Estimating renal function in patients on tenofovir disoproxil fumarate: suggestions for safer use.
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Adenine↗
Biomedical subjects
J Winston
Publications and source records attributed to J Winston.
Cleft lip/palate and CDH1/E-cadherin mutations in families with hereditary diffuse gastric cancer.
We report the association of CDH1/E-cadherin mutations with cleft lip, with or without cleft palate (CLP), in two families with hereditary diffuse gastric cancer (HDGC). In each family, the CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing the extracellular cadherin repeat domains involved in cell-cell adhesion. Such transcripts might encode mutant proteins with trans-dominant negative effects. We found that CDH1 is highly expressed at 4 and 5 weeks in the frontonasal prominence, and at 6 weeks in the lateral and medial nasal prominences of human embryos, and is therefore expressed during the critical stages of lip and palate development. These findings suggest that alteration of the E-cadherin pathway can contribute to human clefting.
Adult↗
Primary adenocarcinoma of cervical esophagus.
Most upper esophageal malignancies are squamous cell carcinomas, rarely adenocarcinomas arising from Barrett's esophagus and very rarely adenocarcinomas from heterotopic gastric mucosa without evidence of Barrett's especially in the cervical part of the esophagus. We report a case of adenocarcinoma of the polypoid type in the upper esophagus (cervical esophagus) arising from ectopic gastric mucosa, in a 60 year-old man who presented with progressive dysphagia. Accurate diagnosis by esophagogram revealed a large mass in the cervical esophagus; CAT scan showed intraluminal mass at the level of thoracic inlet, esophagogastroscopy showed a fleshy polyp (3.2cm x 3.0cm) at 20 cm from the incisors with a biopsy confirming moderately differentiated adenocarcinoma with no evidence of Barrett's esophagus. Through a left cervical approach and resection of medial third of clavicle, the tumor was removed by partial esophagectomy followed by lymph node dissection, and proved to be T1NOMO, stage I (AJCC staging 6th ed.). Post operatively, the patient received chemoradiation with no evidence of recurrence or metastasis in six years of follow up. It seems this tumor has a much better prognosis than adenocarcinomas arising from Barrett's. To our knowledge only 19 cases have been reported in literature so far.
Adenocarcinoma↗
Beauty in a smile: the role of medial orbitofrontal cortex in facial attractiveness.
The attractiveness of a face is a highly salient social signal, influencing mate choice and other social judgements. In this study, we used event-related functional magnetic resonance imaging (fMRI) to investigate brain regions that respond to attractive faces which manifested either a neutral or mildly happy face expression. Attractive faces produced activation of medial orbitofrontal cortex (OFC), a region involved in representing stimulus-reward value. Responses in this region were further enhanced by a smiling facial expression, suggesting that the reward value of an attractive face as indexed by medial OFC activity is modulated by a perceiver directed smile.
Adult↗
Ulcerative pododermatitis in a cat associated with Anatrichosoma sp.
A 9-year-old castrated male Chartreaux cat was presented for an ulcerative pododermatitis of all 4 paws. A clinical exam was inconclusive and supportive therapy did not improve the condition. Histologic examination revealed an ulcerative and eosinophilic dermatitis associated with epidermal and dermal nematodes and ova consistent with the aphasmid Anatrichosoma sp. Treatment with ivermectin completely resolved the skin lesions. Anatrichosomiasis should be included in the differential diagnosis of ulcerative pododermatitis in cats, at least in the southwestern United States.
Animals↗
Time course of LPS-induced gene expression in a mouse model of genitourinary inflammation.
In this study, self-organizing map (SOM) gene cluster techniques are applied to the analysis of cDNA microarray analysis of gene expression changes occurring in the early stages of genitourinary inflammation. We determined the time course of lipopolysaccharide (LPS)-induced gene expression in experimental cystitis. Mice were euthanized 0.5, 1, 4, and 24 h after LPS instillation into the urinary bladder, and gene expression was determined using four replicate Atlas mouse cDNA expression arrays containing 588 known genes at each time point. SOM gene cluster analysis, performed without preconditions, identified functionally significant gene clusters based on the kinetics of change in gene expression. Genes were classified as follows: 1) expressed at time 0; 2) early genes (peak expression between 0.5 and 1 h); and 3) late genes (peak expression between 4 and 24 h). One gene cluster maintained a constant level of expression during the entire time period studied. In contrast, LPS treatment downregulated the expression of some genes expressed at time 0, in a cluster including transcription factors, protooncogenes, apoptosis-related proteins (cysteine protease), intracellular kinases, and growth factors. Gene upregulation in response to LPS was observed as early as 0.5 h in a cluster including the interleukin-6 (IL-6) receptor, alpha- and beta-nerve growth factor (alpha- and beta-NGF), vascular endothelial growth factor receptor-1 (VEGF R1), C-C chemokine receptor, and P-selectin. Another tight cluster of genes with marked expression at 1 h after LPS and insignificant expression at all other time points studied included the protooncogenes c-Fos, Fos-B, Fra-2, Jun-B, Jun-D, and Egr-1. Almost all interleukin genes were upregulated as early as 1 h after stimulation with LPS. Nuclear factor-kappaB (NF-kappaB) pathway genes collected in a single cluster with a peak expression 4 h after LPS stimulation. In contrast, most of the interleukin receptors and chemokine receptors presented a late peak of expression 24 h after LPS coinciding with the peak of neutrophil infiltration into the bladder wall. Selected cDNA microarray observations were confirmed by RNase protection assay. In conclusion, the cDNA array experimental approach provided a global profile of gene expression changes in bladder tissue after stimulation with LPS. SOM techniques identified functionally significant gene clusters, providing a powerful technical basis for future analysis of mechanisms of bladder inflammation.
Animals↗
A phase 1/2 clinical trial of enzyme replacement in fabry disease: pharmacokinetic, substrate clearance, and safety studies.
Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
Adolescent↗
Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons.
Nerve growth factor (NGF) regulates the nociceptive properties including sensitivity to capsaicin of a subset of dorsal root ganglion neurons, which express the high-affinity NGF receptor, trkA. Capsaicin sensitivity co-localizes with the expression of a cloned capsaicin receptor, vanilloid receptor type 1 (VR-1), which displays properties similar to the native capsaicin response. To determine whether VR-1 mRNA levels are regulated by NGF, VR-1 mRNA levels and the ability to respond to capsaicin by release of the neuropeptide calcitonin gene related peptide (CGRP) were measured as a function of NGF concentration in cultures of adult dorsal root ganglion neurons. NGF treatment increased both VR-1 mRNA expression and capsaicin evoked release of CGRP. These effects were inhibited by treatment with the trkA inhibitor k252a.
Animals↗
Noninvasive assessment of glucose and pyruvate uptake by human embryos after intracytoplasmic sperm injection and during the formation of pronuclei.
OBJECTIVE: To improve in vitro culture conditions and human embryo selection before transfer after IVF with intracytoplasmic sperm injection (ICSI). DESIGN: A controlled, randomized, prospective study. SETTING: University hospital-based IVF-ET program. PATIENT(S): Couples undergoing ICSI. INTERVENTION(S): Culture of human embryos in the presence of 1 mM or 5.56 mM glucose and metabolic measurements with the use of noninvasive microfluorescence assays immediately after ICSI to the time of transfer. MAIN OUTCOME MEASURE(S): Embryo development, implantation rate, and glucose and pyruvate uptake. RESULT(S): Fertilization rates, early embryo development, and implantation rates were not significantly different between 1 mM and 5.56 mM glucose. Pyruvate uptake was significantly higher during the formation of the pronuclei, at 15 +/- 0.7 and 11.4 +/- 1.3 pmol/embryo/h for fertilized and unfertilized oocytes, respectively. Pyruvate uptake did not correlate with cleavage stage or embryo morphology. However, during the second day of incubation, pyruvate uptake was significantly higher for the untransferred embryos of pregnant women compared with nonpregnant women, at 17.9 +/- 1.5 and 10.8 +/- 1.0 pmol/embryo/h, respectively. CONCLUSION(S): The increased level of pyruvate uptake during fertilization reflects the increased demand for energy necessary for the formation of the pronuclei. However, the metabolic measurements could not improve the selection of embryos with the best implantation potential. Finally, the reduction of glucose concentration in the culture medium failed to improve embryo viability.
Embryo Implantation↗
Nerve growth factor expression is up-regulated in the rat model of L-arginine-induced acute pancreatitis.
BACKGROUND & AIMS: In somatic pain models, increases in nerve growth factor (NGF) are linked to the development of pain and hyperalgesia. The aim of this study was to examine a rat model of acute necrotizing pancreatitis for changes in NGF expression. METHODS: NGF protein and messenger RNA (mRNA) levels in the pancreas were correlated with histopathologic changes during the course of acute necrotizing pancreatitis in rats induced by the intraperitoneal injection of L-arginine. Immunohistochemistry for NGF localization was performed on the pancreatic tissue. RESULTS: Two phases of NGF production were observed in the inflamed pancreas: an early release from pancreatic islets at 2 and 6 hours and a later increase in mRNA (18-fold at maximum) at 3 days and in protein levels (7-fold at maximum) at 5 days coinciding with maximum parenchymal necrosis. The intense NGF-like immunoreactivity was observed predominantly in the ductal cells in pancreas from rats with pancreatitis at 5 days. CONCLUSIONS: The development of acute necrotizing pancreatitis in this model leads to a significant increase in NGF production and appears to shift the major cellular sites of NGF production from the islets to the ductal cells. It is conceivable that NGF production in the inflamed pancreas is responsible for plastic changes in the sensory neurons that mediate peripheral sensitization and contribute to the generation of pain.
Animals↗
Patterns of nodal metastasis and surgical management of the neck in supraglottic laryngeal carcinoma.
BACKGROUND: Appropriate management of the clinically negative (N0) neck in supraglottic laryngeal cancer continues to be an area of controversy in head and neck surgery. Our treatment policy has been aggressive surgical management even in the clinically N0 neck. METHODS: Between 1971 and 1991, 104 patients had the primary diagnosis of supraglottic laryngeal cancer. Ninety of these patients received their treatment at Roswell Park Cancer Institute and are the subject of this retrospective review. RESULTS: All neoplasms included in this study were squamous cell cancers. The most common subsite involved with tumor in our series was the epiglottis, followed by the aryepiglottic folds and false cords. Supraglottic laryngectomy was performed of 29% of the cases; the remainder received total laryngectomy. Thirty-six percent of the patients had pathologic stage I/II disease, and 64% had stage III/IV. The 5-year survival rates were 100%, 81%, 73%, and 63% for stages I through IV, respectively. Fifty-seven patients had clinically N0 disease at presentation; of these 34 underwent elective neck dissection, and the remaining 23 patients were observed. Of those patients receiving neck dissection, 30% (n = 10) were found to have histologically positive disease, and of the 23 patients observed, 30% (n = 7) had histologically positive regional (neck) disease. Of the 17 clinically N0 and pathologically N+ patients, 82% (14 of 17) had involvement of level I (submandibular triangle), and 100% had involvement of level II. The incidence of bilateral disease in the clinically N0 patient was 44%. There were no local failures. CONCLUSIONS: There is a high incidence of occult regional disease even in early-stage supraglottic squamous cell carcinoma of the larynx. In the surgical management the clinically N0 neck, we presently recommend bilateral neck dissection of levels I through IV to adequately address those regions at highest risk for occult disease.
Carcinoma, Squamous Cell↗
Recurrence of scleroderma in a renal allograft from an identical twin sister.
A patient with scleroderma developed renal failure secondary to recurrence of scleroderma in a renal allograft from an identical twin. This report reviews the previous reports of scleroderma recurrence in renal allografts; the differential diagnosis of scleroderma renal crisis, including cyclosporine toxicity, malignant hypertension, and allograft rejection; and the pathophysiology of this disease.
Diagnosis, Differential↗
Sentinel node biopsy in breast cancer.
BACKGROUND: Sentinel lymph node biopsy (SNB) in breast cancer may be used in place of axillary lymph node dissection (ALND) if SNB accurately stages the axilla. This study assessed the success and accuracy of axillary SNB with isosulfan blue (ISB) and technetium-99 sulfur colloid (TSC) compared to ALND. METHODS: Forty-two women with T1 or T2 breast cancer underwent SNB and ALND. Sixty to 90 minutes before anesthetic induction, a mixture of 3 mL ISB and 1 mCi TSC was injected around the primary cancer or prior biopsy site. Intraoperatively, the SLN was identified using a gamma detector (Neoprobe 1000) or by visualization of the blue-stained lymph node and afferent lymphatics. The SLN was excised separately, and a level I/II ALND was completed. The histologic findings of the axillary contents and SLN were compared. RESULTS: An axillary SLN was found in 38 of 42 (90%) cases. SLN localization rate and predictive value were the same for women who had and those who had not undergone excisional biopsy before the date of SNB. Fifteen of 42 (36%) patients had lymph node metastases. The SLN was positive in all women with axillary metastases (negative predictive value, 100%). CONCLUSIONS: If confirmed by larger series, a negative SNB may eliminate the need for ALND for select women with breast cancer.
Adult↗
HIV-associated nephropathy.
BACKGROUND: Patients with HIV-1 infection are at risk for developing renal diseases with diverse etiologies. Acute renal failure occurs in up to 20% of hospitalized patients with HIV infection, and chronic renal disease of diverse etiology has been reported. The single most common cause of chronic renal insufficiency in HIV-1+ patients is HIV-associated nephropathy (HIVAN). Typical morphologic features include enlarged kidneys, microcystic tubule dilatation, tubulointerstitial inflammation, and focal and segmental glomerulosclerosis. METHODS: The pathogenesis, epidemiology, and treatment options for HIVAN are discussed. In studying the epidemiology of the disease, we reviewed several renal disease databases, including the United States Renal Data Systems and New York State End Stage Renal Disease Network. We have previously reported our experience with HIVAN at Mount Sinai Medical Center. RESULTS: The exact cause of the renal disease remains unknown. The importance of a direct effect of HIV-1 viral protein(s) or renal HIV-1 gene expression in disease pathogenesis is supported in the murine model of HIVAN, but definitive proof of renal cell infection in humans is lacking. Further study is required to clarify this issue. We estimate that HIVAN is the fourth leading cause of end-stage renal disease (ESRD) among Blacks between the ages of 20 and 64 years, only slightly behind hypertension, diabetes, and chronic glomerulonephritis. At Mount Sinai Hospital HIVAN accounts for 20% of newly diagnosed ESRD in young black adults. It has become the third leading cause of ESRD in this group, after hypertension and diabetes. CONCLUSIONS: In seropositive patients with renal disease, renal biopsies should be performed to confirm the diagnosis and determine the true incidence. Special attention should be directed toward understanding the underlying cause(s) of HIVAN. A multicenter trial to explore the potential for antiviral therapy in this disease should be initiated.
AIDS-Associated Nephropathy↗
Isolation and characterization of basal cells from human upper respiratory epithelium.
Cellular pathways of normal and reparative differentiation of upper airway epithelium are not well understood. Of the three main cell types, basal and secretory cells are known to divide, while ciliated cells are considered terminally differentiated. Several investigations support the role of the basal cell as a progenitor cell type, but others suggest that the secretory cell can regenerate a complete mucocilliary epithelium. Thus, lineage relationships within renewing adult epithelia are still unclear. Understanding the pathways involved in upper airway epithelial cell differentiation is critical for studying injury and repair mechanisms and for developing clinical strategies for tracheal reconstruction. We undertook the current studies to determine the integrin profile of isolated human upper airway basal cells. Respiratory epithelial cells (REC) were isolated by elastase digestion, stained with FITC-labeled Griffonia simplicifolia isolectin B4 (GSI-B4), and sorted by flow cytometry. Approximately 80% of the lectin-positive cells were basal cells, as determined by morphology and cytokeratin staining. These cells expressed integrins alpha 1, alpha 2, alpha 3, alpha 5, alpha v beta 5, beta 1, beta 3, and alpha 6 beta 4, by immunohistochemistry. This is the first report to identify the integrin profile of isolated human upper airway basal cells. These basal cells could be maintained on type I collagen for at least 7 days, where they became partially confluent and retained expression of cytokeratins 5 and 14. Availability of pure populations of basal cells should permit investigations of their role in both normal and maladaptive repair of adult upper airway epithelium.
Adult↗
Purification and analysis of CIP/KIP proteins.
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Amino Acid Sequence↗
Differential modulation of G1 cyclins and the Cdk inhibitor p27kip1 by platelet-derived growth factor and plasma factors in density-arrested fibroblasts.
Stimulation of quiescent Balb/c 3T3 fibroblasts into S phase requires the synergistic action of platelet-derived growth factor (PDGF) and progression factors found in platelet-poor plasma (PPP). Traverse of the G1/S phase boundary and the initiation of DNA replication require functional cyclin E-cyclin-dependent kinase (Cdk) 2 and cyclin A-Cdk2 complexes; however, the mechanisms by which PDGF and PPP regulate Cdk2 activation are not known. Density-arrested fibroblasts contain low levels of cyclins E and A, and high levels of the Cdk inhibitor p27kip1. Exposure of PDGF, which stimulates cell cycle entry but not progression through G1, induces the formation of cyclin D1-Cdk4 complexes that bind p27kip1 and titrate the pool of Kip1 available to inhibit Cdk2. In addition, PDGF stimulates a moderate transient reduction in the abundance of p27kip1 protein. However, limited expression of cyclin E and cyclin A is observed after PDGF treatment, and in the absence of PPP, p27 levels are sufficient to bind and inactivate existing cyclin-Cdk complexes. Although plasma does not significantly increase the proportion of Kip1 bound to cyclin D1-Cdk4, stimulation of PDGF-treated cells with plasma does overcome the threshold inhibition of p27kip1 by further increasing the expression of cyclins E and A and decreasing the amount of Kip1 over a prolonged time period. Our results indicate that the distinct mitogenic activities of PDGF and PPP differentially influence the activation of cyclin E- and cyclin A-associated kinases that ultimately regulate entry into S phase.
1-Methyl-3-isobutylxanthine↗
A question of balance: the role of cyclin-kinase inhibitors in development and tumorigenesis.
Cyclin-kinase inhibitors (CKIs) are versatile negative regulators of cell proliferation that function in developmental decisions, checkpoint control and tumour suppression. Phenotypic examination of mice lacking individual CKIs has begun to reveal the specialized roles that each of these proteins play in vivo. This review focuses on what has been learned about the role of CKIs in development and cancer through the generation of knockout animals. The authors discuss whether differences in knockout phenotypes between CKIs reflect differential use of these inhibitors by the organism or a fundamental difference between the inhibitors, and suggest a balance hypothesis to explain the different effects observed.
Journal Article↗