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PubMed2006

Gravity spun polycaprolactone fibers for applications in vascular tissue engineering: proliferation and function of human vascular endothelial cells.

Poly(epsilon-caprolactone) (PCL) fibers produced by wet spinning from solutions in acetone under lowshear (gravity-flow) conditions resulted in fiber strength of 8 MPa and stiffness of 0.08 Gpa. Cold drawing to an extension of 500% resulted in an increase in fiber strength to 43 MPa and stiffness to 0.3 GPa. The growth rate of human umbilical vein endothelial cells (HUVECs) (seeded at a density of 5 x 10(4) cells/mL) on as-spun fibers was consistently lower than that measured on tissue culture plastic (TCP) beyond day 2. Cell proliferation was similar on gelatin-coated fibers and TCP over 7 days and higher by a factor of 1.9 on 500% cold-drawn PCL fibers relative to TCP up to 4 days. Cell growth on PCL fibers exceeded that on Dacron monofilament by at least a factor of 3.7 at 9 days. Scanning electron microscopy revealed formation of a cell layer on samples of cold-drawn and gelatin-coated fibers after 24 hours in culture. Similar levels of ICAM-1 expression by HUVECs attached to PCL fibers and TCP were measured using RT-PCR and flow cytometry, indicative of low levels of immune activation. Retention of a specific function of HUVECs attached to PCL fibers was demonstrated by measuring their immune response to lipopolysaccharide. Levels of ICAM-1 expression increased by approximately 11% in cells attached to PCL fibers and TCP. The high fiber compliance, favorable endothelial cell proliferation rates, and retention of an important immune response of attached HUVECS support the use of gravity spun PCL fibers for three-dimensional scaffold production in vascular tissue engineering.

Animals↗
PubMed2002

A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans.

A PBPK/PD model was developed for the organophosphate insecticide chlorpyrifos (CPF) (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), and the major metabolites CPF-oxon and 3,5,6-trichloro-2-pyridinol (TCP) in rats and humans. This model integrates target tissue dosimetry and dynamic response (i.e., esterase inhibition) describing uptake, metabolism, and disposition of CPF, CPF-oxon, and TCP and the associated cholinesterase (ChE) inhibition kinetics in blood and tissues following acute and chronic oral and dermal exposure. To facilitate model development, single oral-dose pharmacokinetic studies were conducted in rats (0.5-100 mg/kg) and humans (0.5-2 mg/kg), and the kinetics of CPF, CPF-oxon, and TCP were determined, as well as the extent of blood (plasma/RBC) and brain (rats only) ChE inhibition. In blood, the concentration of analytes followed the order TCP >> CPF >> CPF-oxon; in humans CPF-oxon was not quantifiable. Simulations were compared against experimental data and previously published studies in rats and humans. The model was utilized to quantitatively compare dosimetry and dynamic response between rats and humans over a range of CPF doses. The time course of CPF and TCP in both species was linear over the dose range evaluated, and the model reasonably simulated the dose-dependent inhibition of plasma ChE, RBC acetylcholinesterase (AChE), and brain (rat only) AChE. Model simulations suggest that rats exhibit greater metabolism of CPF to CPF-oxon than humans do, and that the depletion of nontarget B-esterase is associated with a nonlinear, dose-dependent increase in CPF-oxon blood and brain concentration. This CPF PBPK/PD model quantitatively estimates target tissue dosimetry and AChE inhibition and is a strong framework for further organophosphate (OP) model development and for refining a biologically based risk assessment for exposure to CPF under a variety of scenarios.

Acetylcholinesterase↗
PubMed1999

Treatment of the postenucleation socket syndrome with a new hydroxyapatite tricalcium phosphate ceramic implant.

PURPOSE: Surgical correction of the postenucleation socket syndrome (PESS) is challenging. Various biomaterials are used for reconstruction of the anophthalmic orbit, often with unsatisfactory long-term results. Implants have been placed between the periorbital and the orbital floor. The authors describe a new material composed of hydroxyapatite tricalcium phosphate (HA-TCP) in the form of ceramic blocks, to be placed into the orbital fat as a new surgical site. METHODS: Ten patients with PESS underwent surgery to compensate the volume deficit of the anophthalmic orbit. Blocks of HA-TCP were created by fragmentation of a larger piece, tailored as needed, and implanted in the orbital fat. The patients were monitored regularly with clinical and radiologic examinations to evaluate the behavior of the implants. RESULTS: The volume of the HA-TCP was measured in 5 cases (mean, 2.95 +/- 1.08 ml). A significant reduction of enophthalmos was obtained: mean Hertel exophthalmometry measured 12.7 +/- 2.5 mm preoperatively and 14 +/- 2.4 mm postoperatively (p < 0.05). The average prosthesis volume was significantly reduced in the cases measured: 2.7 ml +/- 0.94 ml preoperatively and 1.8 +/- 0.7 ml postoperatively (p < 0.02). There was a negative correlation between the HA-TCP implant volume and postoperative prosthesis volume (correlation coefficient = -0.925; p < 0.05). According to photographic evaluation, correction of the enophthalmos and of the superior sulcus depression were obtained in 70% and 90% of cases, respectively. Magnetic resonance imaging seems to demonstrate that the blocks become well integrated into the surrounding orbital tissue. CONCLUSION: The HA-TCP blocks correct some anomalies of PESS. Placement of the blocks directly into the orbital fat is a promising alternative to the traditional subperiosteal location.

Adolescent↗
PubMed1990

Exocrine pancreatic function (serum immunoreactive trypsin, fecal chymotrypsin, and pancreatic isoamylase) in Indian diabetics.

Forty-nine patients with tropical calcific pancreatitis (TCP), 51 insulin-dependent diabetics (IDDMs), 87 non-insulin-dependent diabetics (NID-DMs), and 66 nondiabetic controls were studied to evaluate their exocrine pancreatic function by measurement of serum immunoreactive trypsin (IRT, normal for white caucasians from the U.K. of 140-414 micrograms/L), pancreatic isoamylase (PIA, normal of 35-125 U/L), and fecal chymotrypsin (FCT, normal of greater than 6.6 u/g). The majority of patients were studied within 1 year of diagnosis. TCP subjects included 7 nondiabetics, 6 with impaired glucose tolerance (IGT-TCP), and 36 diabetics [fibrocalculous pancreatic diabetes (FCPD)]. There was evidence of active pancreatitis (IRT greater than 800 micrograms/L) and partial preservation of function in nondiabetic TCP subjects [median IRT of 220 micrograms/L (range of 102-1,360 micrograms/L), FCT of 2.2 u/g (range 0.7-12.8 u/g)] and also in IGT-TCP subjects [IRT of 370 micrograms/L (range of 30-1,360 micrograms/L), FCT of 4.2 u/g (range of 1-38 u/g)]. FCPDs showed severely diminished exocrine function [IRT of 50 micrograms/L (range of 0-184 micrograms/L), FCT of 0.23 u/g (range of 0-10.4 u/g)]; none showed IRT greater than 800 micrograms/L. IDDMs and NIDDMs also showed diminished exocrine pancreatic function in approximately 30 and approximately 10%, respectively. Controls showed a wide range of IRT and FCT concentrations; IRT concentrations tended to be higher than those reported in white Caucasians from the U.K. Three controls, one IDDM, and two NIDDMs showed "pancreatic" IRT concentrations in the absence of symptoms. PIA concentrations were diminished in FCPD but were similar in IDDM and NIDDM subjects compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2003

Le Fort I osteotomy in atrophied maxilla and bone regeneration with pure-phase beta-tricalcium phosphate and PRP.

Le Fort I osteotomy is a versatile procedure in oral and maxillofacial surgery for the correction of dysgnathias as well as for an easy approach to the surgical site in neurosurgery; however, it is rarely performed for a vertical advancement of the maxilla. This paper presents the successful use of the synthetic pure-phase beta-tricalcium phosphate (beta-TCP) Cerasorb (Curasan, Kleinostheim, Germany), together with autogenous bone at a ratio of 4:1, in combination with patients' own platelet-rich plasma for a vertical augmentation of completely atrophied maxillae, resulting in an advancement of 16 and 14 mm, respectively. After a period of 8 months the beta-TCP was completely resorbed and the x-ray control showed no residual granules in the defect sites. Pure-phase beta-TCP proved to be a bone-regeneration material, providing the patient with vital bone at the defect site in a reasonable time, making a second surgical procedure for bone harvesting (e.g., at the iliac crest) unnecessary. The relapse of approximately one third in the second case did not affect the success of treatment and was attributed to the combination of platelet-rich plasma with a resorbable polylactic membrane. Thus, in the combination of pure-phase beta-TCP and platelet-rich plasma, the use of nonresorbable membranes and suture materials is recommended. These results encourage the qualified surgeon to use the pure-phase beta-TCP for bone regeneration even when performing augmentations of this dimension.

Alveolar Bone Loss↗
PubMed2005

The effect of bioactive glass ceramics on the expression of bone-related genes and proteins in vitro.

Using biodegradable bone substitutes in alveolar ridge augmentation avoids second-site surgery for autograft harvesting. Considerable efforts have been undertaken to develop rapidly resorbable bone substitute materials with a higher degree of biodegradability than tricalcium phosphate (TCP). This study examines the effect of novel biodegradable glass ceramics on the expression of bone-related genes and proteins by human bone-derived cells (HBDC) and compares this behavior with that of TCP. Test materials used were alpha-TCP, a surface-treated glass ceramic GB9N with crystalline phase Ca(2)KNa(PO(4))(2) and a small amount of amorphous silica phosphate; AP40 - a glass ceramic based on crystalline phases of apatite and wollastonite; and a glass ceramic Mg5 composed of 20.6% CaO, 58.5% P(2)O(5), 14.4% Na(2)O, 4.1% MgO and 2.4% CaF(2) (wt%). HBDC were grown on the substrata for 3, 5, 7, 14 and 21 days, counted and probed for various bone-related mRNAs and proteins (type I collagen (Col I), osteocalcin (OC), osteopontin (OP), osteonectin (ON), alkaline phosphatase (ALP) and bone sialoprotein (BSP)). The substrata supported continuous cellular growth for 21 days. By day 21, GB9N had the highest number of HBDC. GB9N induced significantly enhanced expression of Col I, ALP, OP, OC and ON mRNA at 3 days; of OP, OC and ON mRNA and protein at 7 and 14 days; and of ALP, OP and OC mRNA and Col I, ALP, BSP, ON and OP protein at 21 days. Since all novel glass ceramics supported cellular proliferation together with expression of bone-related genes and proteins at least as much as TCP, these ceramics can be regarded as potential bone substitutes. GB9N had the most effect on osteoblastic differentiation, thus suggesting that this material may possess a higher potency to enhance osteogenesis than TCP.

Absorbable Implants↗
PubMed2006

Effect of rhPDGF-BB on bone turnover during periodontal repair.

PURPOSE: Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of periodontia. Pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) is a well-known biomarker of bone turnover, and as such is a potential indicator of osseous metabolic activity. The objective of this study was to evaluate the release of the ICTP into the periodontal wound fluid (WF) following periodontal reconstructive surgery using local delivery of highly purified recombinant human PDGF (rhPDGF)-BB. METHODS: Forty-seven human subjects at five treatment centres possessing chronic severe periodontal disease were monitored longitudinally for 24 weeks following PDGF regenerative surgical treatment. Severe periodontal osseous defects were divided into one of three groups and treated at the time of surgery with either: beta-tricalcium phosphate (TCP) osteoconductive scaffold alone (active control), beta-TCP+0.3 mg/ml of rhPDGF-BB, or beta-TCP+1.0 mg/ml of rhPDGF-BB. WF was harvested and analysed for local ICTP levels by radioimmunoassay. Statistical analysis was performed using analysis of variance and an area under the curve analysis (AUC). RESULTS: The 0.3 and 1.0 mg/ml PDGF-BB treatment groups demonstrated increases in the amount of ICTP released locally for up to 6 weeks. There were statistically significant differences at the week 6 time point between beta-TCP carrier alone group versus 0.3 mg/ml PDGF-BB group (p<0.05) and between beta-TCP alone versus the 1.0 mg/ml PDGF-BB-treated lesions (p<0.03). The AUC analysis revealed no statistical differences amongst groups. CONCLUSION: This study corroborates the release of ICTP as a measure of active bone turnover following local delivery of PDGF-BB to periodontal osseous defects. The amount of ICTP released from the WF revealed an early increase for all treatment groups. Data from this study suggests that when PDGF-BB is delivered to promote periodontal tissue engineering of tooth-supporting osseous defects, there is a direct effect on ICTP released from the wound.

Adult↗
PubMed2003

Evaluation of external beam radiotherapy and brachytherapy for localized prostate cancer using equivalent uniform dose.

Various radiotherapy (RT) modalities, such as external beam radiotherapy (EBRT) and permanent/high-dose-rate (HDR) brachytherapy, have been used for the management of localized prostate cancer. Using the linear-quadratic (LQ) model, we compared the relative merits of these modalities in terms of equivalent uniform dose (EUD) and tumor control probability (TCP). The LQ parameters (alpha = 0.15 Gy(-1) and alpha/beta = 3.1 Gy) determined recently from compiled clinical data, as well as other sets of LQ parameters for prostate cancer, were used to carry out the EUD and TCP calculations. A computer code was developed for this purpose. We calculate the EUD for some common RT modalities, and present the corresponding TCP data predicted for a sample patient group (high-risk). Biological equivalence of treatment outcome among various RT modalities is demonstrated. The model suggests that the hypofractionation is preferred in terms of tumor control, due to the lower alpha/beta ratio. Also, the current combined treatment schemes (initial EBRT + permanent/HDR brachytherapy boost) provide higher EUD and TCP than these monotherapies. The study shows that EUD is less sensitive to model parameters than TCP, and EUD can be used to compare and to optimize treatment plans involving different RT modalities. Techniques to further optimize and/or to combine external beams with brachytherapy for better treatment outcomes are proposed.

Brachytherapy↗
PubMed2000

An analysis of the relationship between radiosensitivity and volume effects in tumor control probability modeling.

The dependence of local tumor control probability (tcp) on tumor volume is analyzed and discussed with the help of radiobiological modeling; in particular the impact of possible correlations between mean tumor radiosensitivity and tumor dimensions on the tcp volume dependence is explored. The linear-quadratic Poissonian tumor control probability (tcp) model was modified to account for the possible dependence of clonogenic cell density and radiosensitivity parameters on tumor volume; then the original and modified versions of the model were fitted to published clinical and laboratory tumor control data. These different versions of the tcp model often fitted tumor control data equally well, because of the high degree of correlation between the parameters. Nevertheless the results were very different from a physical point of view and we suggest that sometimes it is possible to choose between equally good fits on the basis of physical considerations. Possible links between the volume dependence of the mean radiosensitivity and the degree of tumor hypoxia were also analyzed through a comparison of the results of the tcp fit to published measurements of oxygen tension in tumors.

Animals↗
PubMed2002

Cork taint of wines: role of the filamentous fungi isolated from cork in the formation of 2,4,6-trichloroanisole by o methylation of 2,4,6-trichlorophenol.

Cork taint is a musty or moldy off-odor in wine mainly caused by 2,4,6-trichloroanisole (2,4,6-TCA). We examined the role of 14 fungal strains isolated from cork samples in the production of 2,4,6-TCA by O methylation of 2,4,6-trichlorophenol (2,4,6-TCP). The fungal strains isolated belong to the genera Penicillium (four isolates); Trichoderma (two isolates); and Acremonium, Chrysonilia, Cladosporium, Fusarium, Mortierella, Mucor, Paecilomyces, and Verticillium (one isolate each). Eleven of these strains could produce 2,4,6-TCA when they were grown directly on cork in the presence of 2,4,6-TCP. The highest levels of bioconversion were carried out by the Trichoderma and Fusarium strains. One strain of Trichoderma longibrachiatum could also efficiently produce 2,4,6-TCA in liquid medium. However, no detectable levels of 2,4,6-TCA production by this strain could be detected on cork when putative precursors other than 2,4,6-TCP, including several anisoles, dichlorophenols, trichlorophenols, or other highly chlorinated compounds, were tested. Time course expression studies with liquid cultures showed that the formation of 2,4,6-TCA was not affected by a high concentration of glucose (2% or 111 mM) or by ammonium salts at concentrations up to 60 mM. In T. longibrachiatum the O methylation of 2,4,6-TCP was catalyzed by a mycelium-associated S-adenosyl-L-methionine (SAM)-dependent methyltransferase that was strongly induced by 2,4,6-TCP. The reaction was inhibited by S-adenosyl-L-homocysteine, an inhibitor of SAM-dependent methylation, suggesting that SAM is the natural methyl donor. These findings increase our understanding of the mechanism underlying the origin of 2,4,6-TCA on cork, which is poorly understood despite its great economic importance for the wine industry, and they could also help us improve our knowledge about the biodegradation and detoxification processes associated with chlorinated phenols.

Anisoles↗
PubMed1994

Role of antibodies against biotype-specific Vibrio cholerae pili in protection against experimental classical and El Tor cholera.

Vibrio cholerae O1, which exists as two biotypes, classical and El Tor, expresses fimbrial antigens called toxin-coregulated pili (TCP) and mannose-sensitive hemagglutinin (MSHA) pili, respectively. We have raised rabbit antisera and monoclonal antibodies against these fimbrial antigens and prepared Fab fragments which possess specific antibodies directed against the respective fimbrial antigens from these antisera. The protective effect of these antibody preparations was studied in the infant mouse cholera model. Antibodies against TCP were able to protect baby mice against challenge with V. cholerae O1 of the classical but not of the El Tor biotype. Similar but reverse biotype differences in protection against challenge with classical and El Tor vibrios were observed when antibodies against MSHA pili were used. The protective effect of V. cholerae O1 antilipopolysaccharide (anti-LPS) antibodies, both alone and in combination with antifimbrial antibodies, was also evaluated. We showed that antibodies to the LPS component also prevented infections with V. cholerae O1. Moreover, our results indicate that antibodies against TCP or MSHA pili and against LPS cooperate at least additively, and possible even synergistically, in protecting baby mice against challenge with group O1 vibrios. These results indicate that TCP and MSHA pili as well as LPS play an important role in the pathogenesis of experimental cholera. We could also demonstrate that antibacterial immunity preventing colonization is biotype specific. Our results might be used for the generation of new oral cholera vaccines including both TCP and MSHA fimbrial antigens.

Animals↗
PubMed1999

Vibrio cholerae intestinal population dynamics in the suckling mouse model of infection.

The suckling mouse has been used as a model to identify Vibrio cholerae intestinal colonization factors for over two decades, yet little is known about the location of recoverable organisms along the gastrointestinal (GI) tract following intragastric inoculation. In the present study, we determined the population dynamics of wild-type and avirulent mutant derivatives of both classical and El Tor biotype strains throughout the entire suckling mouse GI tract at various times after intragastric inoculation. Wild-type strains preferentially colonized the middle small bowel with a sharp demarcation between more proximal segments which had manyfold-fewer recoverable cells. Surprisingly, large and stable populations of viable cells were also recovered from the cecum and large bowel. Strains lacking toxin-coregulated pili (TCP(-)) were cleared from the small bowel; however, an El Tor TCP(-) strain colonized the cecum and large bowel almost as well as the wild-type strain. Strains lacking lipopolysaccharide O antigen (OA(-)) were efficiently cleared from the small bowel at early times but then showed net growth for the remainder of the infections. Moreover, large populations of the OA(-) strains were maintained in the large bowel. These results show that for the El Tor biotype neither TCP nor OA is required for colonization of the suckling mouse large bowel. Finally, similar percent recoveries of wild-type, TCP(-), and OA(-) strains from the small bowel at an early time after infection suggest that TCP and OA are not required for strains of either biotype to resist bactericidal mechanisms in the suckling mouse GI tract.

Animals↗
PubMed2003

Pathogenic potential of environmental Vibrio cholerae strains carrying genetic variants of the toxin-coregulated pilus pathogenicity island.

The major virulence factors of toxigenic Vibrio cholerae are cholera toxin (CT), which is encoded by a lysogenic bacteriophage (CTXPhi), and toxin-coregulated pilus (TCP), an essential colonization factor which is also the receptor for CTXPhi. The genes for the biosynthesis of TCP are part of a larger genetic element known as the TCP pathogenicity island. To assess their pathogenic potential, we analyzed environmental strains of V. cholerae carrying genetic variants of the TCP pathogenicity island for colonization of infant mice, susceptibility to CTXPhi, and diarrheagenicity in adult rabbits. Analysis of 14 environmental strains, including 3 strains carrying a new allele of the tcpA gene, 9 strains carrying a new allele of the toxT gene, and 2 strains carrying conventional tcpA and toxT genes, showed that all strains colonized infant mice with various efficiencies in competition with a control El Tor biotype strain of V. cholerae O1. Five of the 14 strains were susceptible to CTXPhi, and these transductants produced CT and caused diarrhea in adult rabbits. These results suggested that the new alleles of the tcpA and toxT genes found in environmental strains of V. cholerae encode biologically active gene products. Detection of functional homologs of the TCP island genes in environmental strains may have implications for understanding the origin and evolution of virulence genes of V. cholerae.

Animals↗
PubMed2004

A Vibrio cholerae classical TcpA amino acid sequence induces protective antibody that binds an area hypothesized to be important for toxin-coregulated pilus structure.

Vibrio cholerae is a gram-negative bacterium that has been associated with cholera pandemics since the early 1800s. Whole-cell, killed, and live-attenuated oral cholera vaccines are in use. We and others have focused on the development of a subunit cholera vaccine that features standardized epitopes from various V. cholerae macromolecules that are known to induce protective antibody responses. TcpA protein is assembled into toxin-coregulated pilus (TCP), a type IVb pilus required for V. cholerae colonization, and thus is a strong candidate for a cholera subunit vaccine. Polypeptides (24 to 26 amino acids) in TcpA that can induce protective antibody responses have been reported, but further characterization of their amino acid targets relative to tertiary or quaternary TCP structures has not been done. We report a refinement of the TcpA sequences that can induce protective antibody. One sequence, TcpA 15 (residues 170 to 183), induces antibodies that bind linear TcpA in a Western blot as well as weakly bind soluble TcpA in solution. These antibodies bind assembled pili at high density and provide 80 to 100% protection in the infant mouse protection assay. This is in sharp contrast to other anti-TcpA peptide sera (TcpA 11, TcpA 13, and TcpA 17) that bind very strongly in Western blot and solution assays yet do not provide protection or effectively bind TCP, as evidenced by immunoelectron microscopy. The sequences of TcpA 15 that induce protective antibody were localized on a model of assembled TCP. These sequences are centered on a site that is predicted to be important for TCP structure.

Amino Acid Sequence↗
PubMed2005

TcpF is a soluble colonization factor and protective antigen secreted by El Tor and classical O1 and O139 Vibrio cholerae serogroups.

Vibrio cholerae causes diarrhea by colonizing the human small bowel and intoxicating epithelial cells. Colonization is a required step in pathogenesis, and strains defective for colonization are significantly attenuated. The best-characterized V. cholerae colonization factor is the toxin-coregulated pilus (TCP). It has been demonstrated that TCP is required for V. cholerae colonization in both humans and mice. TCP enhances bacterial interactions that allow microcolony formation and thereby promotes survival in the intestine. We have recently discovered that the TCP biogenesis apparatus also serves as a secretion system, mediating the terminal step in the extracellular secretion pathway of TcpF. TcpF was identified in classical isolates of V. cholerae O1 as a soluble factor essential for colonization in the infant mouse cholera model. In the present study, we expanded our analysis of TcpF to include the O1 El Tor and O139 serogroups and investigated how TCP and TcpF act together to mediate colonization. Additionally, we demonstrated that antibodies generated against TcpF are protective against experimental V. cholerae infection in the infant mouse cholera model. This observation, coupled with the fact that TcpF is a potent mediator of colonization, suggests that TcpF should be considered as a component of a polyvalent cholera vaccine formulation.

Animals↗
PubMed2001

Clinical and environmental isolates of Vibrio cholerae serogroup O141 carry the CTX phage and the genes encoding the toxin-coregulated pili.

We report sporadic cases of a severe gastroenteritis associated with Vibrio cholerae serogroup O141. Like O1 and O139 serogroup strains of V. cholerae isolated from cholera cases, the O141 clinical isolates carry DNA sequences that hybridize to cholera toxin (CT) gene probes. The CT genes of O1 and O139 strains are carried by a filamentous bacteriophage (termed CTX phage) which is known to use toxin-coregulated pili (TCP) as its receptor. In an effort to understand the mechanism of emergence of toxigenic O141 V. cholerae, we probed a collection of O141 clinical and environmental isolates for genes involved in TCP production, toxigenicity, virulence regulation, and other phylogenetic markers. The collection included strains isolated between 1964 and 1995 from diverse geographical locations, including eight countries and five U.S. states. Information collected about the clinical and environmental sources of these isolates suggests that they had no epidemiological association. All clinical O141 isolates hybridized to probes specific for genes encoding CT (ctx), zonula occludens toxin (zot), repetitive sequence 1 (RS1), RTX toxin (rtxA), the major subunit of TCP (tcpA), and the essential regulatory gene that controls expression of both CT and TCP (toxR). In contrast, all but one of the nonclinical O141 isolates were negative for ctx, zot, RS1, and tcpA, although these strains were positive for rtxA and toxR. The one toxigenic environmental O141 isolate was also positive for tcpA. Ribotyping and CT typing showed that the O141 clinical isolates were indistinguishable or closely related, while a toxigenic water isolate from Louisiana showed a distantly related ribotype. Nonclinical O141 isolates displayed a variety of unrelated ribotypes. These data support a model for emergence of toxigenic O141 that involves acquisition of the CTX phage sometime after these strains had acquired the pathogenicity island encoding TCP. The clonal nature of toxigenic O141 strains isolated from diverse geographical locations suggests that the emergence is a rare event but that once it occurs, toxigenic O141 strains are capable of regional and perhaps even global dissemination. This study stresses the importance of monitoring V. cholerae non-O1, non-O139 serogroup strains for their virulence gene content as a means of assessing their epidemic potential.

Adult↗
PubMed2006

Comparison of acute structural and histopathological changes in human autopsy eyes after endoscopic cyclophotocoagulation and trans-scleral cyclophotocoagulation.

AIM: To study the histological effects of trans-scleral cyclophotocoagulation (TCP) and endoscopic cyclophotocoagulation (ECP) on the ciliary body and other structures collected at autopsy and to compare with untreated controls. MATERIALS AND METHODS: TCP and ECP were performed on human eyes at autopsy. Detailed histological evaluations were perfomed using light microscopy and scanning electron microscopy on treated eyes and compared with untreated controls. RESULTS: Histological changes were observed with both light microscopy and scanning electron microscopy for all treated tissues. Tissue treated with TCP showed pronounced tissue disruption of the ciliary body muscle and stroma, ciliary processes, and both pigmented and non-pigmented ciliary epithelium. ECP-treated tissue exhibited pronounced contraction of the ciliary processes with disruption of the ciliary body epithelium, sparing of the ciliary body muscle and less architectural disorganisation. The sclera was not affected by either laser treatment. CONCLUSIONS: ECP treatment caused less damage to the ciliary body compared with TCP when evaluated by light microscopy and scanning electron microscopy. Compared with TCP, ECP seems to be a more selective form of cyclophotocoagulation, resulting in less tissue disruption while achieving the goal of destroying ciliary body epithelium.

Autopsy↗
PubMed1987

Tunneling cell processes in myocytes of stretched mouse atria.

Serial section electron micrographs of mouse atria stretched in vitro show that myocytes have cell processes which tunnel into adjacent myocytes for 8 microns or more. The tunneling cell processes (TCP) (diam 4-6.2 microns) lack myofibrils and organelles associated with atrial peptide secretion. The glycogen-rich TCP cytoplasmic matrix contains conspicuous tubules and vesicles originating from endoplasmic reticulum and resembling free sarcoplasmic reticulum (SR). TCP are surrounded by a plasmalemma derived from their myocyte of origin, the plasmalemma of the tunneled myocyte, and an intervening narrow compartment continuous with the interstitial space. Profiles having the characteristics cytoplasmic structure of TCP are also found both in the interstitial space between myocytes and near the longitudinal terminations where myocyte ends about on the interstitial space. We suggest that TCP tubules and vesicles may proliferate and/or transport in response to stretch, might be free SR, and may respond to stretch-activated changes in ionic composition or potential of the surrounding myocyte and narrow intercellular compartment.

Animals↗