The primary prevention of pancreatic fistula using a vascularised rectus abdominis muscle flap - A porcine model.

Background: A pancreatic fistula is one of the most devastating complications following a Whipple's procedure. Fistula rates remain high despite various modifications to surgical techniques. We propose the use of a vascularised muscle flap in the primary prevention of pancreatic fistulas. Method: A distal pancreatectomy was performed on 5 pigs in our porcine model. A pancreaticojejunal (PJ) anastomotic leak was simulated. The pigs were divided into treatment (4 pigs) and control groups (1 pig). A left pedicled rectus abdominis flap was wrapped around the PJ anastomosis for the treatment group and omitted for the control group. Serum and drain amylase levels were recorded. The PJ-rectus abdominis flap complex was evaluated histologically. Results: There was no biochemical evidence of anastomotic leak in the treatment group. The drain-serum amylase ratio was less than 1.5 in the treatment group (p=0.006). Microscopically, the muscle adjacent to the anastomotic leak showed mild necrotic changes with an affected muscle depth of less than 10%. Conclusion: The vascularised rectus abdominis muscle is a durable flap to withstand proteolytic pancreatic enzymes. It is able to provide a water-tight seal around the PJ anastomosis and mitigate intraperitoneal haemorrhage and infection caused by erosion from the pancreatic fistula.

A tumour-resident Lgr5+ stem-cell-like pool drives the establishment and progression of advanced gastric cancers.

Gastric cancer is among the most prevalent and deadliest of cancers globally. To derive mechanistic insight into the pathways governing this disease, we generated a Claudin18-IRES-CreERT2 allele to selectively drive conditional dysregulation of the Wnt, Receptor Tyrosine Kinase and Trp53 pathways within the gastric epithelium. This resulted in highly reproducible metastatic, chromosomal-instable-type gastric cancer. In parallel, we developed orthotopic cancer organoid transplantation models to evaluate tumour-resident Lgr5+ populations as functional cancer stem cells via in vivo ablation. We show that Cldn18 tumours accurately recapitulate advanced human gastric cancer in terms of disease morphology, aberrant gene expression, molecular markers and sites of distant metastases. Importantly, we establish that tumour-resident Lgr5+ stem-like cells are critical to the initiation and maintenance of tumour burden and are obligatory for the establishment of metastases. These models will be invaluable for deriving clinically relevant mechanistic insights into cancer progression and as preclinical models for evaluating therapeutic targets.

Prescription stimulant use is associated with earlier onset of psychosis.

A childhood history of attention deficit hyperactivity disorder (ADHD) is common in psychotic disorders, yet prescription stimulants may interact adversely with the physiology of these disorders. Specifically, exposure to stimulants leads to long-term increases in dopamine release. We therefore hypothesized that individuals with psychotic disorders previously exposed to prescription stimulants will have an earlier onset of psychosis. Age of onset of psychosis (AOP) was compared in individuals with and without prior exposure to prescription stimulants while controlling for potential confounding factors. In a sample of 205 patients recruited from an inpatient psychiatric unit, 40% (n = 82) reported use of stimulants prior to the onset of psychosis. Most participants were prescribed stimulants during childhood or adolescence for a diagnosis of ADHD. AOP was significantly earlier in those exposed to stimulants (20.5 vs. 24.6 years stimulants vs. no stimulants, p < 0.001). After controlling for gender, IQ, educational attainment, lifetime history of a cannabis use disorder or other drugs of abuse, and family history of a first-degree relative with psychosis, the association between stimulant exposure and earlier AOP remained significant. There was a significant gender × stimulant interaction with a greater reduction in AOP for females, whereas the smaller effect of stimulant use on AOP in males did not reach statistical significance. In conclusion, individuals with psychotic disorders exposed to prescription stimulants had an earlier onset of psychosis, and this relationship did not appear to be mediated by IQ or cannabis.

Early prodromal symptoms can predict future psychosis in familial high-risk youth.

BACKGROUND: Efforts to predict psychosis in individuals at high risk for schizophrenia have focused on the identification of sub-threshold clinical criteria and neurobiological markers, including neuropsychological assessment, structural and functional brain imaging, and psychophysiological testing. We sought to evaluate the relative utility of "psychosis-proneness" measures for prospective prediction of psychotic disorders in a group of young relatives at familial risk for schizophrenia. METHODS: We examined the receiver operating characteristics of sub-threshold symptoms in predicting conversion to psychosis in a group of 97 young first- and second- degree relatives of persons with schizophrenia over a 2-year period. Towards this end, we utilized the Structured Interview of prodromal symptoms to derive measures of two of the four Scale of Prodromal Symptoms subscales (positive and disorganized) and the Chapman Magical Ideation and Perceptual Aberration scales. These four measures were, together, taken to reflect a putative index of psychosis-proneness. RESULTS: Eleven of the 97 subjects developed a psychotic disorder over 2 years of follow-up. Seventeen of the 97 subjects tested positive on this index of psychosis-proneness at baseline and of these 10 converted to psychosis. The sensitivity and specificity of the test were 91 percent and 92 percent respectively. The positive predictive value of the test was 59 percent and its negative predictive value was 99 percent. Addition of measures of cognitive or social function to the index decreased its predictive ability, reducing its specificity and/or sensitivity. CONCLUSIONS: A relatively simple set of clinical measures can be utilized to prospectively identify familial high risk individuals who convert to psychosis with high specificity and sensitivity. Implications for the proposed addition of an "attenuated psychosis syndrome" in DSM-5 are discussed.

Differential processing of metacognitive evaluation and the neural circuitry of the self and others in schizophrenia: a pilot study.

BACKGROUND: Impaired awareness of the self and others (i.e., metacognitive evaluations) are seen in schizophrenia. We compared patterns of activation in schizophrenia (SZ) and nonclinical subjects during a functional magnetic resonance imaging (fMRI) task of metacognitive evaluations that has been demonstrated to engage the neural circuitry of the self in healthy subjects. METHODS: Eleven SZ subjects (7 males, mean age 26.6+/-8) and 10 healthy control subjects (4 males, mean age 29.6+/-8.4) were enrolled. Participants completed two runs of a metacognitive evaluation task (self vs. other vs. word meaning). fMRI data was obtained using a full body Bruker MedSped 4.0Tesla system. Group contrasts were performed using an uncorrected p<0.005 with a 50voxel extent threshold. RESULTS: We observed a significant hypoactivation in the left superior temporal sulcus (STS) during metacognitive evaluations of others (OE) vs. semantic positivity evaluations (SPE) and a trend toward significant hypoactivation in the OE vs. self evaluations (SE) in the SZ group. Significant hypoactivation was also seen in the right inferior temporal gyrus (ITG) in the OE vs. SE contrasts in the SZ group. A trendworthy hypoactivation was seen in the SZ group in the right middle frontal gyrus and pole of the left STS during OE vs. SPE and SE contrasts respectively. CONCLUSIONS: These results extend previous findings of impaired metacognitive evaluative processes in schizophrenia to aberrations of the neural circuitry implicated in self/other awareness among SZ patients. Greater understanding of the neural basis of deficits of self/other awareness in early schizophrenia may contribute to improvements in the identification and treatment of individuals at risk for the illness.

Hippocampus and amygdala in schizophrenia: assessment of the relationship of neuroanatomy to psychopathology.

The hippocampus and amygdala are believed to be involved in the pathology of schizophrenia. In this study, we attempted to replicate the reported bilateral volume reduction of the hippocampus and amygdala and to study the relationship of the volumes of these structures to the symptoms of schizophrenia. The hippocampus-amygdala complex (HAC) was manually traced on 3-mm coronal T(1)-weighted MRIs, resampled into 1-mm coronal slices, from 20 male patients with schizophrenia and 20 age-matched male controls. The complex was divided into three parts: anterior one-third representing the amygdala and middle and posterior thirds representing the anterior and posterior halves of the hippocampus. Positive and negative symptoms and severity of hallucinations and thought disorder (conceptual disorganization) were quantified using the Brief Psychiatric Rating Scale (BPRS). None of the above structures, controlled for brain volume, differed significantly in patients compared with normal controls. When the relationship between volumes and symptoms was examined, the left HAC was found to inversely correlate with thought disorder and negative symptoms. Specifically, significant inverse correlations were found between (i) left amygdala and thought disorder, (ii) left hippocampus and negative symptoms, and (iii) left anterior and posterior hippocampus volumes and positive and negative symptoms, respectively. Our findings further support the role of the HAC in the pathophysiology of schizophrenia and suggest unique associations between individual structures and specific symptoms of the illness.

Prevalence of cavum septum pellucidum in schizophrenia studied with MRI.

OBJECTIVE: To study the prevalence of cavum septum pellucidum (CSP), a midline developmental anomaly, in patients with schizophrenia. METHODS: Three-millimeter coronal T1 weighted MRI images of 43 normal controls and 73 patients with schizophrenia were examined. The images were resampled into 1-mm slices and CSP was measured by the number of slices in which it appeared. RESULTS: Patients had significantly higher incidence of CSP (Fisher's exact test 0.042; one-sided). Eighteen (41.9%) of the controls and 44 (60.3%) of patients had a CSP, and one of 46 controls and three of 73 patients had a large CSP of six slices or more. There was no relationship between the presence or size of CSP and regional brain volumes or volumes of hippocampus-amygdala complex, caudate, superior temporal gyrus or ventricular CSF. CONCLUSION: Higher incidence of CSP may reflect a neurodevelopmental disturbance in schizophrenia.

Superior temporal gyrus in schizophrenia: a volumetric magnetic resonance imaging study.

The left superior temporal gyrus (STG) has been reported to be smaller in patients with schizophrenia. The volume of the STG has been found to correlate negatively with severity of hallucinations and thought disorder. In this study, we measured the STG volume of 20 normal controls and 20 patients with schizophrenia using 3 mm contiguous coronal T1 magnetic resonance images. We found that patients had a significantly smaller left anterior STG, and that the volume of this region negatively correlated with the severity of hallucinations. The left posterior STG was not significantly smaller in patients than in controls, but its volume negatively correlated with severity of thought disorder. We also found that the left anterior STG was smaller than the right STG in patients but not in controls. The STG has at least three histologically distinct areas, each with different connections to the rest of the brain. These data are consistent with the proposition that dysfunction of the primary auditory cortex in the anterior and middle STG and auditory association cortex in the posterior STG may play a role in the production of auditory perceptual abnormalities and poor organization of thought respectively.

Acute onset and remission of obsessions and compulsions following medical illnesses and stress.

Obsessive Compulsive Disorder (OCD) is generally chronic. Episodic OCD with complete remission has been rarely reported. Two cases of brief, episodic obsessions and compulsions that appeared for the first time following psychological stress and in the context of medical illness are reported. The possibility of brief episodes of OCD precipitated by stress is illustrated. Exploration of this phenomenon may help us learn more about OCD in general.

Landmark-based registration and measurement of magnetic resonance images: a reliability study.

We report a magnetic resonance imaging (MRI) study in a large number of subjects that examines various analytic techniques for anatomical landmark information. The initial issue involved interrater reliability in locating landmarks along the midsagittal plane. Another issue dealt with using landmarks to register (linear) individual scans for subsequent analyses or more sophisticated registration techniques. We next explore the use of interlandmark distances as indices of brain size. Twenty-seven landmarks were chosen from the midsagittal slice of 101 abnormal subjects. Interrater reliability estimates on a subset of the scans were excellent overall. Rotating to anterior-posterior commissure points was the best of the tested two-point registrations, although an average angular rotation was better. Reliability and validity for landmark-derived measures of size were excellent. Landmark-based analyses offer opportunities to explore shape and size questions, although they are not appropriate for addressing all questions. Under specific conditions, landmark data can be generated quickly and accurately.

Reversibility of brain tissue loss in anorexia nervosa assessed with a computerized Talairach 3-D proportional grid.

We describe the results of our follow-up magnetic resonance imaging (MRI) study of underweight patients with anorexia nervosa, using rigorous methodology to control for head position across time. All subjects first underwent an initial scan and rescan to verify that our computerized three-dimensional co-planar grid method for volume measurement was reliable and accurate, regardless of head positioning. After a period of several months, subjects had a follow-up scan to assess for changes that may have occurred following significant weight gain. Ventricular and total brain volume measurements from the initial scans were compared with the scans from an age- and sex-matched normal control group to determine whether we could replicate previous findings of ventricular enlargement compared with controls and whether brain volume is reduced compared with controls. Anorexic subjects had significantly larger ventricles when compared with normal controls but did not differ significantly in total brain volume. Using a repeated measures analysis of variance, a priori contrasts compared the initial/rescan pair volumes with each other and the initial/rescan pair volumes with the follow-up volume. These analyses showed that ventricular and total brain volumes derived from the initial/rescan pair were nearly identical, but that at follow-up ventricular volume decreased significantly and total brain volume increased significantly after weight gain.

Automatic atlas-based volume estimation of human brain regions from MR images.

OBJECTIVE: MRI offers many opportunities for noninvasive in vivo measurement of structure-function relationships in the human brain. Although automated methods are now available for whole-brain measurements, an efficient and valid automatic method for volume estimation of subregions such as the frontal or temporal lobes is still needed. MATERIALS AND METHODS: We adapted the Talairach atlas to the study of brain subregions. We supplemented the atlas with additional boxes to include the cerebellum. We assigned all the boxes to 1 of 12 regions of interest (ROIs) (frontal, parietal, temporal, and occipital lobes, cerebellum, and subcortical regions on right and left sides of the brain). Using T1-weighted MR scans collected with an SPGR sequence (slice thickness = 1.5 mm), we manually traced these ROIs and produced volume estimates. We then transformed the scans into Talairach space and compared the volumes produced by the two methods ("traced" versus "automatic"). The traced measurements were considered to be the "gold standard" against which the automatic measurements were compared. RESULTS: The automatic method was found to produce measurements that were nearly identical to the traced method. We compared absolute measurements of volume produced by the two methods, as well as the sensitivity and specificity of the automatic method. We also compared the measurements of cerebral blood flow obtained through [15O]H2O PET studies in a sample of nine subjects. Absolute measurements of volume produced by the two methods were very similar, and the sensitivity and specificity of the automatic method were found to be high for all regions. The flow values were also found to be very similar by both methods. CONCLUSION: The automatic atlas-based method for measuring the volume of brain subregions produces results that are similar to manual techniques. The method is rapid, efficient, unbiased, and not subject to the problems of rater drift or potentially poor interrater reliability that plague manual methods. Consequently, this method may be very useful for the study of structure-function relationships in the human brain.

Volume of the pineal gland in schizophrenia; an MRI study.

Pineal gland abnormality has been proposed as a possible biological defect in schizophrenia. This study was designed to investigate volumetric differences of the pineal gland using Magnetic Resonance Imaging (MRI). Patients with a DSM-III-R diagnosis of schizophrenia or schizophreniform disorder (n = 45) and normal controls (n = 86) were scanned using a 1.5 Tesla scanner. The volume of the pineal was obtained by blind manual tracing of the gland on T1 weighted images, using locally developed software, BRAINS. The inter-rater reliability (n = 25) yielded an intraclass r of 0.92. Comparison of the volumes by t-test showed no significant difference between patients and normal controls (p = 0.77). This study, backed by a large sample size, suggests that there are no volumetric differences between schizophrenic patients and controls in regard to the pineal gland.