Citations

Abstract Background Long-term functional outcome after operative treatment of necrotizing pancreatitis (NP) has not been studied extensively. Methods Pancreatic function, performance status, recurrence of symptoms and other related problems were analysed in 44 consecutive patients successfully discharged from hospital after operative necrosectomy (1983–1995) and followed up completely for a mean of 5 years. Results Clinical pancreatic insufficiency developed in half the patients. Diabetes mellitus (11 patients), steatorrhoea (six) or both (five) were associated with a mean estimate of 52, 66 and 67 per cent parenchymal necrosis respectively. Normal pancreatic function was associated with 27 per cent parenchymal necrosis (P < 0·05). Diabetes worsened while steatorrhoea tended to improve over time. Abdominal pain and pancreatitis recurred in six and two patients respectively. Performance status worsened in four patients because of recurrent pancreatitis and severe steatorrhoea. Poor long-term performance was associated with a higher Acute Physiology And Chronic Health Evaluation II score on admission (mean 14 versus 9). Conclusion NP has prominent effects on long-term pancreatic exocrine and endocrine function in half the patients, but most preserve a good overall functional status. The development of pancreatic insufficiency varies with the extent of pancreatic parenchymal necrosis.

Background— Recent studies have identified cardiomyocytes of extracardiac origin in transplanted human hearts, but the exact origin of these myocyte progenitors is currently unknown. Methods and Results— Hearts of female subjects (n=4) who had undergone sex-mismatched bone marrow transplantation (BMT) were recovered at autopsy and analyzed for the presence of Y chromosome–positive cardiomyocytes. Four female gender-matched BMT subjects served as controls. Fluorescence in situ hybridization (FISH) for the Y chromosome was performed on paraffin-embedded sections to identify cells of bone marrow origin with concomitant immunofluorescent labeling for α-sarcomeric actin to identify cardiomyocytes. A total of 160 000 cardiomyocyte nuclei were analyzed approximating 20 000 nuclei per patient. The mean percentage of Y chromosome–positive cardiomyocytes in patients with sex-mismatched BMT was 0.23±0.06%. Not a single Y chromosome–positive cardiomyocyte was identified in any of the control patients. Immunofluorescent costaining for laminin and chromosomal ploidy analysis with FISH showed no evidence of either pseudonuclei or cell fusion in any of the chimeric cardiac myocytes identified. Conclusions— These data establish for the first time human bone marrow as a source of extracardiac progenitor cells capable of de novo cardiomyocyte formation.

Reduced shoulder endurance in rotator cuff tear patients has been observed clinically. A simple and inexpensive shoulder endurance test protocol was developed. This study reports the test-retest reliability of the protocol. Twenty healthy volunteers without a history of shoulder pathology participated in the study. Each subject was tested twice, each on a separate day. Test-retest correlation coefficients of the arm endurance times were 0.59 and 0.60 for the dominant and nondominant sides, respectively. The protocol appears promising for assessing shoulder function.

Thumb motion and stability were examined after sequential division of support ligaments of the trapeziometacarpal (TMC) to simulate the pathologic condition of ligament laxity. The motion obtained with passive circumduction was measured with a magnetic tracking system. The lengths of the TMC joint ligaments were approximated by measuring the distance between origin and insertion of each ligament. The change in this apparent interorigin distance of the ligaments was measured before and after ligament sectioning. The anterior oblique ligament (AOL) and the ulnar collateral ligament (UCL) had the greatest effect on TMC joint stability during circumduction of the thumb. Division of the first intermetacarpal ligament (IML) did not produce a change in apparent length of other ligaments. We conclude that small changes in ligament length affect thumb stability and alter the path of circumduction. Neither the IML or posterior oblique ligaments were major stabilizers of the TMC joint during circumduction, prehensile grasp, or tip pinch. Reconstruction of the AOL and UCL ligaments should be considered for treatment of the initial stages of TMC instability.

Macromolecules are transported in and out of the nucleus through nuclear pores. It is poorly understood how these megadalton conduits support nucleocytoplasmic traffic during genetic reprogramming associated with cell commitment to a specific lineage. Murine embryonic stem cells were differentiated into cardiomyocytes within embryoid bodies, and contracting cells expressing myocardial-specific proteins were isolated from the mesodermal layer. Compared with postmitotic cardiac cells from heart muscle, these proliferative and differentiating stem cell–derived cardiomyocytes demonstrated a significantly lower density of nuclear pores. At nanoscale resolution, the pore channel was commonly unoccupied in heart muscle–isolated cardiac cells, yet a dense material, presumably the central transporter, protruded toward the cytosolic face of the nuclear pore complex in stem cell–derived cardiomyocytes. Stem cell–derived cardiac cells distributed the nuclear transport factor Ran in the nucleus, decreased the number of spare nuclear pore complexes from the cytosolic annulate lamellae reservoir, and expressed a set of nucleoporins, NUP214, NUP358, NUP153, and p62, involved in nuclear transport. Stem cell–derived cardiomyocytes secured transport of nuclear constitutive proteins, cardiogenic transcription factors, and cell cycle regulators, including the prototypic histone H1, myocyte enhancer binding factor 2, and p53. Thus, differentiating stem cell–derived cardiomyocytes undergo structural adaptation and mobilize nuclear transport regulators in support of nucleocytoplasmic communication during commitment to mature cardiac lineage.

One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L- cis -diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca 2+ , or chelation of intracellular Ca 2+ . In fact, both the enterotoxin and 8-br-cGMP induced an L- cis -diltiazem-sensitive conductance, promoting Ca 2+ influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

Abstract Pneumocystis carinii (PC) causes severe pneumonia in immunocompromised patients. PC is intrinsically resistant to treatment with azole antifungal medications. The enzyme lanosterol 14α-demethylase (Erg11) is the target for azole antifungals. We cloned PCERG11 and compared its sequence to Erg11 proteins present in azole-resistant organisms, and performed chromosomal and Northern blot analysis for PCERG11. Of 13 potential sites which could confer resistance to azoles, two were identical to azole-resistant Candida. By site-directed mutagenesis we changed these two sites in PCERG11 to those present in azole-sensitive Candida to generate PCERG11-SDM (E113D, T125K). We tested the susceptibility of ERG11 deletion strains of Saccharomyces cerevisiae (SC) expressing PCERG11, PCERG11-SDM, and wild-type SCERG11 to three azole antifungals: fluconazole, itraconazole, and voriconazole. PCERG11 required a 2.2-fold higher dose of voriconazole and 3.5-fold higher dose of fluconazole than SCERG11 for a 50% reduction in growth. No difference was observed in the sensitivity to itraconazole. PCERG11-SDM has increased sensitivity to fluconazole and voriconazole, but not itraconazole. We believe that the molecular structure of the lanosterol 14α-demethylase encoded by PCERG11 confers inherent resistance to azole antifungals and plays an integral part in the overall resistance of this PC to azole therapy.

Coupled vibration of arterial tubes is analyzed with the wave propagation approach and first-order shear deformation theory. Both the interior and exterior fluids are considered as compressible so that acoustic waves can be generated and propagated in the fluids. Results obtained using the theory have been evaluated against those available in the literature and the agreement has been found to be good. The theory can be used for future research on the vibration and acoustics of arterial walls. Vibration experiments were carried out on a silicone rubber tube in a water tank with a novel ultrasound stimulated optical vibrometry system. This system uses the radiation force of ultrasound to vibrate the tube at low frequency and records the resulting response by a laser vibrometer. Both the excitation and measurement are remote and noncontact. The silicone rubber tube was chosen because it has mechanical properties close to those of arteries. The fundamental frequency is well excited by the radiation force and measured with the laser. The measured fundamental frequency is in good agreement with the present theory.