Retinoic acid receptor ß2 agonists restore glycaemic control in diabetes and reduce steatosis.

AIMS: To investigate the effects of specific retinoic acid receptor (RAR) agonists in diabetes and fatty liver disease. METHODS: Synthetic agonists for RARß2 were administered to wild-type (wt) mice in a model of high-fat-diet (HFD)-induced type 2 diabetes (T2D) and to ob/ob and db/db mice (genetic models of obesity-associated T2D). RESULTS: We show that administration of synthetic agonists for RARß2 to either wt mice in a model of HFD-induced T2D or to ob/ob and db/db mice reduces hyperglycaemia, peripheral insulin resistance and body weight. Furthermore, RARß2 agonists dramatically reduce steatosis, lipid peroxidation and oxidative stress in the liver, pancreas and kidneys of obese, diabetic mice. RARß2 agonists also lower levels of mRNAs involved in lipogenesis, such as sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase, and increase mRNAs that mediate mitochondrial fatty acid ß-oxidation, such as CPT1α, in these organs. RARß2 agonists lower triglyceride levels in these organs, and in muscle. CONCLUSIONS: Collectively, our data show that orally active, rapid-acting, high-affinity pharmacological agonists for RARß2 improve the diabetic phenotype while reducing lipid levels in key insulin target tissues. We suggest that RARß2 agonists should be useful drugs for T2D therapy and for treatment of hepatic steatosis.

[Risk factors for inactivity in patients in long-term care with severe mental illness]. / Risicofactoren voor inactiviteit bij patiënten met ernstige psychiatrische aandoeningen in de langdurige zorg.

BACKGROUND: Inactivity is a major problem in long-stay patients with severe mental illness. Very little research has been done into the variables that can predict and explain this inactivity. AIM: To find associations between inactivity and the variables (psychiatric, pharmacological, lifestyle and comorbidity) of patients with severe mental health illness.methods A cross-sectional study was performed at "Zon en Schild", a centre for mental health care in Amersfoort in the Netherlands. The study included 100 long-stay psychiatric patients hospitalized throughout the period February 2011 till July 2011. All of these patients were being treated with antipsychotics and were long-term inpatients at a psychiatric clinic. At the out-patient clinic of "Zon en Schild"; they were screened for inactivity via a subscale of the Nurses"; Observation Scale for Inpatient Evaluation (NOSIE-30). Data were collected and analysed by means of a validated questionnaire, physical examination and patient records. Simple and multiple regression analyses were performed in order to find associated factors associated with inactivity. RESULTS: We found that 31.3% of the variance predicted by the multiple regression analysis model for inactivity was associated with the variables parkinsonism, negative symptoms, metabolic syndrome, diabetes, body-mass index (BMI), first-generation antipsychotics and combination of first- and second-generation antipsychotics. Age (ß=0.235, p=0.04) and a combination therapy involving traditional and atypical antipsychotics (ß=0.317, p=0.04) were significantly associated with inactivity. CONCLUSION: Age and the combination of first- and second-generation antipsychotics were associated with inactivity. Cross-sectional studies do not demonstrate any causal links, but can generate a hypothesis. One possible hypothesis for the surprising link between inactivity and the combination of traditional and atypical antipsychotics is that the combination of antipsychotics promotes and fosters inactivity.key words clinical, epidemiology, inactivity, long-term care, schizophrenia.

Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease.

Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution's experience with HCT treatment of four Wolman patients, two of whom are long-term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has age-appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center.

Gastric ciliated metaplasia. A study of 3406 gastrectomy specimens from dwellers of the Atlantic and the Pacific basins.

BACKGROUND: Ciliated cells in gastrectomies from patients dwelling in the Pacific and Atlantic basins have been reported previously. AIM: To compare all the results in an attempt to explain the findings. METHODS: Sections from 3406 gastrectomies were reviewed: 1966 and 1440 from the Atlantic and Pacific basins, respectively. Ciliated cells and intestinal metaplasia (IM) were recorded; IM was classified into focal or extensive IM. The total number of sections/gastrectomy was noted. RESULTS: In the Atlantic basin, 5% of specimens had ciliated metaplasia (CM); it was more frequent in intestinal carcinoma (IC; 9%) than diffuse carcinoma (DC; 3%) or miscellaneous gastric diseases (MGD; 3%). In the Pacific basin, the frequency of specimens with CM was 29%: it was more frequent in IC (43%) than in DC (16%) or MGD (10%). The difference between the frequency of CM in specimens with IC or with DC/MGD in the Atlantic and the Pacific basins was significant (p < or = 0.05). The presence of CM was influenced by age and the extent of IM in both basins, but not by sex or the number of sections investigated. CONCLUSIONS: CM-apparently an independent microscopic marker-was significantly higher in the Pacific than in the Atlantic basin. Environmental carcinogens involved in the evolution of IM and IC seem to be implicated in gastric ciliogenesis. Carcinogens that differ in nature and/or in strength in both basins might activate the latent natural genes encoding ciliated processes in gastric cells in patients subsequently developing gastric carcinoma, more notably of intestinal type.

Interobserver variability in the pathological assessment of malignant colorectal polyps.

BACKGROUND: Treatment of patients with malignant large bowel polyps is highly dependent on pathological evaluation. The aim of this study was to evaluate interobserver variability in the pathological assessment of endoscopically removed polyps. METHODS: The records of 88 patients with colorectal cancer who underwent endoscopic removal of malignant polyps were reviewed. Study investigators reviewed the initial pathology report; three experienced gastrointestinal pathologists reviewed all slides in a blinded fashion. Interobserver variability of pathological assessment of malignant polyps was analysed by kappa statistics. RESULTS: Seventy-six (86 per cent) of the 88 patients had malignant polyps and 12 (14 per cent) had carcinoma in situ. Agreement between experienced pathologists was substantial with regard to T stage (kappa = 0.725), resection margin status (kappa = 0.668) and Haggitt's classification (kappa = 0.682), but comparison of initial and experienced pathologists' assessment demonstrated only moderate agreement in these areas (kappa = 0.516, kappa = 0.555 and kappa = 0.578 respectively). Agreement between even experienced pathologists was poor with respect to histological grade of differentiated adenocarcinomas (kappa = 0.163) and angiolymphatic vessel invasion (kappa = - 0.017). CONCLUSION: Pathological assessment of malignant polyps varies between observers. Specialist pathologists appear to have a higher degree of consensus among themselves than with generalist pathologists with respect to T stage. The high interobserver variability with regard to histological grade of differentiated tumours is clinically irrelevant. However, variability in the assessment of angiolymphatic vessel invasion limits the value of this measurement for clinical decision making.

Pulmonary cytolytic thrombi: a previously unrecognized complication of bone marrow transplantation.

Lung injury is a frequent and severe complication of bone marrow transplantation (BMT). Over the past 5 years we have recognized a new noninfectious pulmonary complication of allogeneic BMT in 12 patients, presenting with fever, pulmonary nodules on chest computed tomography, and distinctive histopathologic appearance descriptively termed "pulmonary cytolytic thrombi" (PCT). All but one patient were children transplanted for malignant (9) and nonmalignant (3) conditions. Ten of the patients had active graft-versus-host disease (GVHD) of skin, bowel, or both at the time of diagnosis of the PCT. In all cases occlusive vascular lesions were present, most of them associated with hemorrhagic infarcts. The endothelial cell layer was discontinuous in all cases stained with antibody to CD31. The thrombi had entrapped recognizable leukocytes and CD45-positive cell fragments embedded in a tenacious basophilic material. The symptoms and radiologic findings resolved in weeks to months. PCT may represent a previously unrecognized form of pulmonary acute GVHD.

Hemolytic uremic syndrome in small-bowel transplant recipients: the first two case reports.

Post-transplant hemolytic uremic syndrome (HUS) is an uncommon but well-described complication in solid organ transplant recipients. Believed to be secondary to immunosuppressive therapy, it has been reported after kidney, liver, pancreas, heart, and lung transplants. In all reported cases, the primary organ affected was the kidney (transplant or native). But until now, no cases after small-bowel transplants and no cases in which the kidney was not the primary organ affected have been reported. We report two cases of HUS in small-bowel transplant recipients. In our first case, clinical presentation was with renal failure; biopsy of the native kidney demonstrated the typical histological changes seen with HUS, namely occlusion of the microcirculation by thrombi and platelet aggregation. Immunosuppression was changed from tacrolimus to cyclosporin, but with no improvement in renal function. In our second case, the transplanted bowel was the primary organ affected. This recipient presented with ulcers in the bowel mucosa, which were believed to be ischemic in origin, secondary to occlusive vascular lesions affecting the small vessels in the transplanted bowel. Her tacrolimus dose was decreased with resolution of ulcers and no evidence of rejection. These two cases represent the first reports of HUS after small-bowel transplants; in addition, our second case represents the first report of an extrarenal graft as the primary organ affected. When caring for small-bowel transplant recipients, physicians must be alert to the possibility of HUS and its various presentations.

Sacrococcygeal ependymoma: case report and review of the literature.

Ependymomas are uncommon glial cell tumors found within the brain, spinal cord, cauda equina, or filum terminale. Ependymomas originating in the parasacral soft tissues are exceedingly rare. The authors report the case of a 7-year-old boy with a primary ependymoma of the sacrococcygeal area and review the world literature of this tumor at this location.

Medullary adenocarcinoma of the colon: clinicopathologic study of 11 cases.

Colonic carcinomas with minimal or no glandular differentiation are a heterogeneous group of neoplasms which differ in their histologic appearance, clinical features, prognosis and molecular characteristics. Since 1990, we prospectively identified 11 patients with a predominantly solid (nonglandular) adenocarcinoma of the colon for which the term medullary adenocarcinoma of the colon (MAC) is proposed. The clinical, histological, histochemical, and immunohistochemical features of these neoplasms were studied. All patients with MAC were women with tumors in the cecum or proximal colon. Histological analysis showed nests or trabeculae of regular small to medium-sized cells with moderate amounts of eosinophilic cytoplasm; some cells contained mucin vacuoles. The nuclei had an open chromatin pattern and exhibited prominent nucleoli. Lymphatic permeation was present in most cases. Immunohistochemical reactions were positive for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen. Despite its histological resemblance with endocrine tumors, MAC is negative for endocrine markers. Of the eight patients for whom follow-up is available, four patients (two Dukes B and two Dukes C) are alive and well 1 to 4 years after surgery, one patient (Dukes C) died of tumor, one patient is alive with liver metastasis 4 years after surgery, and two patients died in the postoperative period. MAC appears to be a distinctive clinicopathologic entity. This tumor should be distinguished from other more aggressive, nonglandular tumors of the colon.

Are there cytopathic features associated with cytomegalovirus infection predictive of resistance to antiviral therapy?

Recent awareness of the broader spectrum of morphologic changes induced by cytomegalovirus (CMV) infection prompted us to investigate whether the concurrent introduction of effective antiviral therapy is in some way related to the appearance of atypical cytopathic features. These changes may be easily misinterpreted on histologic examination as reactive or degenerative. In addition, since resistant strain to antiviral therapy has emerged and its demonstration is a laborious process performed in highly specialized laboratories, it is important to determine if resistance to antiviral drugs can be predicted from the microscopic examination of infected tissues. The population consisted of seven immunosuppressed patients with documented CMV infection from which 18 tissue samples were obtained at autopsy or endoscopically. Antiviral susceptibility to ganciclovir was determined by plaque reduction assay and/or a DNA-DNA hybridization method. Eleven tissue specimens from patients harboring resistant strains were compared with seven specimens from patients infected with sensitive strains. Cytopathic changes were classified as typical or atypical according to previously published criteria. Of the 18 biopsy specimens, the cytopathic changes were distributed as follows: typical 1, typical and atypical 5, and atypical 12. Atypical inclusions were found in 10 of 11 and 7 of 7 sensitive and resistant cases, respectively. In conclusion, there are no specific morphologic features in CMV-infected tissues of patients with infections caused by ganciclovir resistant strains.

Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device.

BACKGROUND: Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION: Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.

Thrombotic microangiopathy after liver-small bowel transplant.

We herein report the first case of immunosuppression-associated thrombotic microangiopathy (TMA) in which an extrarenal graft was primarily affected by the characteristic microvascular lesions. Although TMA is a well-known complication of cyclosporine (CSA) or tacrolimus therapy in renal and extrarenal (liver, heart, lung) transplant recipients, the kidney (transplanted or native) is typically the site primarily affected. We describe a combined liver-small bowel transplant recipient who developed tacrolimus-associated TMA that affected both her transplanted small bowel and her native kidneys. Involvement of the bowel, with evidence of microvascular occlusion on biopsy, led to the development of ischemic mucosal ulcers and eventual bowel perforation. Involvement of the kidney manifested with a doubling of the recipient's baseline serum creatinine level. Significant lowering of the tacrolimus dose resulted in healing of the small bowel ulcers and return to her baseline level of renal function. Therefore, it is important to note that, in transplant recipients, TMA with microvascular occlusion may affect extrarenal sites. In small bowel transplant recipients, the result might be ischemic ulcers in the graft and eventual bowel perforation.

Renal pedicle torsion after simultaneous kidney-pancreas transplantation.

BACKGROUND: Simultaneous kidney-pancreas transplantation has become a recognized therapy for type I diabetes mellitus patients with diabetic nephropathy, neuropathy, and retinopathy. In the vast majority of these procedures, both grafts are placed intraperitoneally, which reduces posttransplant morbidity. Recently, in some of our recipients, we noted renal dysfunction related to complications of the renal pedicle. Our objectives in this study were to identify the cause of this renal dysfunction and to prevent its occurrence in future recipients. STUDY DESIGN: We undertook a retrospective chart review of simultaneous kidney-pancreas recipients who experienced renal dysfunction related to renal pedicle complications. RESULTS: We found four recipients with renal dysfunction related to renal pedicle torsion, diagnosed by serial ultrasound scans and kidney graft biopsies. Early diagnosis allowed salvage of three kidney grafts, but one was lost after late diagnosis. CONCLUSIONS: A high level of suspicion is needed to diagnose renal pedicle torsion. If simultaneous kidney-pancreas recipients have recurrent renal dysfunction, and rejection has been excluded, serial ultrasound scans with color flow Doppler examinations are needed. Once the diagnosis is made, a nephropexy to the anterior abdominal wall is indicated to prevent further torsion and save the kidney graft. We recommend prophylactic nephropexy of left renal grafts if the renal pedicle is > or = 5 cm long and if there is a 2 cm or more discrepancy between the length of the artery and the vein.

Diffuse lymphoplasmacytic acalculous cholecystitis: a distinctive form of chronic cholecystitis associated with primary sclerosing cholangitis.

Inflammation of the gallbladder is known to occur in patients with primary sclerosing cholangitis (PSC). However, the histological features of this form of cholecystitis have not been adequately defined. The aim of this study was to compare the inflammatory lesions of PSC-associated cholecystitis with those present in other cholecystopathies. The cases consisted of 11 gallbladders from patients with PSC who underwent liver transplantation. As controls, gallbladders from liver transplant patients with primary biliary cirrhosis (n = 4) and other chronic nonbiliary hepatopathies (n = 8), and 13 cholecystectomies from patients with chronic cholecystitis with (n = 10) and without (n = 3) lithiasis, were studied. The following histological features were tabulated on coded slides: presence, depth of involvement, and distribution of the inflammatory infiltrate, predominant cell type, presence of lymphoid aggregates, epithelial damage, metaplastic changes (pyloric or intestinal), fibrosis, smooth muscle hypertrophy, and presence of Rokitansky-Aschoff sinuses. At variance with the wide range of histological abnormalities present in other forms of chronic cholecystitis, most PSC-related cholecystitis showed a diffuse infiltrate (6 of 11) rich in plasma cells (6 of 11) predominantly confined to the lamina propria (9 of 11). The combination of these three features was present exclusively in PSC (5 of 11 PSC cholecystitis compared with 0 of 25 controls; P = .001). In conclusion, this study suggests that a characteristic form of cholecystitis may develop in patients with PSC.

Do molecular markers predict survival in non-small-cell lung cancer?

Patients with non-small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.

Lysinuric protein intolerance masquerading as celiac disease: a case report.

A 5 1/2-year-old boy presented with delayed growth, chronic diarrhea, and hypoproteinemia. Clinical presentation, initial laboratory data, and evaluation of an intestinal biopsy specimen suggested a diagnosis of celiac disease. Symptoms did not resolve on a gluten-free diet. The development of hyperammonemia prompted further studies that led to the diagnosis of lysinuric protein intolerance. Lysinuric protein intolerance, although a rare disorder, should be included in the differential diagnosis of conditions associated with intestinal villous atrophy.

Fatal disseminated intravascular coagulation after autologous islet transplantation.

Autologous islet transplantation after pancreatectomy has been used in the surgical management of patients with intractable pain secondary to chronic pancreatitis. Total or near total pancreatectomy invariably leads to exogenous insulin dependence in these patients unless they undergo islet transplantation. Transplantation of autologous islet cells harvested from the patient's pancreas into the liver through portal vein infusion has led to long-term euglycemia in 30% to 50% of patients. We report the development of disseminated intravascular coagulation and fatal hemorrhagic shock in a 36-year-old woman after total pancreatectomy and autologous islet transplantation through retrograde infusion into the splenic vein. We report the clinical and pathological findings and discuss the possible pathophysiological mechanisms involved in the development of disseminated intravascular coagulation after this procedure.

Cyclosporine reduces development of obliterative bronchiolitis in a murine heterotopic airway model.

Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologically by fibroproliferation within small airways. The pathogenesis of OB is thought to involve chronic allograft rejection, and therapy frequently includes augmentation of immunosuppression. We have developed a model that reproduces the pathologic lesion of OB and allows study of interventions designed to limit airway fibrosis. In this model, heterotopic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the airway lumen, changes not seen in heterotopic isografts. Cyclosporine (CsA) inhibits activation and proliferation of T lymphocytes and is commonly administered after lung transplantation. We hypothesized that use of CsA in our model system would reduce fibroproliferation in tracheal allografts. To test this hypothesis, murine tracheas were transplanted heterotopically into allo matched and allomismatched recipients, and then treated with varying doses (5, 10, 15, or 25 mg/kg i.p. q.d.) of CsA. Controls included allografts and isografts not treated with CsA. After 30 days, tracheas were harvested and examined histologically. CsA markedly reduced the development of fibroproliferation in allografts (19% in treated allografts versus 90% in untreated allografts, P<0.0001), but did not reduce inflammation or airway epithelial cell injury. High-dose (25 mg/kg/day) CsA was more effective than lower doses in reducing fibroproliferation (0% in high dose versus 29% in low dose, P=0.04). These findings demonstrate that CsA significantly reduces development of the pathologic lesion of OB, and supports the role of alloimmunity in the pathogenesis of this disease.