Collapsing focal segmental glomerulosclerosis with recovery of renal function: an uncommon complication of interferon therapy for hepatitis C.
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Acute Kidney Injury↗
Biomedical subjects
A Ahmed
Publications and source records attributed to A Ahmed.
Purification and partial amino acid sequence of proteins from human epidermal keratinocyte conditioned medium.
Keratinocytes are the main cell type of the epidermis. They secrete a variety of proteins and peptides that have diverse roles in epidermal physiology. In this report, we present purification and partial amino acid sequence of LEKTI, a serine proteinase inhibitor, and DAN (NO3) zinc-finger protein, a tumor suppressor protein of neuroblastoma, from human keratinocyte conditioned medium. Epidermal keratinocytes were isolated from human foreskin and serially passaged in a defined medium (MSBM). At confluence of the fourth passage, MSBM medium was replaced with protein-free Dulbecco's modified Eagle medium/F12 (DMEM:F12) 3:1 base medium and collected every 24 h for 4 days. Medium was pooled and concentrated using a stirred cell concentrator. Concentrated medium was diluted 1:1 in 50 mM sodium phosphate, pH 8 buffer, and loaded onto a preparative heparin affinity column. Proteins/peptides were purified from heparin column passthrough by the combination of preparative and analytical FPLC-based gel filtration chromatography and reversed-phase HPLC. Samples electroblotted onto a PVDF support were sequenced by Edman degradation in a gas-phase sequencing system.
Amino Acid Sequence↗
A transcriptional feedback loop for tissue-specific expression of highly cytotoxic genes which incorporates an immunostimulatory component.
Transcriptional targeting of cytotoxic genes is an important way to control toxicity associated with gene transfer therapies, but supposedly, tissue-specific promoters are often either very weak and/or leaky. In addition, the phenotypic leakiness of such tissue-specific promoters is dependent upon the toxicity of the gene being used. Therefore, we devised a transcriptional feedback loop to restrict gene expression of very potent genes to melanoma cells. We screened different elements of the human tyrosinase promoter to find one which gave no detectable expression in non-melanoma cells but was active in melanoma cell lines. This weak, but highly tissue specific, element (Tyr-300) was then used as the basis for a transcriptional amplification feedback loop in which a consensus heat shock element (HSE) was cloned upstream of Tyr-300. The cytotoxic gene was cloned downstream of the HSE-Tyr-300 element along with a mutated form of the heat shock factor-1 (HSF-1) transcription factor, which no longer requires cellular stress to activate its trimerisation, nuclear localisation and transcriptional activation properties. Low levels of expression from Tyr-300 initiated expression of both the cytotoxic and the HSF-1 genes in melanoma cells. Gradual build up of HSF-1 amplified expression through binding to the HSE to give levels of cytotoxicity similar to that provided by a CMV promoter. However, no leakiness was observed in multiple non-melanoma cell lines tested. In addition to amplifying low levels of weak tissue-specific expression, the use of HSF-1 also leads to activation of endogenous stress-related genes such as hsp70. Induction of these genes, in the presence of cell killing by the cytotoxic gene, is a highly immunostimulatory event which enhances the antitumour vaccination effects of direct tumour cell destruction. Having demonstrated the compatibility of the component elements in plasmid form, we incorporated the feedback loop into a hybrid LTR-modified retroviral vector and confirmed that the system can be effective in the form of a viral vector. The format of the feedback loop described here could be exploited for any tissue type in which a highly tissue-specific element can be identified but which is itself too weak to be effective therapeutically.
Animals↗
A randomised trial of flexible versus rigid nasendoscopy in outpatient sinonasal examination.
Nasendoscopy is used extensively in ENT clinics both as a diagnostic tool and for local postoperative care. Both flexible and rigid fibreoptic scopes are available for the purpose of sinonasal examination. A prospective study of a flexible versus rigid endoscope was carried out, randomly assigning one type of scope to each nostril of 56 patients presenting to clinic with sinonasal symptomatology. Patients awarded each type of scope a pain score on an analogue scale, according to the level of discomfort experienced, and the operator noted the number of structures seen. Significantly more structures were visualized with the rigid scope than the flexible scope (P = 0.05). The pain scores were similarly in favour of the rigid scope, showing a trend to less discomfort. The rigid nasendoscope is the scope of choice for sinonasal examinations in the outpatient clinic based on these data.
Adult↗
Telomeres and telomerase: basic science implications for aging.
Life expectancy in the United States and other developed nations has increased remarkably over the past century, and continues to increase. However, lifespan has remained relatively unchanged over this period. As life expectancy approaches maximum human lifespan, further increase in life expectancy would only be possible if lifespan could also be increased. Although little is known about the aging process, increasing lifespan and delaying aging are the research challenges of the new century, and have caused intense debate and research activities among biogerontologists. Many theories have been proposed to explain the aging process. However, damage to deoxyribonucleic acid (DNA) is the centerpiece of most of these. Recently telomere shortening has been described to be associated with DNA damage. Located at the ends of eukaryotic chromosomes and synthesized by telomerase, telomeres maintain the length of chromosomes. The loss of telomeres can lead to DNA damage. The association between cellular senescence and telomere shortening in vitro is well established. In the laboratory, telomerase-negative differentiated somatic cells maintain a youthful state, instead of aging, when transfected with vectors encoding telomerase. Many human cancer cells demonstrate high telomerase activity. Evidence is also accumulating that telomere shortening is associated with cellular senescence in vivo. What causes changes in expression of telomerase in different cell types and premature aging syndromes? Does the key to "youthfulness" lie in our ability to control the expression of telomerase? We have reviewed the contemporary literature to find answers to these questions and explore the association between aging, telomeres, and telomerase.
Aged↗
The "uninhibited rectum": a cause of fecal incontinence.
OBJECTIVE: The uninhibited (unstable) rectum has been defined as a cause offecal incontinence (FI) in patients with supraconal lesions. In this study, we tested the hypothesis that the uninhibited rectum may be a cause of FI in patients with normal anal pressure and sphincteric mechanism who were considered to have idiopathic FI. METHODS: The study comprised 82 patients (mean age 38.2 +/- 11.2 years; 58 women and 24 men) with idiopathic FI and a control group of 20 healthy volunteers (mean age 36.3 +/- 10.6 years; 14 women and 6 men). Inclusion criteria for FI patients were normal electromyogram of the external anal sphincter and puborectalis muscle, and normal anal sensation, pressure, and endosonography. Rectometry was performed using rectal balloon inflation with CO2 at a rate of 150 cc/min. Rectometrograms were assessed quantitatively and qualitatively. RESULTS: In 79 FI patients, the first rectal sensation was not felt. Urge was perceived at the time of balloon expulsion, which could not be prevented by voluntary sphincteric squeeze. In the remaining 3 patients, the first sensation was perceived but urge coincided with balloon expulsion. Rectometrography showed moderate and gross fluctuations in the tone limb that were not associated with significant changes in intra-abdominal pressure. This contrasted with normal subjects in whom the tone limb exhibited no fluctuations or minor fluctuations that roughly paralleled the intra-abdominal pressure fluctuations. The rectal distension volume at balloon expulsion was significantly lower in FI patients than in controls (P < .05). CONCLUSIONS: These findings suggest that FI can be explained by the fact that the first rectal sensation was that of urge, which was perceived synchronously with balloon expulsion. That is, the balloon had been expelled before the patient could voluntarily squeeze the sphincters to abort expulsion. We postulated that during inflation with small volumes, the rectum did not adapt as in controls, but responded with contractions, which appear to be reflected in the multiple fluctuations in the tone limb. FI in these patients appears to be a consequence of the unstable or uninhibited rectum.
Adolescent↗
Cancer induction in the DMBA hamster cheek pouch: a modified technique using a promoter.
OBJECTIVE: To evaluate a modified method of carcinogenesis induction using the 9,10-dimethyl-1,2-benzanthracene (DMBA) sustained-release suture technique followed by arecaidine promotion in the hamster cheek pouch model. STUDY DESIGN: Prospective, controlled animal study. METHODS: Number 3-0 cotton sutures were impregnated with DMBA and coated with silicone elastomer. These sutures were placed in the cheek pouch of Syrian hamsters in the submucosal space to a length of approximately 1.5 cm. The suture placement was confirmed every 2 weeks and replaced if lost. After 12 weeks, the DMBA-coated sutures were removed. The cheek pouches were everted and painted with a solution of arecaidine three times weekly for up to an additional 4 weeks or until the tumor reached a size of 100 mm2. RESULTS: We placed sutures in 165 Syrian hamster cheek pouches. Of these, 133 hamsters (80.6%) produced squamous cell carcinomas that reached a size of 100 mm2 and then were randomly selected for treatment in a new drug trial. Twenty-six hamsters (15.8%) were found dead and 6 (3.6%) were killed because of severe inflammation. CONCLUSIONS: The DMBA hamster cheek pouch model is a reliable and efficient animal model for inducing squamous cell carcinoma and can be used to study upper aerodigestive tract tumors.
9,10-Dimethyl-1,2-benzanthracene↗
Treating chronic Hepatitis C patients with psychiatric disorders: an uphill battle.
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Clinical Trials as Topic↗
Delayed fatal hemorrhage from pseudoaneurysm of the hepatic artery after percutaneous liver biopsy.
Hemorrhage is the most common serious complication of percutaneous liver biopsy. Liver biopsy is usually done in an outpatient setting because most significant hemorrhage is evident within a few hours after biopsy. Delayed hemorrhage occurs much less frequently but carries a much higher mortality. We present a 41-yr-old man with chronic hepatitis C who underwent a percutaneous liver biopsy uneventfully but was found to have a pseudoaneurysm of the hepatic artery 5 days later. Shortly after admission, the patient experienced bleeding into the liver from the pseudoaneurysm, which was controlled initially by angiographic embolization. However, recurrent bleeding could not be controlled by repeat angiography and surgical intervention, and the patient expired. The diagnosis and management of pseudoaneurysm of the hepatic artery complicating liver biopsy is reviewed.
Adult↗
Liver transplantation: evolving patient selection criteria.
The widespread recognition of the success of liver transplantation as a treatment for most types of acute and chronic liver failure has led to increased referrals for transplantation in the setting of a relatively fixed supply of cadaver donor organs. These events have led to a marked lengthening of the waiting time for liver transplantation, resulting in increased deaths of those on the waiting list and sicker patients undergoing transplantation. Nearly 5000 liver transplantations were performed in the United States in 2000, while the waiting list grew to over 17,000 patients. The mounting disparity between the number of liver transplant candidates and the limited supply of donor organs has led to reassessment of the selection and listing criteria for liver transplantation, as well as revision of organ allocation and distribution policies for cadaver livers. The development of minimal listing criteria for patients with chronic liver disease based on a specific definition for decompensation of cirrhosis has facilitated the more uniform listing of patients at individual centres across the United States. The United Network for Organ Sharing, under pressure from transplant professionals, patient advocacy groups and the federal government, has continuously revised allocation and distribution policies based on the ethical principles of justice for the individual patient versus optimal utility of the limited organ supply available annually. Beginning in 2002, it is likely that the Model for End-stage Liver Disease (MELD) score will be implemented to determine disease severity and direct donor organs to the sickest patients rather than to those with the longest waiting times.
Health Care Rationing↗
Arsonists in maximum security: mental state at time of firesetting and relationship between mental disorder and pattern of behaviour.
Seventy-nine arsonists were identified in a Special Hospital. Sixty-eight had a clinical interview which included an analysis of symptoms present at the time of the most recent fire. Mentally ill arsonists did not differ from Psychopathic Disorder arsonists in their self-report of symptoms at the time of firesetting, the major difference was in the time course of their behaviour. Mentally ill arsonists lit their first fire on average eight years later than did Psychopathic Disorder patients. Further analysis indicates that PD women have a distinct group of current symptoms and behaviours.
Adolescent↗
Influence of HIV infection on presentation of Kaposi's sarcoma.
We report a retrospective review of 57 patients with endemic Kaposi's sarcoma (EKS) seen between 1981 and 1990 and 40 prospectively diagnosed patients with and without human immunodeficiency virus (HIV) infection seen between 1991 and 1995. In the retrospective study 52 patients were males and five were females. Their ages ranged between 15 and 62 years with a mean of 39 years.Thirty-five (61%) patients had symptoms for more than 1 year. Nodular KS was seen in 75% of the patients. In the prospective study 26 patients had EKS while 14 had AIDS associated KS (AAKS). Among the patients with EKS 24 were males and two were females. The mean duration of symptoms was 20 months. The CD4 count done on nine patients ranged between 900 and 1300 cells/mm3 and there was no mortality within 1 year of presentation. Eleven of the patients with AAKS were males and three were females. Their ages ranged between 22 months and 41 years with a mean of 26. Nine patients had symptoms for less than 6 months. Ten patients had peripheral lymphadenopathy. CD4 counts done on 11 patients ranged between 200 and 800 cells/mm3. Five patients (35%) died within 6 months of presentation. Between 1991 and 1995, 486 patients were seen with HIV infection. Patients with AAKS present with fulminant disease which seemed quickly fatal.
Adolescent↗
Activation of functional oxytocin receptors stimulates cell proliferation in human trophoblast and choriocarcinoma cell lines.
Despite oxytocin receptors (OTR) being present in human chorio-decidual tissues, their expression and role in placental trophoblast cells in the context of tumor growth or physiological functions related to cell proliferation have never been examined. In the present study we demonstrate the presence and functionality of OTR in normal human trophoblast cell lines (ED77 and ED27) and a choriocarcinoma cell line (BeWo). RT-PCR and immunofluorescence analysis revealed the presence of OTR messenger RNA and protein in these cells. Binding studies using [(125)I]oxytocin ([(125)I]OT) antagonist confirmed the presence of specific binding sites in ED27, ED77, and BeWo cells. OTR functionality was demonstrated by measuring the OT-induced increase in the intracellular calcium concentrations. This effect was dose dependent and was blocked by the selective OT antagonist d(CH(2))(5)[Tyr(Me)(2),Thr(4), Tyr-NH(2)(9)]OVT (OT antagonist). Furthermore, two proteins with apparent molecular masses of 125 and 60 kDa became tyrosine phosphorylated in all of the cell lines after OT stimulation (and an additional protein of 45 kDa in BeWo choriocarcinoma cells), suggesting that this peptide can stimulate tyrosine kinase activity. Finally, we observed a dose-dependent OT stimulation of cell proliferation associated with OTR activation that was completely abolished by the selective OT antagonist. These findings provide the first evidence of the presence of functional OTR in normal trophoblast cell lines as well as in choriocarcinoma cells and show that a specific effect of OT on normal and neoplastic trophoblast is to promote cellular proliferation.
Calcium↗
Tie-2 is expressed on thyroid follicular cells, is increased in goiter, and is regulated by thyrotropin through cyclic adenosine 3',5'-monophosphate.
Angiogenesis is coordinated with follicular cell growth in goitrogenesis. The angiopoietins, Ang-1 and Ang-2, are angiogenic growth factors acting through Tie-2, a tyrosine kinase receptor. We have examined the expression and regulation of the angiopoietins and Tie-2 in human and rat thyroids. In human goiters there was increased Tie-2 immunostaining, compared with that in normal thyroids, on both follicular and endothelial cells. In an induced goiter in rats, in situ hybridization showed increased expression of messenger ribonucleic acids (mRNAs) for Tie-2 and Ang-1 in follicular cells. As Tie-2 has previously been believed to be restricted to cells of endothelial lineage in adults, we examined its expression further in isolated follicular cells. Tie-2 and Ang-1 mRNA expression in human thyrocytes was confirmed by ribonuclease protection assay. Ang-2 mRNA was not detected in human cultures or rat thyroids. In both human follicular cell cultures and FRTL-5 cells, immunoblotting showed that Tie-2 expression was increased by TSH and agents that increased intracellular cAMP. In conclusion, we have demonstrated the expression of Tie-2 and Ang-1 in thyroid epithelial and endothelial cells, and have shown the regulation of Tie-2 by TSH and cAMP in follicular cells. Tie-2 expression is increased in goiter in both humans and rats, consistent with a role in goitrogenesis.
Angiopoietin-1↗
Two new aurones from marine brown alga Spatoglossum variabile.
Two new aurones, 4'-chloro-2-hydroxyaurone (1) and 4'-chloroaurone (2) were isolated from Spatoglossum variabile. The structures of these compounds were elucidated by modern spectroscopic techniques.
Benzofurans↗
Mediastinal tuberculosis in a 10-month-old child.
We report a rare case of mediastinal tuberculosis in a child who presented as a possible inhaled foreign body. A 10-month-old girl was admitted with a five-month history of cough, wheeze and problematic feeding, thought initially to be due to asthma. A clinical deterioration and subsequent X-rays suggested an inhaled foreign body. However, at direct laryngotracheobronchoscopy no foreign body was found and subsequent investigations revealed a subcarinal mediastinal mass. She underwent a thoracotomy and excision of the mass, the histological analysis of which revealed it to be of tuberculous origin. When a patient presents with symptoms of upper airway obstruction which are highly suggestive of a foreign body, other causes such as mediastinal tuberculosis must be borne in mind when no foreign body can be found. Although rare, cases of tuberculosis are apparently increasing and the otolaryngologist must be aware of its various manifestations and submit specimens for appropriate analysis. We also briefly review mediastinal lymphadenopathy due to tuberculosis.
Bronchi↗
Abdominal tuberculosis: the great mimic.
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Adult↗
Expression of VEGF-C and activation of its receptors VEGFR-2 and VEGFR-3 in trophoblast.
Placental villous development requires the co-ordinated action of angiogenic factors on both endothelial and trophoblast cells. Like vascular endothelial growth factor (VEGF), VEGF-C increases vascular permeability, stimulates endothelial cell proliferation and migration. In the present study, we investigated the expression of VEGF-C and its receptors VEGFR-3 and VEGFR-2 in normal and intrauterine growth-restricted (IUGR) placenta. Immunolocalisation studies showed that like VEGF and VEGFR-1, VEGF-C, VEGFR-3 and VEGFR-2 co-localised to the syncytiotrophoblast, to cells in the maternal decidua, as well as to the endothelium of the large placental blood vessels. Western blot analysis demonstrated a significant decrease in placental VEGF-C and VEGFR-3 protein expression in severe IUGR as compared to gestationally-matched third trimester pregnancies. Conditioned medium from VEGF-C producing pancreatic carcinoma (Suit-2) and endometrial epithelial (Hec-1B) cell lines caused an increased association of the phosphorylated extracellular signal regulated kinase (ERK) in VEGFR-3 immunoprecipitates from spontaneously transformed first trimester trophoblast cells. VEGF121 caused dose-dependant phosphorylation of VEGFR-2 in trophoblast cells as well as stimulating DNA synthesis. In addition, premixing VEGF165 with heparin sulphate proteoglycan potentiated trophoblast proliferation and the association of phospho-ERK with the VEGFR-2 receptor. VEGF165-mediated DNA synthesis was inhibited by anti-VEGFR-2 neutralising antibody. The results demonstrate functional VEGFR-2 and VEGFR-3 receptors on trophoblast and suggest that the decreased expression of VEGF-C and VEGFR-3 may contribute to the abnormal villous development observed in IUGR placenta.
Blotting, Western↗