Functional Localization of Adult-Onset Idiopathic Nesidioblastosis.

Nesidioblastosis is a rare pancreatic disorder involving enlarged beta cells throughout the pancreas, causing elevated insulin production. We present the case of a 53-year-old woman with the initial symptom of fasting hypoglycemia. No pancreatic lesions were indicated on computed tomography and magnetic resonance imaging scans, and an octreotide scan was negative for insulinoma. Selective arterial calcium stimulation (SACST) showed increased insulin production from the stimulation of 3 out of 5 arteries. The SACST results suggested a diagnosis of nesidioblastosis, which was confirmed by histopathology after a subtotal distal pancreatectomy. The patient has normal glucose tolerance after surgery with no further problems of hypoglycemia, indicating that this is a rare case of nesidioblastosis extending only partially through the pancreas.

Circulating Microvesicle-Associated Inducible Nitric Oxide Synthase Is a Novel Therapeutic Target to Treat Sepsis: Current Status and Future Considerations.

To determine whether mitigating the harmful effects of circulating microvesicle-associated inducible nitric oxide (MV-A iNOS) in vivo increases the survival of challenged mice in three different mouse models of sepsis, the ability of anti-MV-A iNOS monoclonal antibodies (mAbs) to rescue challenged mice was assessed using three different mouse models of sepsis. The vivarium of a research laboratory Balb/c mice were challenged with an LD80 dose of either lipopolysaccharide (LPS/endotoxin), TNFα, or MV-A iNOS and then treated at various times after the challenge with saline as control or with an anti-MV-A iNOS mAb as a potential immunotherapeutic to treat sepsis. Each group of mice was checked daily for survivors, and Kaplan-Meier survival curves were constructed. Five different murine anti-MV-A iNOS mAbs from our panel of 24 murine anti-MV-A iNOS mAbs were found to rescue some of the challenged mice. All five murine mAbs were used to genetically engineer humanized anti-MV-A iNOS mAbs by inserting the murine complementarity-determining regions (CDRs) into a human IgG1,kappa scaffold and expressing the humanized mAbs in CHO cells. Three humanized anti-MV-A iNOS mAbs were effective at rescuing mice from sepsis in three different animal models of sepsis. The effectiveness of the treatment was both time- and dose-dependent. Humanized anti-MV-A iNOS rHJ mAb could rescue up to 80% of the challenged animals if administered early and at a high dose. Our conclusions are that MV-A iNOS is a novel therapeutic target to treat sepsis; anti-MV-A iNOS mAbs can mitigate the harmful effects of MV-A iNOS; the neutralizing mAb's efficacy is both time- and dose-dependent; and a specifically targeted immunotherapeutic for MV-A iNOS could potentially save tens of thousands of lives annually and could result in improved antibiotic stewardship.

Inducible Nitric Oxide Synthase in Circulating Microvesicles: Discovery, Evolution, and Evidence as a Novel Biomarker and the Probable Causative Agent for Sepsis.

Background: The sepsis pathology remains an enormous medical problem globally because morbidity and mortality remain unacceptably high in septic patients despite intense research efforts. The economic and societal burden of sepsis makes it the most pressing patient care issue in the United States and worldwide. Sepsis is a dysregulated immune response normally initiated by an infection. The need for an early, accurate, and reliable biomarker test to detect the onset of sepsis and for a targeted sepsis therapy are widely recognized in the biomedical community. Content: This report reviews the published findings relevant to microvesicle-associated inducible nitric oxide synthase (MV-A iNOS) as a novel plasma biomarker for the onset of sepsis including human clinical studies and animal studies. Plasma iNOS as a standalone test and as one of the components of a novel panel of biomarkers to stage the progression of sepsis are presented and discussed in comparison to other biomarkers and other proposed panels of biomarkers for sepsis. Summary: The data strongly support the concept that extracellular plasma MV-A iNOS in circulating microvesicles is centrally involved in the initiation of sepsis, and a diagnostic test based upon plasma iNOS can serve as an early pre-symptomatic warning signal for the onset of sepsis. A novel panel of plasma biomarkers comprised of iNOS, pro-IL-18, pro-IL-33, and Reg-1α is proposed as a multianalyte pre-symptomatic method to stage the onset of sepsis for improved prompt data driven patient care.

Pheochromocytoma-Induced Takotsubo Syndrome Treated With Extracorporeal Membrane Oxygenation: Beware of the Apical Sparing Pattern.

A 45-year-old female presents with suspected acute myocardial infarction with cardiogenic shock requiring mechanical circulatory support. Pheochromocytoma-induced atypical Takotsubo syndrome is diagnosed. Clinicians should suspect high catecholamine states as a cause of the basal subtype of atypical Takotsubo syndrome. (Level of Difficulty: Beginner.).

In-hospital post-transplant acute hepatitis A viral (HAV) infection in a liver transplant recipient who was HAV seropositive pre-transplant.

Acute hepatitis A viral (HAV) infection is rare in the liver transplant population due to recommended pre-transplant vaccinations. We report a case of acute hepatitis A infection in a liver transplant recipient. This individual had immunity to hepatitis A with protective IgG antibodies and presented with abnormal liver biochemistry in the post-transplant in-patient setting. Hepatitis A infection was confirmed by positive HAV IgM whereas other etiologies, including acute cellular rejection, were ruled out by laboratory tests and liver biopsies. He was treated conservatively with supportive care and liver enzymes recovered to normal baseline. Despite adequate pre-transplant immunity, in the post-transplant setting there may be loss of protective immunity due to profound immunosuppression and hence hepatitis A should remain an important differential diagnosis in the setting of acute hepatitis.

F-group bZIPs in barley-a role in Zn deficiency.

Zinc (Zn) deficiency negatively impacts the development and health of plants and affects crop yield. When experiencing low Zn, plants undergo an adaptive response to maintain Zn homeostasis. We provide further evidence for the role of F-group transcription factors, AtbZIP19 and AtbZIP23, in responding to Zn deficiency in Arabidopsis and demonstrate the sensitivity and specificity of this response. Despite their economic importance, the role of F-group bZIPs in cereal crops is largely unknown. Here, we provide new insights by functionally characterizing these in barley (Hordeum vulgare), demonstrating an expanded number of F-group bZIPs (seven) compared to Arabidopsis. The F-group barley bZIPs, HvbZIP56 and HvbZIP62, partially rescue the Zn-dependent growth phenotype and ZIP-transporter gene regulation of an Arabidopsis bzip19-4 bzip23-2 mutant. This supports a conserved mechanism of action in adapting to Zn deficiency. HvbZIP56 localizes to the cytoplasm and nucleus when expressed in Arabidopsis and tobacco. Promoter analysis demonstrates that the barley ZIP transporters that are upregulated under Zn deficiency contain cis Zn-deficiency response elements (ZDREs). ZDREs are also found in particular barley bZIP promoters. This study represents a significant step forward in understanding the mechanisms controlling Zn responses in cereal crops, and will aid in developing strategies for crop improvement.

Morphological Convergence Between an Allopolyploid and One of its Parental Species Correlates with Biased Gene Expression and DNA Loss.

The contribution of gene expression modulation to phenotypic evolution is of major importance to an understanding of the origin of divergent or convergent phenotypes during and following polyploid speciation. Here, we analyzed genome-wide gene expression in 2 subspecies of the allotetraploid species, Senecio mohavensis A. Gray, and its diploid parents S. flavus (Decne.) Sch. Bip. and S. glaucus L. The tetraploid is morphologically much more similar to S. flavus, leading to earlier confusion over its taxonomic status. By means of an analysis of transcriptomes of all 3 species, we show that gene expression divergence between the parent species is relatively low (ca. 14% of loci), whereas there is significant unequal expression between ca. 20-25% of the parental homoeologues (gene copies) in the tetraploid. The majority of the expression bias in the tetraploid is in favor of S. flavus homoeologues (ca. 65% of the differentially expressed loci), and overall expression of this parental species subgenome is higher than that of the S. glaucus subgenome. To determine whether absence of expression of a particular S. glaucus homoeologue in the allotetraploid could be due to loss of DNA, we carried out a PCR-based assay and confirmed that in 3 out of 10 loci the S. glaucus homoeologue appeared absent. Our results suggest that biased gene expression is one cause of the allotetraploid S. mohavensis being more similar in morphology to one of its parent, S. flavus, and that such bias could result, in part, from loss of S. glaucus homoeologues at some loci in the allotetraploid.

CPR-associated right ventricular rupture in the setting of pulmonary embolism.

Cardiopulmonary resuscitation (CPR) is an inherently traumatic procedure. Successful resuscitations are often complicated by iatrogenic injuries to structures of the neck, thorax, or abdomen. Rib and sternal fractures are the most frequently induced injuries. However, rare and life-threatening trauma to vital organs such as the heart may also occur during CPR. We describe a novel case of CPR-associated right ventricular rupture in a woman with acute-on-chronic pulmonary embolism and no known pre-existing cardiac disease. We propose that chest compressions in the setting of elevated right ventricular pressure resulted in cardiac rupture, in this case.

Immunophenotyping of ampullary carcinomata allows for stratification of treatment specific subgroups.

BACKGROUND: Ampullary carcinomata (AC) can be separated into intestinal (IT) or pancreatobiliary (PB) subtypes. Although morphological, immunohistochemical and molecular differentiation of IT and PB have been well documented; the prognostic significance of histological subtype and whether patients with either subtype benefit from differential chemotherapeutic regimens remains unclear. METHODS: As part of a larger cohort study, patients who underwent resection for AC or pancreatic ductal adenocarcinoma (PDAC) were retrospectively identified. Clinicopathological covariates and outcome were obtained and MUC1, MUC2, CDX2 and CK20 were assessed with immunohistochemistry. RESULTS: Of 99 ACs, the resultant immunophenotypes indicated 48% and 22% were IT and PB, respectively. Thirty (30%) cases were quadruple negative (QN). Within the PDAC cohort (N = 257), the most prevalent immunophenotype was QN (53%). Subsequently, all QN ACs were classified as PB immunohistochemically yielding 47.5% and 52.5% classified as IT and PB, respectively. Involved regional lymph nodes and elevated T-stage were significantly associated with PB compared with IT AC (p = 0.0032 and 0.0396, respectively). Progression-free survival revealed inferior survival for PB versus IT AC (p = 0.0156). CONCLUSIONS: AC can be classified into prognostic groups with unique clinicopathological characteristics using immunohistochemistry. Immunophenotypical similarity of PB and PDAC suggests that treatment regimens similar to those used in PDAC should be explored.

Tumor budding is an independent adverse prognostic factor in pancreatic ductal adenocarcinoma.

Tumor budding is a well-established adverse prognostic factor in colorectal cancer. However, the significance and diagnostic reproducibility of budding in pancreatic carcinoma requires further study. We aimed to assess the prognostic significance of tumor budding in pancreatic ductal adenocarcinoma, determine its relationship with other clinicopathologic features, and assess interobserver variability in its diagnosis. Tumor budding was assessed in 192 archival cases of pancreatic ductal adenocarcinoma using hematoxylin and eosin (H&E) sections; tumor buds were defined as single cells or nonglandular clusters composed of <5 cells. The presence of budding was determined through assessment of all tumor-containing slides, and associations with clinicopathologic features and outcomes were analyzed. Six gastrointestinal pathologists participated in an interobserver variability study of 120 images of consecutive tumor slides stained with H&E and cytokeratin. Budding was present in 168 of 192 cases and was associated with decreased overall survival (P=0.001). On multivariable analysis, tumor budding was prognostically significantly independent of stage, grade, tumor size, nodal status, lymphovascular invasion, and perineural invasion. There was substantial agreement among pathologists in assessing the presence of tumor budding using both H&E (K=0.63) and cytokeratin (K=0.63) stains. The presence of tumor budding is an independent adverse prognostic factor in pancreatic ductal carcinoma. The assessment of budding with H&E is reliable and could be used to better risk stratify patients with pancreatic ductal adenocarcinoma.

Drug-induced fulminant hepatic failure in pregnancy.

Liver disease in pregnancy can be classified as predating, co-incidental or unique to pregnancy. Medications are often overlooked as a significant cause of liver disease. We present the case of a 39-year-old patient who presented at 20 weeks with jaundice, elevated liver enzymes, and abnormal liver function progressing eventually to fulminant hepatic failure. The patient was on methyldopa and labetalol from 12 weeks' gestational age. Liver biopsy was consistent with drug-induced liver injury. Both methyldopa and labetalol have been associated with hepatotoxicity including liver failure. This case highlights the importance of including medications as a cause of liver failure in pregnant patients.

The impact of work-limiting disability on labor force participation.

According to the justification hypothesis, non-employed individuals may over-report their level of work limitation, leading to biased census/survey estimates of the prevalence of severe disabilities and the associated labor force participation rate. For researchers studying policies which impact the disabled or elderly (e.g., Supplemental Security Income, Disability Insurance, and Early Retirement), this could lead to significant bias in key parameters of interest. Using the American Community Survey, we examine the potential for both inflated and deflated reported disability status and generate a general index of disability, which can be used to reduce the bias of these self-reports in other studies. We find that at least 4.8 million individuals have left the labor force because of a work-limiting disability, at least four times greater than the impact implied by our replication of previous models.

Primary hepatic neuroendocrine tumour requiring live donor liver transplantation: case report and concise review.

Primary hepatic neuroendocrine tumours are rare tumours effecting relatively young patients. As metastatic neuroendocrine tumours to the liver are much more common, extensive investigations are crucial to exclude a primary tumour elsewhere. We report a case of a 27 year old woman who presented with fatigue, increased abdominal girth and feeling of early satiety and bloating. Extensive work up failed to show tumour at another primary site. Hepatic artery embolization showed no effect, so the patient underwent total hepatectomy and live-donor liver transplant. Grossly the tumour measured 27 cm. Microscopic examination showed bland, monomorphic cells growing in tubuloglandular and trabecular growth patterns. Cells were positive for neuroendocrine (synaptophysin, chromogranin, CD56) and epithelial markers (MOC31, CK7, CK19). Cytoplasmic dense neurosecretory vesicles were seen on ultrastructural examination. Based on the Ki-67 rate, mitotic count, lack of marked nuclear atypia and absence of necrosis, a diagnosis of primary neuroendocrine grade 2 was conferred.

Mucinous carcinoma in Crohn's disease originating in a fistulous tract.

Malignant disease, including mucinous carcinomas of the colorectum, may complicate long-standing Crohn's disease. An 18-year-old male with extensive small and large bowel involvement with Crohn's disease developed recurrent peri-rectal fistulous disease that persisted for more than a decade despite pharmacological and surgical therapy as well as later therapy with biological agents. Eventually, an extensive and difficult-to-detect mucinous carcinoma developed in the fistulous tract. Although fistula cancer is rarely described in Crohn's disease, use of immunosuppressant and biological agents may play an initiating or exacerbating role in its development or progression. As potent biological agents are frequently used, often to avoid surgical treatment, clinicians should have an increasingly high index of suspicion for this potential complication, especially if fistulous drainage persists and remains refractory to medical therapy.