Impact of STIMUlant and osmotic LAXatives (STIMULAX trial) on gastrointestinal recovery after colorectal surgery: randomized clinical trial.

BACKGROUND: Recovery of gastrointestinal (GI) function is often delayed after colorectal surgery. Enhanced recovery protocols (ERPs) recommend routine laxative use, but evidence of benefit is unclear. This study aimed to investigate whether the addition of multimodal laxatives to an ERP improves return of GI function in patients undergoing colorectal surgery. METHODS: This was a single-centre, parallel, open-label RCT. All adult patients undergoing elective colorectal resection or having stoma formation or reversal at the Royal Adelaide Hospital between August 2018 and May 2020 were recruited into the study. The STIMULAX group received oral Coloxyl® with senna and macrogol, with a sodium phosphate enema in addition for right-sided operations. The control group received standard ERP postoperative care. The primary outcome was GI-2, a validated composite measure defined as the interval from surgery until first passage of stool and tolerance of solid intake for 24 h in the absence of vomiting. Secondary outcomes were the incidence of prolonged postoperative ileus (POI), duration of hospital stay, and postoperative complications. The analysis was performed on an intention-to-treat basis. RESULTS: Of a total of 170 participants, 85 were randomized to each group. Median GI-2 was 1 day shorter in the STIMULAX compared with the control group (median 2 (i.q.r. 1.5-4) versus 3 (2-5.5) days; 95 per cent c.i. -1 to 0 days; P = 0.029). The incidence of prolonged POI was lower in the STIMULAX group (22 versus 38 per cent; relative risk reduction 42 per cent; P = 0.030). There was no difference in duration of hospital day or 30-day postoperative complications (including anastomotic leak) between the STIMULAX and control groups. CONCLUSION: Routine postoperative use of multimodal laxatives after elective colorectal surgery results in earlier recovery of gastrointestinal function and reduces the incidence of prolonged POI. Registration number: ACTRN12618001261202 (www.anzctr.org.au).

Decomposing the constituent oscillatory dynamics underlying mismatch negativity generation in schizophrenia: Distinct relationships to clinical and cognitive functioning.

Abnormalities in early auditory information processing (EAIP) contribute to higher-order deficits in cognition and psychosocial functioning in schizophrenia. A passive auditory oddball paradigm is commonly used to evoke event-related potential (ERP) measures of EAIP reflecting auditory sensory registration and deviance detection, including mismatch negativity (MMN) and P3a responses. MMN and P3a have been extensively studied in healthy subjects and neuropsychiatric patient populations and are increasingly used as translational biomarkers in the development of novel therapeutics. Despite widespread use, relatively few studies have examined the constituent oscillatory elements and the extent to which sensory registration and deviance detection represent distinct or intercorrelated processes. This study aimed to determine the factor structure and clinical correlates of these oscillatory measures in schizophrenia patients (n = 706) and healthy comparison subjects (n = 615) who underwent clinical, cognitive, and functional characterization and EEG testing via their participation in the Consortium of Genomics in Schizophrenia (COGS-2) study. Results revealed significant deficits in theta-band (4-7 Hz) evoked power and phase locking in patients. Exploratory factor analyses of both ERP and oscillatory measures revealed two dissociable factors reflecting sensory registration and deviance detection. While each factor shared a significant correlation with social cognition, the deviance detection factor had a unique relationship to multiple cognitive and clinical domains. Results support the continued advancement of functionally relevant oscillatory measures underlying EAIP in the development of precognitive therapeutics.

Molecular cloning of MIS, a myeloid inhibitory siglec, that binds protein-tyrosine phosphatases SHP-1 and SHP-2.

We describe the molecular cloning and characterization of a novel myeloid inhibitory siglec, MIS, that belongs to the family of sialic acid-binding immunoglobulin-like lectins. A full-length MIS cDNA was obtained from murine bone marrow cells. MIS is predicted to contain an extracellular region comprising three immunoglobulin-like domains (V-set amino-terminal domain followed by two C-set domains), a transmembrane domain and a cytoplasmic tail with two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like sequences. The closest relative of MIS in the siglec family is human siglec 8. Extracellular regions of these two siglecs share 47% identity at the amino acid level. Southern blot analysis suggests the presence of one MIS gene. MIS is expressed in the spleen, liver, heart, kidney, lung and testis tissues. Several isoforms of MIS protein exist due to the alternative splicing. In a human promonocyte cell line, MIS was able to bind Src homology 2-containing protein-tyrosine phosphatases, SHP-1 and SHP-2. This binding was mediated by the membrane-proximal ITIM of MIS. Moreover, MIS exerted an inhibitory effect on FcgammaRI receptor-induced calcium mobilization. These data suggest that MIS can play an inhibitory role through its ITIM sequences.

Characterization of a protein tyrosine phosphatase (RIP) expressed at a very early stage of differentiation in both mouse erythroleukemia and embryonal carcinoma cells.

From our previous studies, several protein tyrosine phosphatases (PTPase) are implicated in the early events leading to in vitro differentiation of both mouse erythroleukemia (MEL) and embryonal carcinoma (F9) cells. Among the PTPases, recent experiments suggest that a new PTPase (RIP) plays a critical role in differentiation processes, particularly at their early stages. We isolated cDNA clones for RIP from a RNA preparation isolated from differentiating MEL cells, and determined the total 7932 bp base sequence for RIP cDNA. The cDNA codes for a putative 269.8 kDa (2450 amino acids) protein with a PTPase catalytic domain. We have demonstrated that the transcripts exist in multiple forms, and among mouse tissues they were found predominantly in kidney and, to a lesser extent, in lung, heart, brain and testis. The RIP gene was mapped between D5Mit90 and D5Mit25 on mouse chromosome 5.

Leukocyte common antigen-related phosphatase (LRP) gene structure: conservation of the genomic organization of transmembrane protein tyrosine phosphatases.

The leukocyte common antigen-related protein tyrosine phosphatase (LRP) is a widely expressed transmembrane glycoprotein thought to be involved in cell growth and differentiation. Similar to most other transmembrane protein tyrosine phosphatases, LRP contains two tandem cytoplasmic phosphatase domains. To understand further the regulation and evolution of LRP, we have isolated and characterized mouse lambda genomic clones. Thirteen genomic clones could be divided into two non-overlapping clusters. The first cluster contained the transcription initiation site and the exon encoding most of the 5' untranslated region. The second cluster contained the remaining exons encoding the protein and the 3' untranslated region. The gene consists of 22 exons spanning over 75 kb. The distance between exon 1 and exon 2 is at least 25 kb. Characterization of the 5' ends of LRP mRNA by S1 nuclease protection identifies putative initiation start sites within a G/C-rich region. The upstream region does not contain a TATA box. Comparison of the LRP gene structure to the mammalian protein tyrosine phosphatase gene, CD45, shows striking similarities in size and genomic organization.

The relationship between long bone growth rate and duodenal calcium transport in female rats.

Studies were carried out to determine the relationship between long bone growth and duodenal calcium (Ca) transport in female rats and the regulation of these two parameters by ovarian hormones. Female rats were ovariectomized (ovx) at 6 weeks of age. Some animals were implanted with silastic implants containing either estradiol or progesterone at the time of ovx. Studies were carried out 3 weeks later when the rats were 9 weeks old. Ovx resulted in an increase in long bone growth rate and duodenal Ca transport without any alteration in circulating levels of parathyroid hormone or 1,25-dihydroxyvitamin D [1,25-(OH)2D]. Animals receiving estradiol exhibited decreased long bone growth rate and duodenal Ca transport relative to ovx animals. These animals were mildly hypercalcemic and had lower levels of 1,25-(OH)2D than ovx or intact animals. The results of these studies suggest that the effects of ovarian hormone status on duodenal Ca transport are more closely related to long bone growth rate than to circulating levels of 1,25-(OH)2D. Further studies are required to determine whether the two parameters are coregulated by some as-yet-unidentified factor or whether bone growth is able to emit some signal, directly or indirectly, to increase duodenal Ca transport.

The effect of low dietary calcium and calcium supplementation on calcium metabolism and bone in the immature, growing rat.

The data presented here were obtained from a series of experiments designed to determine 1) whether normal growth and bone development could be maintained in young, growing rats (3-9 weeks of age) on a diet containing 0.1% Ca, and 2) whether Ca presented in a bolus would be utilized as effectively as the same amount of Ca distributed throughout the diet. Weanling female rats were raised to 9 weeks of age on diets containing 0.4% P and either 0.5% or 0.1% Ca. One group of animals on the 0.1% Ca diet was given oral supplements of CaCO3 twice each day to supply the same amount of Ca consumed by age-matched animals on the 0.5% Ca diet. We found that animals consuming diet containing 0.1% Ca grew at the same rate as animals receiving 0.5% Ca, or 0.1% Ca + supplement for up to 9 weeks of age when the experiment was terminated. Measurement of femur length indicated that long bone length was the same for all animals. However, the 0.1% Ca group exhibited mild hypocalcemia (9.1 mg/dl vs 10.4 for controls), a 2.6-fold elevation in immunoreactive parathyroid hormone, and an increase of similar magnitude in circulating levels of 1,25-dihydroxyvitamin D. Bones from the 0.1% Ca group contained less than half as much Ca as bones from the 0.5% Ca group, and exhibited significant decreases in mid-shaft diaphyseal thickness, % trabecular volume of the distal metaphysis and breaking strength (torsion testing). These results suggest that while a diet containing 0.1% Ca is able to maintain normal growth, bone mineralization is compromised.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics and bacteriological efficacy of mezlocillin in experimental Escherichia coli and Listeria monocytogenes meningitis.

The purpose of this study was to determine the pharmacokinetics and bacteriological effect of mezlocillin in experimental meningitis caused by Listeria monocytogenes and two Escherichia coli strains. The half-life of mezlocillin in cerebrospinal fluid (CSF) was approximately twice that in serum of experimentally infected animals, and the penetration of drug into CSF was 5 to 15% after a single dose and 5 to 20% after continuous-infusion experiments. The bactericidal titer in CSF for both susceptible E. coli and L. monocytogenes was 1:8, whereas for the resistant E. coli strain, titers were less than 1:2 after single doses of 50 or 100 mg of mezlocillin per kg and 1:4 with continuous infusion. After single-dose and continuous-infusion experiments, the bacteriological effect of mezlocillin in experimental L. monocytogenes infections was similar to that of ampicillin. Mezlocillin reduced the colony counts of of susceptible E. coli in CSF by 90% or more after a single dose or continuous infusion but had no appreciable effect on resistant E. coli after a single dose of 50 mg/kg. In contrast, a single dose of 100 mg of mezlocillin per kg eradicated the resistant strain from CSF, despite a bactericidal titer in CSF of less than 1:2. This unexpected finding prompted us to evaluate the effect of serum on the in vitro susceptibilities of selected coliforms to mezlocillin. The activity of mezlocillin against one susceptible and four resistant strains of gram-negative, enteric bacilli was enhanced manyfold by the addition of fresh rabbit serum; this effect was abolished by heating the serum at 56 degrees C for 30 min. This interaction of mezlocillin and serum against coliform bacteria should be examined in a larger number of experimentally infected animals and in specimens obtained from mezlocillin-treated infants.