Meta-analysis of in-hospital delay before surgery as a risk factor for complications in patients with acute appendicitis.

BACKGROUND: The traditional fear that every case of acute appendicitis will eventually perforate has led to the generally accepted emergency appendicectomy with minimized delay. However, emergency and thereby sometimes night-time surgery is associated with several drawbacks, whereas the consequences of surgery after limited delay are unclear. This systematic review aimed to assess in-hospital delay before surgery as risk factor for complicated appendicitis and postoperative morbidity in patients with acute appendicitis. METHODS: PubMed and EMBASE were searched from 1990 to 2016 for studies including patients who underwent appendicectomy for acute appendicitis, reported in two or more predefined time intervals. The primary outcome measure was complicated appendicitis after surgery (perforated or gangrenous appendicitis); other outcomes were postoperative surgical-site infection and morbidity. Adjusted odds ratios (ORs) were pooled using forest plots if possible. Unadjusted data were pooled using generalized linear mixed models. RESULTS: Forty-five studies with 152 314 patients were included. Pooled adjusted ORs revealed no significantly higher risk for complicated appendicitis when appendicectomy was delayed for 7-12 or 13-24 h (OR 1·07, 95 per cent c.i. 0·98 to 1·17, and OR 1·09, 0·95 to 1·24, respectively). Meta-analysis of unadjusted data supported these findings by yielding no increased risk for complicated appendicitis or postoperative complications with a delay of 24-48 h. CONCLUSION: This meta-analysis demonstrates that delaying appendicectomy for presumed uncomplicated appendicitis for up to 24 h after admission does not appear to be a risk factor for complicated appendicitis, postoperative surgical-site infection or morbidity. Delaying appendicectomy for up to 24 h may be an acceptable alternative for patients with no preoperative signs of complicated appendicitis.

Systematic review of antibiotic treatment for acute calculous cholecystitis.

BACKGROUND: Intravenous antibiotics are frequently used in the initial management of acute calculous cholecystitis (ACC), although supportive care alone preceding delayed elective cholecystectomy may be sufficient. This systematic review assessed the success rate of antibiotics in the treatment of ACC. METHODS: A systematic search of MEDLINE, Embase and Cochrane Library databases was performed. Primary outcomes were the need for emergency intervention and recurrence of ACC after initial non-operative management of ACC. Risk of bias was assessed. Pooled event rates were calculated using a random-effects model. RESULTS: Twelve randomized trials, four prospective and ten retrospective studies were included. Only one trial including 84 patients compared treatment with antibiotics to that with no antibiotics; there was no significant difference between the two groups in terms of length of hospital stay and morbidity. Some 5830 patients with ACC were included, of whom 2997 had early cholecystectomy, 2791 received initial antibiotic treatment, and 42 were treated conservatively. Risk of bias was high in most studies, and all but three studies had a low level of evidence. For randomized studies, pooled event rates were 15 (95 per cent c.i. 10 to 22) per cent for the need for emergency intervention and 10 (5 to 20) per cent for recurrence of ACC. The pooled event rate for both outcomes combined was 20 (13 to 30) per cent. CONCLUSION: Antibiotics are not indicated for the conservative management of ACC or in patients scheduled for cholecystectomy.

A randomized controlled trial to compare a restrictive strategy to usual care for the effectiveness of cholecystectomy in patients with symptomatic gallstones (SECURE trial protocol).

BACKGROUND: Five to 22 % of the adult Western population has gallstones. Among them, 13 to 22 % become symptomatic during their lifetime. Cholecystectomy is the preferred treatment for symptomatic cholecystolithiasis. Remarkably, cholecystectomy provides symptom relief in only 60-70 % of patients. The objective of this trial is to compare the effectiveness of usual (operative) care with a restrictive strategy using a standardized work-up with stepwise selection for cholecystectomy in patients with gallstones and abdominal complaints. DESIGN AND METHODS: The SECURE-trial is designed as a multicenter, randomized, parallel-arm, non-inferiority trial in patients with abdominal symptoms and ultrasound proven gallstones or sludge. If patients meet the inclusion criteria they will be randomized to either usual care or the restrictive strategy. Patients in the usual care group will be treated according to the physician's knowledge and preference. Patients in the restrictive care group will be treated with interval evaluation and stepwise selection for laparoscopic cholecystectomy. In this stepwise selection, patients strictly meeting the preselected criteria for symptomatic cholecystolithiasis will be offered a cholecystectomy. Patients not meeting these criteria will be assessed for other diagnoses and re-evaluated at 3-monthly intervals. Follow-up consists of web-based questionnaires at 3, 6, 9 and 12 months. The main end point of this trial is defined as the proportion of patients being pain-free at 12 months follow-up. Pain will be assessed with the Izbicki Pain Score and Gallstone Symptom Score. Secondary endpoints will be the proportion of patients with complications due to gallstones or cholecystectomy, the association between the patients' symptoms and treatment and work performance, and ultimately, cost-effectiveness. DISCUSSION: The SECURE trial is the first randomized controlled trial examining the effectiveness of usual care versus restrictive care in patients with symptomatic gallstones. The outcome of this trial will inform clinicians whether a more restrictive strategy can minimize persistent pain in post-operative patients at least as good as usual care does, but at a lower cholecystectomy rate. (The Netherlands National Trial Register NTR4022, 17th December 2012) TRIAL REGISTRATION: The Netherlands National Trial Register NTR4022 http://www.zonmw.nl/nl/projecten/project-detail/scrutinizing-inefficient-use-of-cholecystectomy-a-randomized-trial-concerning-variation-in-practi/samenvatting/.

Germline activating TYK2 mutations in pediatric patients with two primary acute lymphoblastic leukemia occurrences.

The contribution of genetic predisposing factors to the development of pediatric acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in childhood, has not been fully elucidated. Children presenting with multiple de novo leukemias are more likely to suffer from genetic predisposition. Here, we selected five of these patients and analyzed the mutational spectrum of normal and malignant tissues. In two patients, we identified germline mutations in TYK2, a member of the JAK tyrosine kinase family. These mutations were located in two adjacent codons of the pseudokinase domain (p.Pro760Leu and p.Gly761Val). In silico modeling revealed that both mutations affect the conformation of this autoregulatory domain. Consistent with this notion, both germline mutations promote TYK2 autophosphorylation and activate downstream STAT family members, which could be blocked with the JAK kinase inhibitor I. These data indicate that germline activating TYK2 mutations predispose to the development of ALL.

Laparoscopy in cholecysto-choledocholithiasis.

Gallstone disease is one of the most common problems in the gastroenterology and is associated with significant morbidity. It may present as stones in the gallbladder (cholecystolithiasis) or in the common bile duct (choledocholithiasis). At the end of the 1980s laparoscopy was introduced and first laparoscopic cholecystectomy was performed in 1985. The laparoscopic technique for removing the gallbladder is the current treatment of choice, although indications for open surgery exist. To perform laparoscopic cholecystectomy as safe as possible multiple safety measures were developed. The gold standard for diagnosing and removing common bile duct stones is Endoscopic Retrograde Cholangiopancreatography (ERCP). The surgical treatment option for choledocholithiasis is laparoscopic cholecystectomy with common bile duct exploration. If experience is not available, than ERCP followed by elective cholecystectomy is by far the best therapeutic modality. The present review will discuss the use, benefits and drawbacks of laparoscopy in patients with cholecystolithiasis and choledocholithiasis.

Severe Progressive Autism Associated with Two de novo Changes: A 2.6-Mb 2q31.1 Deletion and a Balanced t(14;21)(q21.1;p11.2) Translocation with Long-Range Epigenetic Silencing of LRFN5 Expression.

In a 19-year-old severely autistic and mentally retarded girl, a balanced de novo t(14;21)(q21.1;p11.2) translocation was found in addition to a de novo 2.6-Mb 2q31.1 deletion containing 15 protein-encoding genes. To investigate if the translocation might contribute to developmental stagnation at the age of 2 years with later regression of skills, i.e. a more severe phenotype than expected from the 2q31.1 deletion, the epigenetic status and expression of genes proximal and distal to the 14q21.1 breakpoint were investigated in Ebstein Barr Virus-transformed lymphoblast and primary skin fibroblast cells. The 14q21.1 breakpoint was found to be located between a cluster of 7 genes 0.1 Mb upstream, starting with FBXO33, and the single and isolated LRFN5 gene 2.1 Mb downstream. Only expression of LRFN5 appeared to be affected by its novel genomic context. In patient fibroblasts, LRFN5 expression was 10-fold reduced compared to LRFN5 expressed in control fibroblasts. In addition, a relative increase in trimethylated histone H3 lysine 9 (H3K9M3)-associated DNA starting exactly at the translocation breakpoint and going 2.5 Mb beyond the LRFN5 gene was found. At the LRFN5 promoter, there was a distinct peak of trimethylated histone H3 lysine 27 (H3K27M3)-associated DNA in addition to a diminished trimethylated histone H3 lysine 4 (H3K4M3) level. We speculate that dysregulation of LRFN5, a postsynaptic density-associated gene, may contribute to the patient's autism, even though 2 other patients with 14q13.2q21.3 deletions that included LRFN5 were not autistic. More significantly, we have shown that translocations may influence gene expression more than 2 Mb away from the translocation breakpoint.

The C terminus of the synovial sarcoma-associated SSX proteins interacts with the LIM homeobox protein LHX4.

As a result of the synovial sarcoma-associated t(X;18) translocation, the SS18 gene on chromosome 18 is fused to either one of the three closely related SSX genes on the X chromosome. The SS18 protein is thought to act as a transcriptional co-activator, whereas the SSX proteins are thought to act as transcriptional corepressors. The main SSX-repression domain is located in its C terminus, a domain that is retained in the respective SS18-SSX fusion proteins. Both the SS18 and SSX proteins lack DNA-binding domains. Previously, we found that the SS18 and SS18-SSX fusion proteins may be tethered to DNA targets via the SS18-interacting protein AF10. Here, we set out to isolate proteins that interact with the SSX C-terminal repression domain using a yeast two-hybrid interaction trap. Of the positive clones isolated, two corresponded to the LIM homeobox protein LHX4, a DNA-binding protein that is involved in transcription regulation. An endogenous interaction was subsequently established in mammalian cells via colocalization and coimmunoprecipitation of the respective proteins. Interestingly, the LHX4 gene was previously found to be deregulated in various human leukemias. In addition, it was previously found that LIM homeobox proteins may bind to and activate the glycoprotein-alpha (CGA) promoter. Using LHX4 chromatin immunoprecipitation and CGA-promoter assays, we found that endogenous LHX4 binds to the CGA promoter and that LHX4-mediated CGA activation is enhanced by the SS18-SSX protein, but not by the SSX protein. Taken together, we conclude that this novel protein - protein interaction may have direct consequences for the (de)regulation of SSX and/or SS18-SSX target genes and, thus, for the development of human synovial sarcomas.

Targeted disruption of the synovial sarcoma-associated SS18 gene causes early embryonic lethality and affects PPARBP expression.

The synovial sarcoma-associated protein SS18 (also known as SYT or SSXT) is thought to act as a transcriptional co-activator. This activity appears to be mediated through the SWI/SNF proteins BRG1 and INI1 and the histone acetyl transferase p300. Here, we report that disruption of the mouse Ss18 gene results in a recessive embryonic lethal phenotype, due to placental failure caused by impairment of placental vascularization and/or chorio-allantoic fusion. This phenotype resembles the p300 knockout phenotype, but is distinct from the Brg1 and Ini1 knockout phenotypes. Through expression profiling of knockout embryos, we observed altered expression of genes known to affect placental development, including the peroxisome proliferator-activated receptor-binding protein (Pparbp). Since Pparbp null mutant embryos display a similar, lethal phenotype with placental failure, we suggest that the functional and phenotypic co-linearities between Ss18 and p300 may also include the transcriptional co-activator Pparbp. Additional interbreeding of Ss18 and Ss18l1 (Crest) mutant mice indicates that these two functionally and structurally related genes may act synergistically during critical stages of embryonic development.

Leber's optic neuropathy II. Fluorescein angiographic studies.

Fluorescein angiography was performed in 71 persons at risk to develop Leber's Optic Neuropathy (L.O.N.), in 10 females carriers of this disease and in 5 patients during the acute phase. The examination was performed in three university eye clinics. The angiograms were randomly mixed with an equal number of 'controls' and reviewed in a blind fashion on two occasions by two observers. A scoring system was developed on the basis of the peripapillary microvascular changes known to occur in the acute phase of L.O.N. All 5 patients could be recognised in this manner. In the pictures of one of the clinics, which were of good quality, a significant difference in scoring between the at risk and control groups appeared to exist. The results suggest that carriers also may have the same fluorescein angiographic abnormalities. One man from the at risk group who obtained high abnormal scores-identical to patients in the acute phase-developed L.O.N. 6 months later.

Diffuse retinal pigment epitheliopathy.

19 patients showing the features of diffuse retinal pigment epitheliopathy, as described by Zweng and Little, were studied. Diffuse retinal pigment epitheliopathy resembles both pigment epithelial detachment and central nervous choriopathy, but can be differentiated by the following characteristic features: widespread distribution of small pigment epithelial detachments, little or no leakage visible on the fluorescence angiogram, extensive pigmentary changes, chronic course with exacerbations and remissions, and fair visual prognosis.