred and eleven male Wistar rats. INTERVENTION: Three groups of rats underwent caecal ligation and puncture (CLP) and three groups laparotomy only (LAP). Survivors were killed at 24, 72, and 96 h. All animals were starved during the study. Twelve rats were killed at the start of the experiment (baseline) and twelve (allowed food) at 96 h. MEASUREMENTS AND RESULTS: Plasma levels of IGF-I and GHBP and binding of 125I-labelled human GH in liver homogenates were measured. IGF-I fell significantly following both CLP and LAP; at 24 h, IGF-I levels were lower after CLP than LAP (950 +/- 74 vs 1,522 +/- 60 microg/l, P = < 0.001). GHBP increased at 24 h following both CLP and LAP (45.6 +/- 1.87 and 47.7 +/- 3.01 vs 38.7 +/- 1.98 ng/ml at baseline, P = < 0.05). In LAP animals GHBP fell to below baseline by 72 h, and significantly so by 96 h (33.5 +/- 1.43, P = < 0.05), whereas GHBP remained elevated 72 h following CLP, returning to baseline by 96 h. The density of GH-binding sites in liver tended to increase, following both CLP and LAP at both 24 and 96 h, but these changes failed to achieve statistical significance. CONCLUSION: Reduced IGF-I levels in sepsis in the rat are associated with elevations in GHBP and a trend to increased hepatic GH binding. This suggests that in sepsis 'GH resistance' is not associated with reduced GH receptor numbers.

Neuromuscular dysfunction in critical illness: what are we dealing with?

Neuromuscular weakness is a very common and debilitating problem for survivors of critical illness. Neurophysiological abnormalities are almost ubiquitous in these patients, and often favour a diagnosis of axonal polyneuropathy, whereas muscle histology, where available, reveals a high incidence of atrophy and necrosis. The precise nature and aetiology of this complex disorder is not yet well understood.