Liver biopsy: evolving role in the new millennium

Since the origination of the liver biopsy, the technique has evolved into an essential diagnostic tool, with very few complications. In addition to the percutaneous approach, a liver biopsy can also be obtained via transjugular, laparoscopic, or intraoperative approach. While in the early 1960s and 1970s the liver biopsy was used for making a diagnosis in cases of clinically suspected medical liver disease, today it is more often performed to assess disease prognosis and evaluate therapeutic strategies. As a result, indications for the liver biopsy have evolved over the past 2 decades. However with advances in serologic diagnosis of viral/autoimmune hepatitis and laboratory tests for genetic disorders, the role of liver biopsy in certain clinical settings is currently debated. This review discusses the technique, indications, contraindications, and the changing role of liver biopsy in some of the common disorders and the associated controversies.     

Problem-based learning and research at the Harvard School of Dental Medicine: a ten-year follow-up

Dental students at the Harvard School of Dental Medicine (HSDM) are required to pursue and complete research projects in order to obtain the doctor of dental medicine (D.M.D.) degree. The purpose of this study was to evaluate the effect of curriculum changes on a set of measurable outcomes related to research pursuits. This study was designed as a retrospective analysis of outcomes data from the period 1992-2002. The predictor variable was program format (non-PBL vs. PBL); the outcome variables were the percentage of students listed as authors on an IADR/AADR abstract during their tenure at HSDM and the percentage of students listed as first and/or presenting authors. Univariate statistics were computed for each class, and independent samples t-tests were used to compare the study groups with regard to our outcomes. For the majority of our outcomes, there was no statistically significant difference between the PBL and non-PBL groups, possibly due to sample size limitations. While the implementation of PBL at HSDM has not universally increased student productivity in research, it has not had an adverse effect either. It is possible that students in the PBL curriculum are nurturing other interests, such as community service, while retaining productivity in research.     

Photorefractive keratectomy versus laser in situ keratomileusis to prevent keratectasia after corneal ablation

A 27-year-old man had excimer photoastigmatic keratectomy in the right eye and laser in situ keratomileusis in the left eye for the treatment of equivalent myopia. Preoperative slitlamp examination did not reveal evidence of keratoconus, central corneal pachymetry was 485 microm in the right eye and 500 microm in the left eye, and corneal topography revealed asymmetric bow-tie astigmatism with inferior steepening in the right eye and a small area of inferior steepening in the left eye. Twenty-two months after surgery, the patient complained of poor vision in the left eye. Slitlamp examination of the left eye revealed central corneal thinning and protrusion, with a Fleischer ring within the flap. Corneal topographic evaluation revealed a stable map in the right eye and central corneal steepening indicative of keratectasia in the left eye.     

Safety, tolerability, pharmacokinetics, and pharmacodynamics of an orally active novel camptothecin analog, DRF-1042, in refractory cancer patients in a phase I dose escalation study

The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.     

Effects of uridine, isomatitol and 4-thiouridine on in vitro cell adhesion and in vivo effects of 4-thiouridine in a lung inflammation model

Since leukocyte adhesion to endothelial cells is crucial for extravasation of leukocytes to sites of inflammation, inhibition of cell-cell adhesion has been suggested as a means to achieve selective modulation of the immune system. We have, using a static in vitro adhesion assay involving adhesion of granulocytes to tumor necrosis factor alpha (TNFalpha)-stimulated human umbilical vein endothelial cells (HUVEC), found three substances--uridine, isomaltitol and 4-thiouridine-that, independently and significantly, reduced leukocyte adhesion by approximately 30-65%. 4-Thiouridine was also tested in an in vivo model of Sephadex (SDX)-induced lung inflammation with Sprague-Dawley rats. Intratracheal instillation of Sephadex (5 mg/kg) alone resulted in a dramatic increase in lung edema and total leukocyte count after 24 h. A differential count of bronchoalveolar lavage (BAL) cells indicated an increased influx of macrophages, eosinophils and neutrophils. Co-administration of 4-thiouridine significantly reduced lung edema by 38%. There was also a significant reduction of the total leukocyte count by 58%. The differential leukocyte count indicated that eosinophil influx alone was reduced by 70%. After Sephadex challenge, we found elevated levels of TNFalpha--an important inflammatory mediator--in the bronchoalveolar lavage fluid (BALF). TNFalpha levels were significantly reduced by more than 80% by co-administration of 4-thoiuridine. These results suggest that uridine, isomaltitol and, especially, 4-thiouridine affect adhesion between leukocytes and activated endothelium, and warrant further in vitro and in vivo studies.     

Plumbagin induces reactive oxygen species, which mediate apoptosis in human cervical cancer cells

There is an emerging evidence that plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone) may have potential as a chemotherapeutic agent. However, the growth inhibitory mechanisms of plumbagin have remained unexplored. The aim of the study was to determine whether plumbagin-induced cell death in human cervical cancer cell line, ME-180, exhibited biochemical characteristics of apoptosis and to check whether N-acetyl-l-cysteine (NAC), which is a free radical scavenger, can reverse the cytotoxic effects of plumbagin. It can be concluded from the results that plumbagin inhibits the growth of ME-180 cells in a concentration and time-dependent manner. The cytotoxic effect of plumbagin induced cell death is through the generation of reactive oxygen species (ROS) and subsequent induction of apoptosis as demonstrated by the present data. Treatment of cells with plumbagin caused loss of mitochondrial membrane potential (DeltaPsi(m)), and morphological changes characteristic of apoptosis, such as the translocation of phosphatidyl serine, nuclear condensation, and DNA fragmentation. Moreover, plumbagin-induced apoptosis involved release of mitochondrial cytochrome c and apoptosis inducing factor (AIF), thus activation of caspase-dependent and -independent pathways, as shown by the plumbagin-mediated activation of caspase-3 and -9. Our results also show that pretreatment of ME-180 cells with NAC blocks plumbagin-induced loss of DeltaPsi(m) and subsequent release of cytochrome c, AIF, and caspase-9 and -3 activation, thus inhibiting the apoptotic ability of plumbagin.     

Predicting mortality in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention (PAMI risk score)

We performed a pooled analysis of the Primary Angioplasty in Myocardial Infarction (PAMI) trials to examine predictors of death after primary percutaneous coronary intervention. Using these data, we developed a risk score with a range of 0 to 15 points. The PAMI risk score was found to be a strong predictor of late mortality.     

CD34-reactive trichodiscoma

BACKGROUND: Trichodiscomas are rare hamartomas of the dermal portion of the hair disc, a specialized component of the perifollicular mesenchyme. They are usually found as asymptomatic multiple skin-colored papules on the face and extremities and may have an autosomal dominant inheritance pattern. However, a solitary variant has been described. CASE REPORT: A 78-year-old woman presented with a single, non-pigmented, firm papule on the left tip of the nose, measuring 3.5 mm in diameter. RESULTS: The histological examination revealed the previously described features of a trichodiscoma. The immunohistochemical analysis showed strong immunoreactivity for CD34 in the spindle cell component. Spindle cells were negative for S-100, HMB-45, Melan-A, EMA, neurofilament, desmin, and Factor XIIIa by immunohistochemistry. CONCLUSIONS: We report strong reactivity for CD34 in the spindle cell component of a trichodiscoma. We suggest that this lesion be considered in the differential diagnosis of any CD34+ dermal spindle cell proliferation, in which an adjacent epithelial component cannot be entirely excluded.     

The endocytotic pathway is required for increased A beta 42 secretion during apoptosis

Secretion and progressive cerebral accumulation of beta-amyloid peptides (A beta), which derive by endoproteolytic ('amyloidogenic') processing of beta-amyloid precursor protein (APP), are felt to represent collectively an early and necessary event in the pathogenesis of Alzheimer's disease. APP amyloidogenic processing can occur via secretory or endocytotic pathways, but the relative contribution of these pathways to A beta secretion remains to be established. The effect of apoptosis on amyloidogenic processing and A beta secretion similarly is incompletely understood. We tested the hypothesis that APP processing by the endocytotic pathway represents a stress-related neural cell response, by comparing A beta secretion after induction of apoptosis in PC12 cells transfected either for endocytosis-competent or -deficient APP. Newly prepared adenoviral vectors encompassing targeted mutagenesis of the cytoplasmic tail YENP tetrapeptide sequence, which serves as the principal APP internalization signal, were used to express endocytosis-deficient holoprotein. We report that the endocytotic pathway is required for the generation and secretion of A beta 42, and that secretion of this neurotoxic peptide increases significantly during apoptosis. We demonstrate additionally that more A beta 40 apparently is generated in secretory compartments during apoptosis when APP processing by the endocytotic pathway is impaired.