The good and bad of chemoprophylaxis.
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Abdomen↗
Biomedical subjects
J D Williams
Publications and source records attributed to J D Williams.
A history of the dissolution of retained choledocholithiasis.
BACKGROUND: Common duct calculi retained after gallbladder surgery continue to present a clinical challenge especially in the era of minimally invasive surgery. This review examines the strategy of dissolution therapy used throughout the history of biliary tract surgery and its use to the modern surgeon. DATA SOURCES: Original journal articles and reviews were identified using standard surgical textbooks and MEDLINE. Keywords for searching included choledocholithiasis, dissolution, mono-octanoin, common duct stones, MTBE, cholic acid, and gallstones. CONCLUSIONS: Dissolution therapy used initially as an alternative to open surgery is now used more effectively as an adjunct to laparoscopic or endoscopic biliary tract surgery. The current review demonstrates a majority of patients with retained choledocholithiasis respond to dissolution and can be safely managed without choledochotomy.
Administration, Topical↗
In vivo exposure to bicarbonate/lactate- and bicarbonate-buffered peritoneal dialysis fluids improves ex vivo peritoneal macrophage function.
The impact on peritoneal macrophage (PMO) function of acidic lactate-buffered (Lac-PDF [PD4]; 40 mmol/L of lactate; pH 5.2) and neutral-pH, bicarbonate-buffered (TB; 38 mmol/L of bicarbonate; pH 7. 3) and bicarbonate/lactate-buffered (TBL; 25 mmol/L of bicarbonate/15 mmol/L of lactate; pH 7.3) peritoneal dialysis fluids (PDFs) was compared during a study of continuous therapy with PD4, TB, or TBL. During a run-in phase of 6 weeks when all patients (n = 15) were treated with their regular dialysis regimen with Lac-PDF, median PMO tumor necrosis factor alpha (TNFalpha) release values were 203.6, 89.9, and 115.5 pg TNFalpha/10(6) PMO in the patients subsequently randomized to the PD4, TB, and TBL treatment groups, respectively. Median stimulated TNFalpha values (serum-treated zymosan [STZ], 10 microgram/mL) were 1,894.6, 567.3, and 554.5 pg TNFalpha/10(6) PMO in the same groups, respectively. During the trial phase of 12 weeks, when the three groups of patients (n = 5 per group) were randomized to continuous treatment with PD4, TB, or TBL, median constitutive TNFalpha release values were 204.7, 131.4, and 155.4 pg TNFalpha/10(6) PMO, respectively. Stimulated TNFalpha values (STZ, 10 microgram/mL) were 1,911, 1,832, and 1,378 pg TNFalpha/10(6) PMO in the same groups, respectively. Repeated-measures analysis of variance comparing the run-in phase with the trial phase showed that PMO TNFalpha release was significantly elevated in patients treated with both TB (P = 0.040) and TBL (P = 0.014) but not in patients treated with Lac-PDF (P = 0. 795). These data suggest that patients continuously exposed to bicarbonate- and bicarbonate/lactate-buffered PDFs might have better preserved PMO function and thus improved host defense status.
Adult↗
Low-density lipoprotein stimulates mesangial cell proteoglycan and hyaluronan synthesis.
BACKGROUND: Hyperlipidaemia leads to glomerulosclerosis in small mammals and may contribute to progressive renal disease in man. One prominent feature of lipid-induced glomerular injury in animal models is the accumulation of mesangial matrix. These studies were designed to investigate whether low-density lipoprotein (LDL) enhanced mesangial cell (MC) matrix deposition by modulating the production of proteoglycans (PG) and hyaluronan (HA). METHODS: Growth arrested human MC were metabolically labelled with either 50 microCi/ml Na(2)[(35)S]sulphate or 25 microCi/ml [(3)H]glucosamine and stimulated with LDL (10-100 microg/ml). The radiolabelled PG and HA extracted from the cell layer and the culture medium were isolated, quantified and characterized. Comparison of the PG core proteins synthesized by MC was carried out using Western blot analysis. RESULTS: LDL stimulation led to a dose- and time-dependent increase in [(35)S]sulphate incorporation into PG in the culture medium and to a lesser extent in the cell layer. Analysis of the glycosaminoglycan (GAG) chains showed no difference in either their size or charge. Enzyme digestion studies demonstrated that the synthesis of both chondroitin sulphate PG (CSPG) and heparan sulphate PG (HSPG) was enhanced as was the production of the core proteins of versican (a large CSPG), perlecan (a basement membrane HSPG) and to a lesser extent decorin (a small dermatan sulphate PG (DSPG)). An increase in HA synthesis was also demonstrated in [(3)H]glucosamine labelled cells following LDL stimulation. CONCLUSION: LDL selectively enhances the synthesis of specific PG and HA by mesangial cells. Such effects may contribute to the expansion of the mesangial matrix and modify cell-matrix interactions in lipid-induced renal damage.
Blotting, Western↗
The prevention of antibiotic resistance during treatment.
Prevention of emergence of antibiotic resistance during treatment is an important goal when prescribing antimicrobials. Antibiotic resistant bacteria can emerge in three main ways--by acquisition of new genes via transposons or horizontal gene transfer, by selection of resistant variants and by selection of naturally resistant strains. In order to minimize emergence of antibiotic resistance during therapy it is important to try and avoid antibiotics which encourage the transfer of resistance genes, to avoid selection of resistant variants from susceptible pathogens and to avoid ablation of antibiotic susceptible normal flora. However, implementing these objectives is not always easy. This paper discusses possible ways of limiting the emergence of resistant bacteria during treatment. It does not consider how to prevent the spread of these strains from person to person. The prevalence of antibiotic-resistant bacteria depends upon the selection of antibiotic-resistant strains and spread of these strains from person to person. Prevention therefore consists of two parts--the prevention of acquisition of resistance/selection of antibiotic-resistant variants and interrupting the mechanisms by which person-to-person spread can occur. This paper considers only the first of these two influences on prevalence of resistance.
Anti-Bacterial Agents↗
Mycosis fungoides masquerading as an ischemic foot.
This case is of a man with bilateral lower-extremity ischemia and a solitary nonhealing ulcerated lesion of the right great toe. After revascularization with an aortobifemoral bypass, his right ABI increased from 0.5 to approximately 0.75, but the ulcerated toe lesion did not show signs of healing and instead progressed to a deeper ulceration exposing bone. Because of presumptive osteomyelitis, we performed a great toe amputation, and immunohistochemical analysis of the lesion revealed late plaque stage mycosis fungoides (MF). We present this case to alert the vascular surgeon to this diagnostic possibility when confronted with an apparent ischemic lesion and to describe what made this particular lesion suspicious for MF. To the best of our knowledge, this is the first case of MF presenting solely as an ischemic lesion.
Adult↗
Augmentation of kidney injury by basic fibroblast growth factor or platelet-derived growth factor does not induce progressive diabetic nephropathy in the Goto Kakizaki model of non-insulin-dependent diabetes.
Diabetes is now the most common cause of kidney failure. The pathogenesis of diabetic nephropathy in both type 1 and type 2 diabetes, however, is still incompletely understood. Two mechanisms postulated to contribute to the pathogenesis of progressive diabetic nephropathy are glomerular cell proliferation and glomerular visceral epithelial cell or podocyte injury. The aim of the current study was to determine whether the aggravation of mesangial cell injury or podocyte injury in isolation would induce progressive diabetic nephropathy. Specifically, we examined whether the administration of either platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in sub-nephritogenic doses might lead to an aggravation of kidney structural changes associated with hyperglycemia, resulting in progressive kidney damage in the Goto Kakizaki (GK) rat, which is a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), in which progressive kidney disease does not develop spontaneously. The results demonstrate that the administration of PDGF to hyperglycemic GK rats led to acute mesangial cell proliferation and activation as assessed by 5-bromo-2'-deoxyuridine-positive nuclei and immunostaining for alpha-smooth muscle actin. Despite acute mesangial cell activation and proliferation, PDGF treatment had no long-term effect on either kidney structure or function. Similarly, treatment of GK rats with bFGF, despite the augmentation of podocyte injury as demonstrated by de novo expression of glomerular desmin expression, did not lead to the development of progressive diabetic nephropathy. In summary, the data in the current manuscript suggest that the additive effect of hyperglycemia and superimposed isolated mesangial cell or podocyte injury does not lead to progressive diabetic nephropathy. This further emphasises the multifactorial nature of the pathogenesis of progressive diabetic nephropathy.
Actins↗
Differential changes in frontal and sub-temporal components of mismatch negativity.
Novel evidence is reported showing changes in the mismatch negativity (MMN) event-related potential (ERP) that followed a different time course in frontal and sub-temporal (mastoid) electrodes. MMN recorded in frontal electrode sites, assumed to originate predominantly in the superior temporal gyrus, showed amplitude enhancement from the first to the second recording block. In contrast, the amplitude of the sub-temporal, mastoid component (termed mismatch positivity, MMP) diminished. In addition to these changes in the MMN elicited by tone duration deviants, there were also significant changes in the ERP to the standard stimulus. The positivity in the standard ERP between 50 and 150 ms increased in bilateral mastoid electrodes but showed no reliable change in frontal electrodes. This suggests that more than one generator underpins the two mismatch components, and that the sub-temporal mismatch component does not only represent a polarity reversal of the main MMN component in the superior temporal gyrus.
Acoustic Stimulation↗
Isolation and identification of cyclic imide and deamidation products in heat stressed pramlintide injection drug product.
This report summarizes the identification of six cyclic imide [Asu] and two deamidation products from a sample of pramlintide final drug product that had been stressed at 40 degrees C for 45 days. The pramlintide degradation products were isolated by cation exchange high-performance liquid chromatography (HPLC) followed by reversed-phase HPLC. The isolated components were characterized by mass spectrometry (MS), tandem MS (MS/MS) and when necessary, by enzymatic (thermolysin) digestion followed by liquid chromatography/mass spectrometry (LC/MS) and sequence analysis. The isolated products were identified as [Asu14]-pramlintide, [Asu21]-pramlintide, [Asu22]-pramlintide, [Asu35]-pramlintide, [1-21]-succinimide-pramlintide, and [1-22]-succinimide-pramlintide. Also identified were [Asp35]-pramlintide, the deamidation product of pramlintide at Asn35, and [Tyr37-OH]-pramlintide, the deamidation product of the pramlintide amidated C-terminal Tyr. Together these data support those presented earlier (C. Hekman et al., Isolation and identification of peptide degradation products of heat stressed pramlintide injection drug product. Pharm Res 1998;15:650-9) indicating that the primary mechanism of degradation for pramlintide in this pH 4.0 formulation is deamidation, with six of the eight possible deamidation sites observed to undergo deamidation. Gln-10 and Asn-31 are the only two residues subject to deamidation for which none is observed. The data indicate that the cyclic imide products account for approximately 20% of the total thermal degradation while the deamidation products account for 64%. The remaining degradation is due to peptide backbone hydrolysis.
Amino Acid Sequence↗
Selection of resistant variants of respiratory pathogens by quinolones.
Quinolones are widely used in the treatment of respiratory tract infections. However, some disquiet has been expressed over using quinolones for community-acquired pneumonia since their activity is generally rather poor against Streptococcus pneumoniae. In addition, it is known that resistant variants emerge at a fairly high frequency during exposure of Enterobacteriaceae to quinolones; if this also occurred during quinolone treatment of community-acquired pneumonia it could lead to an increased risk of clinical failure. We therefore determined the selection rate of quinolone-resistant variants for six strains of S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis with nalidixic acid (except for S. pneumoniae), ciprofloxacin, ofloxacin and levofloxacin. We were only able to select resistant variants at low frequency from two of the six strains of S. pneumoniae with ciprofloxacin: no resistant variants were selected by either ofloxacin or levofloxacin. Variants of H. influenzae and M. catarrhalis with decreased susceptibility to quinolones were produced both with more strains and with a greater frequency; however, these variants still remained susceptible according to the NCCLS guidelines. Our study suggests that resistant variants of S. pneumoniae are relatively unlikely to occur in individuals treated with fluoroquinolones especially if they are given quinolones with enhanced anti-gram-positive activity compared to ciprofloxacin.
Anti-Infective Agents↗
The WHO model list of essential drugs.
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Catalogs, Drug as Topic↗
Beta-lactamases and beta-lactamase inhibitors.
Penicillin, the first of the beta-lactam antibiotics, was introduced into medical practice in the 1940s. Since then, a large number of different beta-lactams, including penicillins, cephalosporins, monobactams, and carbapenems, have been developed, all of which are structurally related through the presence of a core beta-lactam ring. Resistance to beta-lactam antibiotics among target pathogens developed early in the history of their use. Of the mechanisms of resistance, the most widespread and most important is the destruction of the beta-lactam ring, which is mediated by beta-lactamases. The fact that these resistance enzymes may be coded on plasmids means that they are mobile within a bacterial community, and that they have spread widely. Resistance to beta-lactams mediated by beta-lactamases can be overcome successfully with the use of beta-lactamase inhibitors. The combination of beta-lactams with beta-lactamase inhibitors restores the activity of the beta-lactams, allowing their continued clinical use. The development of beta-lactamase inhibitors allows clinicians to rely on the well-tolerated, clinically effective beta-lactam antibiotics to treat a variety of bacterial infections.
Anti-Bacterial Agents↗
Renal proximal tubular cell fibronectin accumulation in response to glucose is polyol pathway dependent.
BACKGROUND: Thickening and reduplication of the tubular basement membrane have been reported as early events in diabetic nephropathy. In this study, we have examined the polar requirements of proximal tubular cells for the d-glucose-stimulated accumulation of fibronectin and the mechanism by which this occurred, with particular emphasis on the polyol pathway. METHODS: To determine the polarity of fibronectin generation in response to glucose, LLC-PK1 cells were grown on porous tissue culture inserts. Monolayer confluence was determined by serial measurement of transepithelial resistance. Confluent cells were growth arrested by serum deprivation, and all experiments were performed under serum-free conditions. RESULTS: Application of 25 mm d-glucose to either the apical or basolateral aspect of LLC-PK1 cells led to fibronectin accumulation in the basolateral compartment. This reached statistical significance 24 hours following apical addition of glucose (2.6-fold increase compared with 5 mm d-glucose, P = 0.0025, N = 6 vs. N = 4 controls) and 12 hours after the basolateral addition of glucose (2.5-fold increase compared with 5 mm d-glucose, P = 0.03, N = 6 vs. N = 4 controls). Exposure of cells to glucose at either their apical or basolateral aspect leads to accumulation of intracellular glucose and polyol pathway activation, as assessed by sorbitol accumulation. The increase in fibronectin concentration in response to glucose was inhibited by the aldose reductase inhibitor sorbinil. At a dose of 100 micron sorbinil, there was a 59% inhibition of fibronectin accumulation in response to apical glucose (P = 0.004, N = 3 sorbinil vs. N = 4 controls) and a 66% inhibition in response to basolateral glucose (P = 0.008, N = 3 sorbinil vs. N = 4 controls) 48 hours after the addition of the inhibitor. Furthermore, fibronectin accumulation was also demonstrated following both the apical and basolateral addition of 1 mm sorbitol, but not following the addition of 25 mm galactose to either aspect of the cells. Following the addition of sorbitol, there was a 2. 8-fold increase in fibronectin 48 hours after apical stimulation (P = 0.01, N = 3 treated vs. N = 4 control) and a 2.27-fold increase following basolateral stimulation (P = 0.04, N = 3 treated vs. N = 4 control) at 24 hours. CONCLUSIONS: In summary, these data demonstrate that fibronectin generation in response to glucose was nonpolar in terms of application of glucose but was polar in terms of fibronectin accumulation. The mechanisms of glucose-induced modulation of fibronectin were mediated by polyol pathway activation and were more specifically related to the metabolism of sorbitol to fructose.
Aldehyde Reductase↗
TGF-beta1 stimulates the release of pre-formed bFGF from renal proximal tubular cells.
BACKGROUND: It is now clear that the progression of renal disease is closely correlated to the degree of renal interstitial fibrosis. We have previously demonstrated that the renal proximal tubular epithelial cell may contribute to the fibrotic response by the generation of profibrotic cytokines. Transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) are two of a group of profibrotic cytokines that have been associated with the development of renal interstitial fibrosis. In this study, we have examined the influence of TGF-beta1 on the generation of bFGF by renal tubular epithelial cells. METHODS: HK2 cells were grown to confluence and were serum deprived and stimulated with recombinant TGF-beta1 under serum-free conditions. Subsequently, supernatant, cell-associated, intracellular, and matrix-associated bFGF concentrations were determined by enzyme-linked immunosorbent assay (ELISA). bFGF mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The exposure of confluent serum-deprived HK2 cells to TGF-beta1 led to a significant increase in bFGF concentration in the cell culture supernatant. Twenty-four hours following the addition of 10 ng/ml TGF-beta1, this represented a twofold increase in bFGF concentration (control, 102 pg/ml, N = 24, vs. 202 pg/ml, N = 19, P = 0.0001). Despite the increase in bFGF concentration in the supernatant, there was no change in the expression of bFGF mRNA following the addition of TGF-beta1. The addition of 10 ng/ml of TGF-beta1 led to a 30% decrease in the total cell-associated bFGF concentration (control, 8.51 ng/ml, N = 16, TGF-beta1, 6.01 ng/ml, N = 13, P = 0.0042). This decrease in intracellular bFGF was associated with a 15% reduction in anti-bFGF antibody binding to fixed permeabilized cells, following the addition of 10 ng/ml of recombinant TGF-beta1 (N = 9, P = 0.0007), suggesting that the mechanism of stimulation of bFGF by TGF-beta1 involved the release of preformed bFGF from within the cells. In addition, following the addition of TGF-beta1, there was a significant dose-dependent decrease in the amount of bFGF sequestered in the extracellular matrix. At a dose of 10 ng/ml TGF-beta, this represented a greater than sevenfold decrease (N = 9, P = 0.0007) in matrix-bound bFGF, although this represented less than 3% of the total bFGF released into the supernatant. CONCLUSION: The data presented suggest that the main mechanism by which TGF-beta1 stimulates bFGF generation by proximal tubular epithelial cells is by stimulation of the secretion of preformed cytokine from within the cells.
Cell Line, Transformed↗
A scientific perspective on macrolide susceptibility. Introduction.
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Anti-Bacterial Agents↗
A comparison between single-dose fosfomycin trometamol (Monuril) and a 5-day course of trimethoprim in the treatment of uncomplicated lower urinary tract infection in women.
This study is a comparison of the microbiological and clinical efficacy of single-dose fosfomycin trometamol therapy and a 5 day course of trimethoprim in the treatment of uncomplicated urinary tract infection in female patients. Urine dip-slide samples were obtained from 547 female patients aged 18-65 by 22 General Practitioners (GPs) participating in the study from 21 centres in the UK. All patients were diagnosed as having a urinary tract infection by their GP on the basis of history and clinical examination. Patients were randomised to receive either single dose fosfomycin trometamol or a 5 day course of trimethoprim in a 2:1 ratio. Patients who had significant bacteriuria (> or = 10(5) c.f.u/ml) at the first visit (300) were included in the microbiological analysis. The two commonest urinary pathogens isolated were Escherichia coli and Staphylococcus saprophyticus. Trimethoprim resistance was more frequent amongst E. coli isolates whereas fosfomycin trometamol resistance was more common amongst S. saprophyticus isolates. Microbiological cure was demonstrated in 83.3% of the trimethoprim treated group and 83% of the fosfomycin trometamol treated group. Persistence of the infecting bacteria was seen in 17% of each treatment arm.
Adult↗
Isolation and identification of peptide degradation products of heat stressed pramlintide injection drug product.
PURPOSE: This report summarizes the identification of nine deamidation and four hydrolysis products from a sample of pramlintide injection final drug product that was subjected to stress at 40 degrees C for 45 days. METHODS: The pramlintide degradation products were isolated by strong cation exchange HPLC followed by reversed-phase HPLC. Subsequent to isolation, the molecular weight of each component was determined by liquid chromatography-mass spectrometry (LC/MS). Further characterization was accomplished by amino acid sequence analysis and/ or enzymatic (thermolysin) digestion followed by LC/MS and sequence analysis. RESULTS: The isolated products were identified as [iso-Asp21]-pramlintide, [iso-Asp3]-pramlintide, and [iso-Asp22]-pramlintide, the deamidation products of pramlintide with rearrangement at Asn21, Asn3, and Asn22, respectively. Also found were [Asp/iso-Asp14]-pramlintide, and [Asp/iso-Asp35]-pramlintide, the deamidation products at Asn14, and Asn35, and [Asp21]-pramlintide together with [Asp22]-pramlintide. For the deamidations at the 14th and 35th residues, it could not be determined whether the substance corresponded to the Asp or the iso-Asp product. The [Asp21] and [Asp22] products could not be separated from each other chromatographically but were both identified in a single fraction. Two minor degradation products were also identified as deamidated species. However, the sites of deamidation remain unknown. Also identified were [1-18]-pramlintide, [1-19]-pramlintide, [19-37]-pramlintide, and [20-37]-pramlintide, the products of hydrolytic peptide backbone cleavage at amino acids His18/Ser19 and Ser19/Ser20, respectively. One other product was isolated and tentatively identified as a cyclic imide intermediate preceeding deamidation. CONCLUSIONS: The primary mode of thermally induced degradation for this peptide is deamidation. A second degradation mechanism is peptide backbone hydrolysis.
Amino Acid Sequence↗
Leukocyte migration across human peritoneal mesothelial cells is dependent on directed chemokine secretion and ICAM-1 expression.
BACKGROUND: Leukocyte migration into the peritoneal cavity is a diagnostic feature of peritonitis in patients treated with peritoneal dialysis (PD). While neutrophil (PMN) influx is characteristic of the acute phase of peritoneal infection, significant mononuclear cell (MNC) infiltration, occurs throughout the whole period of infection. Recent data suggests that human peritoneal mesothelial cell (HPMC) adhesion molecule expression and the synthesis of chemotactic cytokines may be important in the process. METHODS: In the present study we have examined, the regulation and directed secretion of chemokines (IL-8, MCP-1 and RANTES) and the basolateral to apical migration of unstimulated leukocytes across mesothelial cell monolayers using an in vitro model where HPMC were grown on the porous membrane of tissue culture inserts. Separate experiments have defined the importance of chemokine synthesis and ICAM-1 expression in the transmigration process. RESULTS: Apical stimulation of HPMC with IL-1 beta or TNF alpha resulted in a time and dose dependent up-regulation of IL-8, MCP-1 and RANTES mRNA expression and synthesis. This secretion was predominately into the apical compartment (> 85%) with all chemokines. Apical pre-stimulation of HPMC resulted in a dose- and time-dependent migration of both PMN and MNC across HPMC. Neutrophil migration was significantly reduced in the presence of appropriate concentrations of polyclonal IL-8 antibody (IL-1 beta (100 pg/ml) 153 +/- 12 versus anti-IL-8 (100 ng/ml) 71 +/- 7 (X 10(3)) PMN, N = 6, P < 0.02) and in the presence of anti-ICAM-1 F(ab)'2 fragments or soluble ICAM-1. Constitutive and cytokine stimulated mononuclear cell migration was significantly reduced in the simultaneous presence of polyclonal MCP-1 or RANTES antibody. CONCLUSIONS: These data demonstrate that HPMC synthesize IL-8, MCP-1 and RANTES in response to inflammatory cytokines. HPMC-derived C-x-C and C-C chemokines might contribute to the intra-peritoneal recruitment of leukocytes during peritoneal inflammation.
Antibodies↗