Incidental Coronary Artery Calcification Seen on Low-Dose Computed Tomography Is a Risk Factor for Obstructive Coronary Artery Disease in Patients Undergoing Liver Transplant.

Incidental arterial calcification (Ca) on low-dose computed tomography (CT) prior to liver transplant (LT) may help identify those at risk for obstructive coronary artery disease (CAD). A single-center retrospective study of 358 consecutive patients who had undergone LT was performed. Of the 296 patients who met inclusion criteria, 193 patients (65.2%) had CT Ca. Aortic Ca was seen in 116 (39.2%), coronary Ca in 141 (47.6%), and peripheral Ca in 8 patients (2.7%). Patients with coronary Ca were assigned ordinal coronary artery Ca scores and classified as mild, moderate, and severe. All-cause mortality was higher in patients with Ca in any location (14.5% vs 6.8%, P = .05). Of the patients who underwent coronary angiography, those with obstructive CAD were more likely to have aortic and coronary Ca than patients with nonobstructive or no CAD (85.7% vs 50.0%, P = .02 and 92.9% vs 37.9%, P = < .001, respectively). Severe coronary artery Ca scores were more frequent in patients with obstructive CAD (35.7% vs 0%, P < .001). Any severity coronary Ca had an odds ratio of 11.57 (95% CI, 1.61-244.92; P = .04) for obstructive CAD. In conclusion, incidental coronary Ca seen on low-dose CT is a risk factor for obstructive CAD in patients undergoing LT.

Dietary supplementation with flaxseed meal and oat hulls modulates intestinal histomorphometric characteristics, digesta- and mucosa-associated microbiota in pigs.

The establishment of a healthy gastrointestinal milieu may not only offer an opportunity to reduce swine production costs but could also open the way for a lifetime of human health improvement. This study investigates the effects of feeding soluble fibre from flaxseed meal-containing diet (FM) and insoluble fibre from oat hulls-containing diet (OH) on histomorphological characteristics, digesta- and mucosa-associated microbiota and their associations with metabolites in pig intestines. In comparison with the control (CON) and OH diets, the consumption of FM increased (P < 0.001) the jejunal villi height (VH) and the ratio of VH to crypt depths. The PERMANOVA analyses showed distinct (P < 0.05) microbial communities in ileal digesta and mucosa, and caecal mucosa in CON and FM-diets fed pigs compared to the OH diet-fed pigs. The predicted functional metagenomes indicated that amino acids and butanoate metabolism, lysine degradation, bile acids biosynthesis, and apoptosis were selectively enhanced at more than 2.2 log-folds in intestinal microbiota of pigs fed the FM diet. Taken together, flaxseed meal and oat hulls supplementation in growing pigs' diets altered the gastrointestinal development, as well as the composition and function of microbial communities, depending on the intestinal segment and physicochemical property of the dietary fibre source.

Plasmacytoma-like posttransplant lymphoproliferative disorder following orthotopic liver transplantation: a case report.

Posttransplant lymphoproliferative disorders (PTLDs) are among the most serious and potentially fatal complications of both stem-cell and solid-organ transplantation. Most monomorphic PTLDs are of B-cell origin and frequently associated with Epstein-Barr virus (EBV) infection in the setting of pharmacological immunosuppression posttransplantation. The majority of monomorphic PTLDs commonly resemble diffuse large B-cell or Burkitt's lymphoma; plasmacytoma-like PTLDs are very rare. We report a case of plasmacytoma-like PTLD arising in the allograft in a 66-year-old male diagnosed 2 months following an orthotopic liver transplant for alcohol-related end-stage liver disease. The liver biopsy revealed marked infiltration of atypical plasma cells with lambda light chain restriction and positivity for EBV by in situ hybridization confirming the diagnosis. Also noted was a remarkable increase of tissue eosinophils. Reduction of immunosuppression led to improvement in his clinical condition, and also resolution of the hepatic lesions and abdominal lymphadenopathy noted on imaging studies. While a few cases of plasmacytoma-like PTLDs have been described in literature, to our knowledge, this is the first reported case of early onset plasmacytoma-like PTLD in a liver transplant recipient occurring in the allograft with associated lymphadenopathy having distinct histopathologic features including tissue eosinophilia. Timely recognition of such an entity is critical in order to initiate early and appropriate intervention.

Loss of type III transforming growth factor-beta receptor expression is due to methylation silencing of the transcription factor GATA3 in renal cell carcinoma.

Loss of transforming growth factor-beta receptor III (TbetaRIII) correlates with loss of transforming growth factor-beta (TGF-beta) responsiveness and suggests a role for dysregulated TGF-beta signaling in clear cell renal cell carcinoma (ccRCC) progression and metastasis. Here we identify that for all stages of ccRCC TbetaRIII expression is downregulated in patient-matched tissue samples and cell lines. We find that this loss of expression is not due to methylation of the gene and we define GATA3 as the first transcriptional factor to positively regulate TbetaRIII expression in human cells. We localize GATA3's binding to a 10-bp region of the TbetaRIII proximal promoter. We demonstrate that GATA3 mRNA is downregulated in all stages, of ccRCC, mechanistically show that GATA3 is methylated in ccRCC patient tumor tissues as well as cell lines, and that inhibiting GATA3 expression in normal renal epithelial cells downregulates TbetaRIII mRNA and protein expression. These data support a sequential model whereby loss of GATA3 expression through epigenetic silencing decreases TbetaRIII expression during ccRCC progression.

Arthroscopic release of first metatarsophalangeal arthrofibrosis.

Various degrees of first metatarsophalangeal joint arthrofibrosis frequently occur in patients with bunion surgery or big toe trauma. In those patients with functional limitation who fail to respond to conservative treatment, surgery is indicated. We describe here an arthroscopic approach to first metatarsophalangeal release that is designed to improve functional results. Dorsomedial and dorsolateral portals are established at the medial and lateral sides of the extensor hallucis longus tendon. Through these 2 portals, the dorsal capsule is released and the medial and lateral joint gutters can be cleared up. The metatarsosesamoid compartment is approached through the straight medial portal and the working portal, the latter of which is located 4 cm proximal to the joint line between the abductor hallucis tendon and the medial head of the flexor hallucis brevis. Under visualization through the medial portal, adhesions around the sesamoid apparatus can be debrided with a shaver through the working portal. This completes the release of joint circumference and improves the motion range of the joint.

Etanercept therapy for late-onset idiopathic pneumonia syndrome after nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication of allogeneic hematopoietic stem cell transplantation (AHSCT), which usually develops within the first 100 days after transplantation. Donor T-cell-derived tumor necrosis factor-alpha (TNF-alpha) may play a crucial role in the pathogenesis of IPS, and inhibition of TNF-alpha has been used as a therapeutic option. We report two patients who had late-onset IPS about day 150 after nonmyeloablative AHSCT (NMA-AHSCT). They responded well to etanercept in combination with standard immunosuppressive drugs. Both patients had relapses and responded to retreatment with etanercept-based therapy. One patient was alive at 30 months after the initial diagnosis on long-term maintenance therapy with etanercept. The second patient was lost to follow-up at our institution but died 13 months after the onset of IPS. Our two cases showed that IPS could develop late after NMA-AHSCT and inhibition of TNF-alpha activity can be therapeutically effective.

Hepatitis C-related posttransplant plasma cell proliferative disorder with hepatitis C virus in neoplastic plasma cells: a new posttransplant disease entity?

Plasma cell proliferative disorder (PCPD) developed in two patients with actively replicating hepatitis C virus (HCV) in neoplastic plasma cells after orthotopic liver transplantation for HCV-related end-stage liver disease. PCPD was confined to the transplanted liver and was associated with monoclonal proteins in blood. Bone marrow biopsy did not show any evidence of PCPD. Epstein-Barr virus was not detected by in situ hybridization in either case. In situ hybridization for HCV RNA with sense and antisense probes in liver biopsy specimens showed signals in neoplastic plasma cells as well as in hepatocytes. We suggest that our patients had posttransplant PCPD resulting from HCV. It may represent a new posttransplant disease entity different from previously described posttransplant lymphoproliferative disorder. The findings raise intriguing questions about the role of HCV in PCPDs in patients with chronic HCV infection.

Sex-related differences in nortriptyline-induced side-effects among depressed patients.

1. Men and women may differ in their pharmacokinetic responses to tricyclic antidepressants (TCAs), in a number of autonomic indices, and in various adrenergic receptor mediated responses. Emerging evidence also suggests that women may have a lower rate of serotonin synthesis in brain and a greater sensitivity to the depressant effects of tryptophan depletion, relative to men. However, sex-related differences in TCA-induced side-effects, including increases in heart rate (HR), dry mouth, constipation, and difficulty urinating, has not been systematically investigated. 2. The authors examined potential sex-related differences in the pattern of side-effects during treatment with nortriptyline (NT), a TCA that is still widely used. Seventy-eight healthy outpatients who met Research Diagnostic Criteria and DSM-III-R criteria for major depression participated in a double-blind, randomized parallel trial of NT versus placebo. 3. Each subject was acutely challenged with either placebo or 50 mg NT prior to and after a 6-week treatment with NT. NT doses were adjusted weekly to maintain therapeutic plasma levels. Patients were assessed at multiple time points to detect the presence of NT-induced side-effects. 4. The initial, single (50 mg) dose of NT significantly increased supine HR. Six-week treatment with NT was found to significantly increase supine and sitting HRs, irrespective of sex. In rechallenge with the single NT dose, there were no significant effects on HR. 5. When sex-related differences were examined, HR increases were greater in men than women during weeks 4 through 6 of the NT treatment, although no sex-related differences were present in plasma NT levels or metabolites. In addition, there was a significant NT to placebo difference in self-rated dry mouth for women during all 6-weeks of treatment, whereas men showed a significant NT-placebo difference during weeks 3 and 5. 6. The results suggest the presence of sex-related differences in elevated supine HR response during the course of 6-week NT treatment. Depressed men may be more susceptible to NT-induced increases in supine HR than women.

A novel gamma -secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor.

Alzheimer's disease is characterized by the deposits of the 4-kDa amyloid beta peptide (A beta). The A beta protein precursor (APP) is cleaved by beta-secretase to generate a C-terminal fragment, CTF beta, which in turn is cleaved by gamma-secretase to generate A beta. Alternative cleavage of the APP by alpha-secretase at A beta 16/17 generates the C-terminal fragment, CTFalpha. In addition to A beta, endoproteolytic cleavage of CTF alpha and CTF beta by gamma-secretase should yield a C-terminal fragment of 57-59 residues (CTF gamma). However, CTF gamma has not yet been reported in either brain or cell lysates, presumably due to its instability in vivo. We detected the in vitro generation of A beta as well as an approximately 6-kDa fragment from guinea pig brain membranes. We have provided biochemical and pharmacological evidence that this 6-kDa fragment is the elusive CTF gamma, and we describe an in vitro assay for gamma-secretase activity. The fragment migrates with a synthetic peptide corresponding to the 57-residue CTF gamma fragment. Three compounds previously identified as gamma-secretase inhibitors, pepstatin-A, MG132, and a substrate-based difluoroketone (t-butoxycarbonyl-Val-Ile-(S)-4-amino-3-oxo-2, 2-difluoropentanoyl-Val-Ile-OMe), reduced the yield of CTF gamma, providing additional evidence that the fragment arises from gamma-secretase cleavage. Consistent with reports that presenilins are the elusive gamma-secretases, subcellular fractionation studies showed that presenilin-1, CTF alpha, and CTF beta are enriched in the CTF gamma-generating fractions. The in vitro gamma-secretase assay described here will be useful for the detailed characterization of the enzyme and to screen for gamma-secretase inhibitors.

The acute and chronic performance effects of alprazolam and lorazepam in the elderly: relationship to duration of treatment and self-rated sedation.

We examined the acute performance and sedative effects of single high and low doses of alprazolam and lorazepam, both before and after chronic, 3-week b.i.d. treatment in elderly adults. The effects of chronic treatment also were examined in this parallel, double-blind, placebo-controlled study. Initial acute low doses significantly impaired total recall and increased intrusion errors. High doses also impaired delayed recall and critical flicker fusion threshold (CFF). Only chronic treatment with high-dose alprazolam increased intrusions and self-rated sedation. Single-dose rechallenge after chronic treatment was associated with significantly less impairment than the initial challenge in memory tasks but not in the discriminant reaction time (DRAT) task. For most memory measures, the development of tolerance was only partial; rechallenge still produced significant deficits in relation to placebo. The development of tolerance was task-specific and depended on drug type and dosage. Despite impairments in various memory functions, CFF, and DRAT, volunteers did not report significant drug-induced changes in sedation.

Detection of Borrelia burgdorferi OspA in Ixodes scapularis larvae by an antigen-capture enzyme-linked immunosorbent assay.

The Borrelia burgdorferi outer surface protein A (OspA) was quantified by an antigen-capture ELISA. The test detected 0.156 ng OspA/B, using purified rabbit IgG as a detection system. Dose-response relationship was described by a three-parameter equation and second degree polynomials. The estimated amount of OspA in host-attached Ixodes scapularis larvae was positively correlated with the tick's engorgement status, whereas the presence of blood in OspA-negative larvae reduced test absorbance. The antigen-capture ELISA can be effectively used in the ecology and epidemiology of Lyme borreliosis. However, host attached larvae should be matched by engorgement level to remove the effect of this variable on test results.

Role of nitric oxide and endothelin-1 in monocrotaline-induced pulmonary hypertension in rats.

OBJECTIVE: Nitric oxide (NO) and endothelin-1 (ET-1) have both been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, we examined NO-related relaxation and ET-1 levels in rat hilar pulmonary arteries (PA) during the progression of monocrotaline (MCT)-induced PH. METHODS: Rats were studied 1 and 2 weeks after a single subcutaneous injection of MCT (80 mg/kg). Pulmonary artery pressure (PAP), right ventricular hypertrophy (RVH), NO-related relaxation and tissue ET-1 levels in PA were evaluated and compared with control (C). RESULTS: One week post-MCT, endothelium (E)-dependent relaxation to 10(-5) M adenosine diphosphate (ADP), 10(-5) M A23187 and 10(-5) M acetylcholine (ACh) and tissue ET-1 levels in PA were normal. Rats in this group did not develop PH or RVH. Two weeks post-MCT, E-dependent relaxation was impaired (ADP, 7 +/- 3% VS. c, 62 +/- 5%; A23187, 2 +/- 7% vs. C, 58 +/- 2%; ACh, 33 +/- 7% vs. C, 86 +/- 2%; P < 0.05) and ET-1 levels were elevated (1925 +/- 244 pg/g wwt vs. C, 469 +/- 59 pg/g wwt, P < 0.05), In addition, significant PH and RVH were present (PAP 33 +/- 4 mmHg vs. C 18 +/- 0.8 mmHg, P < 0.05; RVH index 0.40 +/- 0.006 vs. C, 0.25 +/- 0.01, P < 0.05). Incubation with 10 microM indomethacin, 150 U/ml superoxide dismutase or 300 microM L-arginine failed to restore impaired relaxation to ACh. In E-intact rings, relaxation to 10(-6) M glyceryl trinitrate (GTN) was inhibited at 1 week post-MCT (72 +/- 2% vs. C, 87 +/- 3%, P < 0.05) with further inhibition at 2 weeks (39 +/- 4%). Response to GTN in E-denuded rings was normal in MCT groups. CONCLUSIONS: These results indicate that MCT injection in rats results in delayed but progressive endothelial injury and PH. Despite mild endothelial dysfunction 1 week post-MCT, NO-related relaxation and ET-1 levels are normal. At 2 weeks post-MCT, inhibition of E-dependent NO-related relaxation and elevation of ET-1 levels are associated with PH and RVH. Thus inhibition of NO production associated with elevated ET-1 levels may play an important role in the pathophysiology of MCT-induced PH.

Gross anatomy

This is an illustrated manual of gross anatomy. It was designed as a supplement to lectures

Development of congenital laryngeal atresias and clefts.

Congenital supraglottic laryngeal obstruction still is being described as subglottic stenosis. There are three clearly defined types of congenital laryngeal atresia, which result from arrest at consecutive developmental stages. Type 1 consists of a supraglottic obstruction, absent vestibule, and stenotic infraglottis, and type 2 is a supraglottic obstruction that separates a shallow primitive vestibule above from a nonstenotic infraglottis. These two types usually are accompanied by other defects, many of them severe. In type 3, a perforated membrane partly obstructs the glottis. Arrest of the dorsal advance of the chondrifying cricoid before the ends meet to form the dorsal lamina results in a complete laryngeal cleft, and incomplete fusion of the ends may leave a notch and/or foramen within the lamina. Failure of the interarytenoid tissue to develop will produce a local cleft, and maldevelopment of the cricoid cartilage or infraglottic submucosa can result in true subglottic stenosis without supraglottic obstruction.