Primary colorectal linitis plastica presenting as rapid acute deterioration: a diagnostic dilemma.

We present a rare case of primary colorectal linitis plastica presenting as an acute admission to hospital with a wide range of systemic symptoms, sudden rapid deterioration and subsequent mortality. A postmortem examination revealed a primary linitis plastica of the colon and rectum with diffuse metastatic disease. To our knowledge, this is the first report of primary colorectal linitis plastica presenting as an acute deterioration as a result of extensive metastatic disease.

The role of surgery in the management of "body packers".

INTRODUCTION: The concealment of packets of illegal substances within body cavities is a common technique for drug smuggling worldwide. The goal of our study was to analyze the results of conservative treatment of "body packers", indications for surgical intervention, and postoperative morbidity. METHODS: This is a retrospective study of patients admitted to our hospital and diagnosed as body packers. The diagnostic protocol included an abdominal X-ray and urinalysis for toxic substances. Only patients with gastrointestinal symptoms, signs of intoxication, or a positive urinalysis were admitted for observation. Conservative management included bowel rest and serial abdominal radiographs to confirm the passage per rectum of all foreign bodies. Asymptomatic patients were given laxatives in the emergency department (ED) to promote bowel movements and were not admitted to the hospital. RESULTS: A total of 763 body packers were admitted to the hospital, all of whom were initially treated conservatively. Of these patients, 47 (6 %) developed complications: 28 with bowel obstruction, three with bowel perforation, and 16 with substance intoxication. In patients developing complications, urinalysis for toxic substances was negative in 19 (40 %). Sixteen (34 %) patients who developed complications were successfully managed nonoperatively. Three (6 %) other patients died before surgery: two deaths resulted from acute toxicity (one of them with an acute onset and a negative urinalysis) and the third patient died of bowel perforation. Laparotomy was required in 28 (3.5 %) body packers admitted for observation. Enterotomy and/or gastrotomy to remove the packets were the most frequently performed procedures. Postoperative morbidity occurred in 57 % of patients, with wound infection being the most frequent complication. CONCLUSIONS: Conservative management was effective in 94 % of symptomatic patients. A laparotomy was required in only 3.5 % of cases. The mortality rate in this series was low, resulting from either severe cocaine poisoning from ruptured packets or bowel perforation.

Laparoscopic adrenalectomy: Single centre experience.

BACKGROUND: Laparoscopic adrenalectomy is an attractive alternative to the traditional open approach in the surgical excision of an adrenal gland. It has replaced open adrenalectomy in our institution and we review our experience to date. METHODS: All cases of laparoscopic adrenalectomies in our hospital over eight years (from 2001 to May 2009) were retrospectively reviewed. Patient demographics, diagnosis, length of hospital stay, histology and all operative and post-operative details were evaluated. RESULTS: Fifty-five laparoscopic adrenalectomies (LA) were performed on 51 patients over eight years. The mean age was 48 years (Range 16-86 years) with the male: female ratio 1:2. Twenty-three cases had a right adrenalectomy, 24 had a left adrenalectomy and the remaining four patients had bilateral adrenalectomies. 91% were successfully completed laparoscopically with five converted to an open approach. Adenomas (functional and non functional) were the leading indication for LA, followed by phaeochromocytomas. Other indications for LA included Cushing's disease, adrenal malignancies and rarer pathologies. There was one mortality from necrotising pancreatitis following a left adrenalectomy for severe Cushing's disease, with subsequent death 10 days later. CONCLUSION: Laparoscopic adrenalectomy is effective for the treatment of adrenal tumours, fulfilling the criteria for the ideal minimally invasive procedure. It has replaced the traditional open approach in our centre and is a safe and effective alternative. However, in the case of severe Cushing's disease, laparoscopic adrenalectomy has the potential for significant adverse outcomes and mortality.

Inappropriate prescribing in older residents of Australian care homes.

WHAT IS KNOWN AND OBJECTIVE: The incidence of inappropriate prescribing is higher amongst the older age group than the younger population. Inappropriate prescribing potentially leads to drug-related problems such as adverse drug reactions. We aimed to determine the prevalence of inappropriate prescribing in residents of Tasmanian (Australia) residential care homes using Beers and McLeod criteria. METHODS: Patient demographics, medical conditions and medications were collected from medical records. The patients who fulfilled either Beers or McLeod criteria were identified and the characteristics of these patients were then compared. RESULTS: Data for 2345 residents were collected between 2006 and 2007. There were 1027 (43.8%) patients prescribed at least one inappropriate medication. Beers criteria identified more patients (828 patients, 35.3%) as being prescribed inappropriate medication compared with McLeod criteria (438 patients, 18.7%). Patients taking psychotropic medication/s, more than six medications or diagnosed with five or more medical conditions were more likely to be prescribed an inappropriate medication (P<0.001). The most frequently identified inappropriate medications included benzodiazepines, amitriptyline, oxybutynin and non-steroidal anti-inflammatory drugs. WHAT IS NEW AND CONCLUSION: Inappropriate prescribing, as defined by either Beers criteria or McLeod criteria, is relatively common in Australian nursing homes. The prevalence of inappropriate prescribing, and factors influencing it, are consistent with other countries. Both Beers and McLeod criteria are a general guide to prescribing, and do not substitute for professional judgment.

Hypersulfated low molecular weight heparin with reduced affinity for antithrombin acts as an anticoagulant by inhibiting intrinsic tenase and prothrombinase.

In buffer systems, heparin and low molecular weight heparin (LMWH) directly inhibit the intrinsic factor X-activating complex (intrinsic tenase) but have no effect on the prothrombin-activating complex (prothrombinase). Although chemical modification of LMWH, to lower its affinity for antithrombin (LA-LMWH) has no effect on its ability to inhibit intrinsic tenase, N-desulfation of LMWH reduces its activity 12-fold. To further explore the role of sulfation, hypersulfated LA-LMWH was synthesized (sLA-LMWH). sLA-LMWH is not only a 32-fold more potent inhibitor of intrinsic tenase than LA-LMWH; it also acquires prothrombinase inhibitory activity. A direct correlation between the extent of sulfation of LA-LMWH and its inhibitory activity against intrinsic tenase and prothrombinase is observed. In plasma-based assays of tenase and prothrombinase, sLA-LMWH produces similar prolongation of clotting times in plasma depleted of antithrombin and/or heparin cofactor II as it does in control plasma. In contrast, heparin has no effect in antithrombin-depleted plasma. When the effect of sLA-LMWH on various components of tenase and prothrombinase was examined, its inhibitory activity was found to be cofactor-dependent (factors Va and VIIIa) and phospholipid-independent. These studies reveal that sLA-LMWH acts as a potent antithrombin-independent inhibitor of coagulation by attenuating intrinsic tenase and prothrombinase.

Functional regulation of gamma-aminobutyric acid transporters by direct tyrosine phosphorylation.

Tyrosine phosphorylation regulates multiple cell signaling pathways and functionally modulates a number of ion channels and receptors. Neurotransmitter transporters, which act to clear transmitter from the synaptic cleft, are regulated by multiple second messenger pathways that exert their effects, at least in part, by causing a redistribution of the transporter protein to or from the cell surface. To test the hypothesis that tyrosine phosphorylation affects transporter function and to determine its mechanism of action, we examined the regulation of the rat brain gamma-aminobutyric acid (GABA) transporter GAT1 expressed endogenously in hippocampal neurons and expressed heterologously in Chinese hamster ovary cells. Inhibitors of tyrosine kinases decreased GABA uptake; inhibitors of tyrosine phosphatases increased GABA uptake. The decrease in uptake seen with tyrosine kinase inhibitors was correlated with a decrease in tyrosine phosphorylation of GAT1 and resulted in a redistribution of the transporter from the cell surface to intracellular locations. A mutant GAT1 construct that was refractory to tyrosine phosphorylation could not be regulated by tyrosine kinase inhibitors. Activators of protein kinase C, which are known to cause a redistribution of GAT1 from the cell surface, were additive to the effects of tyrosine kinase inhibitors suggesting that multiple signaling pathways control transporter redistribution. Application of brain-derived neurotrophic factor, which activates receptor tyrosine kinases, up-regulated GAT1 function suggesting one potential trigger for the cellular regulation of GAT1 signaling by tyrosine phosphorylation. These data support the hypothesis that transporter expression and function is controlled by the interplay of multiple cell signaling cascades.

Comparison of heparin- and dermatan sulfate-mediated catalysis of thrombin inactivation by heparin cofactor II.

Heparin and dermatan sulfate activate heparin cofactor II (HCII) comparably, presumably by liberating the amino terminus of HCII to bind to exosite I of thrombin. To explore this model of activation, we systematically substituted basic residues in the glycosaminoglycan-binding domain of HCII with neutral amino acids and measured the rates of thrombin inactivation by the mutants. Mutant D, with changes at Arg(184), Lys(185), Arg(189), Arg(192), Arg(193), demonstrated a approximately 130-fold increased rate of thrombin inactivation that was unaffected by the presence of glycosaminoglycans. The increased rate reflects displacement of the amino terminus of mutant D because (a) mutant D inactivates gamma-thrombin at a 65-fold slower rate than alpha-thrombin, (b) hirudin-(54-65) decreases the rate of thrombin inactivation, and (c) deletion of the amino terminus of mutant D reduces the rate of thrombin inactivation approximately 100-fold. We also examined the contribution of glycosaminoglycan-mediated bridging of thrombin to HCII to the inhibitory process. Whereas activation of HCII by heparin was chain-length dependent, stimulation by dermatan sulfate was not, suggesting that dermatan sulfate does not utilize a template mechanism to accelerate the inhibitory process. Fluorescence spectroscopy revealed that dermatan sulfate evokes greater conformational changes in HCII than heparin, suggesting that dermatan sulfate stimulates HCII by producing more effective displacement of the amino terminus.

Physical mapping of the autoimmune disease susceptibility locus, Bphs: co-localization with a cluster of genes from the TNF receptor superfamily on mouse chromosome 6.

An important approach to understanding complex diseases is to reduce them into well-characterized subphenotypes that are under monogenic control. One such example is Bordetella pertussis toxin-induced histamine sensitization in mice, a subphenotype of experimental allergic encephalomyelitis and experimental allergic orchitis. This subphenotype is controlled by a single locus, Bphs, previously mapped to a 33 cM region on mouse Chromosome (Chr) 6. We achieved considerable reduction of this candidate region and constructed a YAC contig across the refined interval. Our results demonstrate that Bphs is located between D6Mit151 and a newly developed marker, EC108RR, a region containing a small cluster of genes belonging to the TNF receptor superfamily. Sequence and quantitative analysis of the candidate gene, tumor necrosis factor receptor 1 (Tnfr1, p55), indicates that it is unlikely to be Bphs. However, the location of Bphs, together with physiologic effects it shares with Tnfr1 activation, suggest that Bphs may prove to be another member of the TNF receptor superfamily.

Linkage disequilibrium and physical mapping of Pas1 in mice.

By using linkage disequilibrium (LD) analysis in 21 strains of known susceptibility to lung cancer and by assembling a YAC contig, we mapped to a approximately 1.5-Mb region on distal mouse chromosome 6 the Pas1 locus, the major determinant of lung cancer predisposition in mice. Our results, on the basis of haplotype and phenetic analysis, suggest that the Pas1(s) susceptibility allele is shared by several mouse-inbred strains of independent origin, which show either high or intermediate predisposition to lung tumorigenesis. Therefore, the Pas1(s) allele is probably derived from an ancestral mouse rather than from independent mutations of the same gene. We showed the feasibility of LD in common inbred strains for the fine mapping of disease loci, and provided the biological basis and the reagents for the cloning of the Pas1 gene.

Biosynthesis of ricinoleate in castor oil.

Castor oil is 90% ricinoleate (12-hydroxyoleate) and has numerous industrial uses. Components of castor bean (Ricinus communis L.) pose serious problems to processors. Other researchers have cloned the gene for the oleoyl hydroxylase, but transgenic plants produce only about 20% hydroxy fatty acid. To improve such transgenic substitutes for castor, we are using HPLC analysis of castor bean microsomal suspensions to follow the hydroxylase reaction and the movement of 14C-ricinoleate through phospholipid into triacylglycerol. Most labeled ricinoleate is rapidly removed from the phospholipid fraction as free fatty acid and incorporated into triacylglycerol, with triricinolein predominating. Elucidation of the basis for high incorporation of ricinoleate and exclusion of oleate from triacylglycerols will identify genes that can be used to engineer high ricinoleate production in transgenic plants.

Biosynthesis of triacylglycerols containing ricinoleate in castor microsomes using 1-acyl-2-oleoyl-sn-glycero-3-phosphocholine as the substrate of oleoyl-12-hydroxylase.

We have examined the biosynthetic pathway of triacylglycerols containing ricinoleate to determine the steps in the pathway that lead to the high levels of ricinoleate incorporation in castor oil. The biosynthetic pathway was studied by analysis of products resulting from castor microsomal incubation of 1-palmitoyl-2-[14C]oleoyl-sn-glycero-3-phosphocholine, the substrate of oleoyl-12-hydroxylase, using high-performance liquid chromatography, gas chromatography, mass spectrometry, and/or thin-layer chromatography. In addition to formation of the immediate and major metabolite, 1-palmitoyl-2-[14C]ricinoleoyl-sn-glycero-3-phosphocholine, 14C-labeled 2-linoleoyl-phosphatidylcholine (PC), and 14C-labeled phosphatidylethanolamine were also identified as the metabolites. In addition, the four triacylglycerols that constitute castor oil, triricinolein, 1,2-diricinoleoyl-3-oleoyl-sn-glycerol, 1,2-diricinoleoyl-3-linoleoyl-sn-glycerol, 1,2-diricinoleoyl-3-linolenoyl-sn-glycerol, were also identified as labeled metabolites in the incubation along with labeled fatty acids: ricinoleate, oleate, and linoleate. The conversion of PC to free fatty acids by phospholipase A2 strongly favored ricinoleate among the fatty acids on the sn-2 position of PC. A major metabolite, 1-palmitoyl-2-oleoyl-sn-glycerol, was identified as the phospholipase C hydrolyte of the substrate; however, its conversion to triacylglycerols was blocked. In the separate incubations of 2-[14C]ricinoleoyl-PC and [14C]ricinoleate plus CoA, the metabolites were free ricinoleate and the same triacylglycerols that result from incubation with 2-oleoyl-PC. Our results demonstrate the proposed pathway: 2-oleoyl-PC-->2-ricinoleoyl-PC-->ricinoleate-->triacylglycerols. The first two steps as well as the step of diacylglycerol acyltransferase show preference for producing ricinoleate and incorporating it in triacylglycerols over oleate and linoleate. Thus, the productions of these triacylglycerols in this relatively short incubation (30 min), as well as the availability of 2-oleoyl-PC in vivo, reflect the in vivo drive to produce triricinolein in castor bean.

Mutations and phenotype in isolated glycerol kinase deficiency.

We demonstrate that isolated glycerol kinase (GK) deficiency in three families results from mutation of the Xp21 GK gene. GK mutations were detected in four patients with widely differing phenotypes. Patient 1 had a splice-site mutation causing premature termination. His general health was good despite absent GK activity, indicating that isolated GK deficiency can be silent. Patient 2 had GK deficiency and a severe phenotype involving psychomotor retardation and growth delay, bone dysplasia, and seizures, similar to the severe phenotype of one of the first described cases of GK deficiency. His younger brother, patient 3, also had GK deficiency, but so far his development has been normal. GK exon 17 was deleted in both brothers, implicating additional factors in causation of the severe phenotype of patient 2. Patient 4 had both GK deficiency with mental retardation and a GK missense mutation (D440V). Possible explanations for the phenotypic variation of these four patients include ascertainment bias; metabolic or environmental stress as a precipitating factor in revealing GK-related changes, as has previously been described in juvenile GK deficiency; and interactions with functional polymorphisms in other genes that alter the effect of GK deficiency on normal development.

Characterization of oleoyl-12-hydroxylase in castor microsomes using the putative substrate, 1-acyl-2-oleoyl-sn-glycero-3-phosphocholine.

We have characterized the oleoyl-12-hydroxylase in the microsomal fraction of immature castor bean using the putative substrate, 1-acyl-2-oleoyl-sn-glycero-3-phosphocholine (2-oleoyl-PC). Previous characterizations of this enzyme used oleoyl-CoA as substrate and relied on the enzyme transferring oleate from oleoyl-CoA to lysophosphatidylcholine to form 2-oleoyl-PC (acyl-CoA:lysophosphatidylcholine acyltransferase) in addition to oleoyl-12-hydroxylase. The present assay system and characterization use 2-oleoyl-PC as substrate (oleoyl-12-hydroxylase alone). Use of the actual substrate for assay purposes is important for the eventual purification of the oleoyl-12-hydroxylase. Ricinoleate (product of oleoyl-12-hydroxylase) and linoleate (product of oleoyl-12-desaturase) were identified as metabolites of oleate of 2-oleoyl-PC by high-performance liquid chromatography and gas chromatography/mass spectrometry. The activity of oleoyl-12-hydroxylase in the microsomal fraction reached a peak about 44 d after anthesis of castor, while the activity of oleoyl-12-desaturase reached a peak about 23 d after anthesis. The optimal temperature for the oleoyl-12-hydroxylase was about 22.5 degrees C, and the optimal pH was 6.3. Catalase stimulated oleoyl-12-hydroxylase while bovine serum albumin and CoA did not activate oleoyl-12-hydroxylase. The phosphatidylcholine analogue, oleoyloxyethyl phosphocholine, inhibited the activity of oleoyl-12-hydroxylase. These results further support the hypothesis that the actual substrate of oleoyl-12-hydroxylase is 2-oleoyl-PC.

Isolation and characterization of a MAGE gene family in the Xp21.3 region.

A human gene with strong homology to the MAGE gene family located in Xq27-qter has been isolated by using exon-trapping of cosmids in the Xp21.3 region. We have mapped and sequenced cDNA and genomic clones corresponding to this gene, MAGE-Xp, and shown that the last exon contains the open reading frame and is present in a minimum of five copies in a 30-kb interval. MAGE-Xp is expressed only in testis and, unlike the Xq27-qter MAGE genes, it is not expressed in any of 12 different tumor tissues tested. However, the gene and predicted protein structure are conserved, suggesting a similar function. MAGE-Xp is located in the 160-kb critical interval defined for the locus involved in sex determination within Xp21 and is 50 kb distal to the DAX-1 gene, which is responsible for X-chromosome-linked adrenal hypoplasia congenita.

Neonatal outcome of fetuses with urinary tract abnormalities diagnosed by prenatal ultrasonography.

Between 1979 and 1986 an abnormality of the urinary tract was diagnosed by prenatal ultrasound examination in 93 fetuses. Postnatal investigation at a large teaching hospital showed a definite abnormality in 85 infants, 66 of whom were boys. An obstructed urinary tract, usually requiring surgery, was present in 46 infants. Other abnormalities included a multicystic kidney (in 15 infants), vesicoureteric reflux (in 9), prune-belly syndrome (in 5) and polycystic kidneys (in 5). Early recognition and treatment of urinary tract disorders in infants should be accompanied by informed prenatal counselling to minimize parents' anxiety.

Biologically potent analogues of salmon calcitonin which do not contain an N-terminal disulfide-bridged ring structure.

The disulfide bridge formed between the cysteine residues at positions 1 and 7 of salmon calcitonin (sCT) is not required for biological activity. The analogues [Ala1,7]sCT,[AcmCys1,7]sCT and [AmcCys1,Ala7]sCT (AcmC = S-acetamido-methylcysteine) are linear sequences which retain full hypocalcemic activity in the intact rat and ability to activate adenylate cyclase of rat renal membranes. The secondary structure of these peptides in aqueous solution in the presence or absence of lipid is not greatly perturbed by the opening of the disulfide ring. In contrast with salmon calcitonin, substitution of Cys by AcmCys in human calcitonin results in greatly reduced hypocalcemic activity but no loss in the ability of the peptide to activate renal adenylate cyclase. Thus in vitro activation of adenylate cyclase by human calcitonin analogues is not always correlated with in vivo hypocalcemic potency.

CT in advanced gastric carcinoma: is exploratory laparotomy avoidable?

The value of CT in the staging and assessment of resectability is demonstrated in 40 patients with advanced gastric carcinoma. The accuracy of CT using the pTNM classification of gastric carcinoma was 90% in the T category, 52.5% in the N category, 80% in the M category, and 72.5% as regards the correct staging. CT estimation of resectability was 80% correct. Based on these results, exploratory laparotomy is essential to evaluate the operability of gastric carcinoma. Exploratory laparotomy can only be avoided in patients with a proximal gastric carcinoma with clear CT demonstration of organ infiltration, N3 lymph node metastases, and distant metastases.