Wednesday, January 06, 2010

2010 - cured!

OK, it's been so long that I forgot this blog even existed! Nonetheless, it apparently still gets some traffic, and I'm happy to learn that I might be able to help someone else out. James, this is for you!

In late 2006, I stumbled upon the work of John Sarno, MD. I ordered his (then) latest book, read through it, then put aside without really understanding. It didn't help that I had recently begun oral prednisone, which seemed to be the miracle I had needed. a few weeks went by, and I went on vacation. I had a great time...until the prednisone stopped working, despite repeated increases in dosage. I had to cut my vacation short, and I was terribly upset about it. My wife, having read the book as well, started talking with me about it on the flight back to Shanghai, and suddenly things clicked. I began doing what Sarno suggested, and within 2-3 weeks, I was 95% better. In no time at all it became a non-issue - a thing that would pop up once every few weeks for a minute or two as if to say "Hi, remember me? I'm still here! TREMBLE IN FEAR!". I would refuse, and it would quietly disappear.

It's amazing to me that this issue, which dominated my life so completely, is entirely gone and most days never enters my mind. Rather than explain how this great change came about, I'm just going to point you in the right direction with some links. If you have questions later, I'll be happy to answer them.

First, the books:

http://www.amazon.com/Mindbody-Prescription-Healing-Body-Pain/dp/0446675156

This was the book that changed everything for me. It is not, however, his latest work. Sorry, Blogspot is blocked in China, and I'm using a proxy to get to it. For some reason, I can't post the actual link.

http://www.amazon.com/Divided-Mind-Epidemic-Mindbody-Disorders/dp/0061174300/ref=pd_sim_b_1

This is the more recent book, which goes much deeper into explaining what's going on with people like myself. Highly recommended.

http://tmswiki.wetpaint.com/

This is an excellent resource for conditions like mine.

http://www.tmshelp.com/forum/forum.asp?FORUM_ID=2

This forum is filled with great people with really tough issues; many of them have overcome their pain completely. They have helped me through some incredibly rough times.

James, I really hope you find your way out as fast as possible; you have my complete sympathy. No one should ever have to live in that kind of pain without at least knowing what's going on. I am much more skeptical of modern medicine as a result of my experience. The great news is, assuming you've been through all the appropriate medical tests and nothing life-threatening was found, I think the links above are your ticket out of the pain. I wish you the best of luck with this.

Cheers,

Me

Monday, November 27, 2006

Candidiasis

I came across a discussion of candida infections on the EP board today. A little research turned up incredible amounts of information. Try googling "Candida epididymitis". It even turns up research articles on PubMed from 1993 detailing an actual condition called Candida Epididymitis...yet not a single doctor I've seen has ever even mentioned it as a possible cause! And there's a fairly simple treatment too: Fluconazole and possibly diet modification.

I'm going to get tested later today for candidiasis.

Doctors: Patients pay you so much because you are supposed to know this stuff...and when you are presented with problems you can't find a cause for much less treat, you're supposed to research so you can do both. Few of the doctors I've seen for this problem have earned the money I paid for them. Instead, they've done no research, then laughed at mine as if I'm an illiterate peasant. I've lost so much respect for doctors in general. Way to go guys...keep it up and you will create activists that will make you wish you had chosen other professions.

Sunday, November 19, 2006

Pathogenicity of Enterococci

Pathogenicity of Enterococci


Lynn E. Hancock and Michael S. Gilmore*
Department of Microbiology and Immunology
University of Oklahoma Health Sciences Center
Oklahoma City, OK 73104
Phone: 405-271-1083
Fax: 405-271-8128
Email: michael-gilmore@ouhsc.edu


INTRODUCTION

Enterococcal pathogenicity was initially addressed at the end of the 19th century by MacCallum and Hastings (46), who isolated an organism from a case of acute endocarditis, and designated it Micrococcus zymogenes based on its fermentative properties. The organism was shown to be resistant to dessication, heating to 60°C, and several antiseptics, including carbolic acid and chloroform (46). It was also found to be lethal when injected intraperitoneally in white mice, and capable of producing endocarditis in a canine model (46). A century later, enterococci are prominent among nosocomial pathogens, ranking second only to E. coli in total nosocomial infections, accounting for more than 12% of all cases (56).

Infections caused by the genus Enterococcus (most notably Enterococcus faecalis, which accounts for ~80% of all infections) include urinary tract infections, bacteremia, intra-abdominal infections, and endocarditis (33, 53). The problem of nosocomial enterococcal infection is compounded by multiple antibiotic resistance. A comparison of outcomes for patients with bacteremia due to vancomycin-resistant Enterococcus faecium or vancomycin-susceptible E. faecium found a median length of stay of 46 days after the first episode of bacteremia in the group of patients with vancomycin-resistant E. faecium, as compared to 19 days for patients infected by a susceptible strain (43). The presence of VRE (vancomycin-resistant enterococci) in the bloodstream has also been associated with increased mortality (14). Patients with enterococcal bacteremia were observed to be twice as likely to die (37% vs. 16%) when the infecting isolate was resistant to vancomycin (14). However, more recent studies indicate that VRE-status is not a major predictor for clinical outcome (45, 48). Whether more recent findings describe cases that benefit from further evolution in the treatment of VRE requires further analysis. As vancomycin frequently represents the last available therapeutic for multiple antibiotic resistant enterococci, the rapid increase in vancomycin resistance (33) indicates that enterococcal infection will pose an increasing therapeutic challenge.

Resistance trends among E. faecalis and E. faecium were recently reviewed (33). Data compiled for approximately 15,000 isolates over a 3 year period (1995-1997) showed that while resistance to ampicillin and vancomycin is relatively uncommon among E. faecalis isolates (<2%),>

Biology and Epidemiology

The classification of enterococci as group D streptococci dates back to the scheme established by Rebecca Lancefield in the early 1930's (42). In 1984, enterococci were given formal genus status after DNA-DNA and DNA-RNA hybridization studies demonstrated a more distant relationship with the streptococci (64).

Enterococci are generally considered commensals of the gastrointestinal tract of a variety of organisms including man, and are morphologically indistinguishable from other streptococci. They are found in a number of environments, probably because of dissemination in animal excrement and environmental persistence. Several intrinsic features of Enterococcus may allow members of this genus to survive for extended periods of time, leading to its persistence and nosocomial spread. E. faecalis is able to grow in 6.5% NaCl, at temperatures ranging from 10-45°C, and can survive 30 minutes at 60°C. Additionally, the organism grows in the presence of 40% bile salts and over a broad pH range (53). The earliest descriptions of the organism noted that it was "hardy and tenacious of life" (46).
Several studies have examined the nature of the environmental ruggedness of the organism (16, 18). E. faecalis were observed to adapt to the presence of lethal levels of bile salts and detergents, such as sodium dodecyl sulfate (SDS), when first cultured at sub-lethal levels for as little as five seconds (16). The ability of enterococci to adapt and persist in the presence of detergents may allow them to survive inadequate cleaning regimens, contributing to their persistence in the hospital. Numerous epidemiologic studies have shown that enterococci can be transmitted from person to person in the hospital (8, 38). This transmission typically occurs via the hands of healthcare workers or on clinical instruments, such as ear-probe thermometers (61).

Antibiotic Resistance

The intrinsic ruggedness of enterococci also confers an unusual level of tolerance to several classes of antibiotics including aminoglycosides, beta-lactams and quinolones. For example, the resistance of enterococci to aminoglycosides results from the ability of enterococci to block the uptake of the drug at the cell wall (29, 51). Consequently, aminoglycosides are only effective against enterococci when used in combination with cell wall active antibiotics. This combination treatment modality has been compromised, however, by the rapid spread of high-level aminoglycoside resistance among enterococci (>2000 µg/ml) (30). Although the mechanism of high-level resistance was determined to be the result of a bifunctional enzyme (15), the molecular basis for the intrinsic resistance of enterococci to low-levels of aminoglycosides remains to be determined. Further discussion of the genetic and physiologic basis for antibiotic resistance can be found elsewhere in this volume.

PATHOGENIC MECHANISMS

In order to infect, enterococci must first be able to colonize, primarily at mucosal surfaces. From the site of colonization, the organism must then evade the host clearance, and ultimately produce pathologic changes in the host, either through direct toxic activity, or indirectly by inducing an inflammatory response (40).

Colonization and Translocation

Enterococci normally colonize the gastrointestinal tract of man. They are found in relative abundance in human feces (105-107 organisms per gram) (57). A close association is likely to exist between enterococci and its host, or the organism would be eliminated due to normal intestinal motility (38). Studies in progress are examining the specific binding of enterococci to intestinal epithelium (63). Many infection-derived enterococcal isolates were found to be clonal, indicating nosocomial transmission. Moreover, a number of studies have documented patient colonization following hospital admission, and have shown that colonization with multiply resistant strains is a predisposing factor for subsequent infection (33, 55). To colonize the lower bowel, enterococci must survive transit through the low pH of the stomach. Several studies have examined the acid tolerance of E. faecalis (17, 71). Flahaut et al. (17) demonstrated that exposure of E. faecalis to a sub-lethal pH (pH 4.8) for 15-30 minutes protected the organism from a normally lethal challenge at pH 3.2. Suzuki and colleagues (71) have shown that an E. faecalis mutant defective in F1 -F0 H+-ATPase activity was unable to grow at pH<6. The H+-ATPase is used to regulate the cytoplasmic pH of E. faecalis by proton extrusion. This enzyme has been shown to be activated at low pH (71). From these studies, it is apparent that enterococci possess the ability to withstand the low gastric pH, which would facilitate colonization. This attribute may be critical in the ability of multi-drug resistant enterococcal strains to colonize the intestinal tract and cause hospital ward outbreaks. Whether infection-derived enterococcal isolates show enhanced acid tolerance is yet to be determined.

Therapy with antibiotics possessing little anti-enterococcal activity is a key predisposing factor leading to enterococcal colonization and infection (8). Studies in mice with antibiotic- induced intestinal E. faecalis overgrowth demonstrated that organisms can adhere to epithelial surfaces of the ileum, cecum, and colon (74, 75). These same studies showed that enterococci possess the ability to translocate from the intestinal lumen to the mesenteric lymph nodes, liver, and spleen (74, 75). As prior antibiotic therapy appears to be a predisposing factor for enterococcal infection, antibiotic-induced intestinal overgrowth by E. faecalis, followed by translocation of the organism into the circulation may offer one explanation for bacteremias of unknown etiology (23).

The mechanisms responsible for enterococcal translocation are not clearly defined. One hypothesis is that enterococci are phagocytosed by tissue macrophages or intestinal epithelial cells, and are transported across the intestinal wall to the underlying lymphatic system. Failure to kill the phagocytosed organisms could then lead to systemic spread (76). Olmsted et al. (59) examined the role of the plasmid-encoded surface protein, aggregation substance, in the ability of E. faecalis to be internalized by cultured intestinal epithelial (HT-29) cells. The presence of aggregation substance significantly augmented E. faecalis internalization by HT-29 cells. However, in contrast to the one order of magnitude in enhanced uptake efficiency conferred by aggregation substance, a difference of three orders of magnitude of difference was observed between various enterococcal strains tested. This indicated that additional unknown features of this species play major roles as determinants of internalization efficiency.

The vast majority (87/91) of E. faecalis produce superoxide (O2-), whereas E. faecium isolates (5/13) do so less frequently (32). When clinical and commensal isolates of E. faecalis were compared for O2- production, strains associated with bacteremia produced O2- in vitro at a rate 60% higher than stool isolates. What role, if any, superoxide production plays in enterococcal pathogenesis, however, is not well defined. Perhaps, enterococcal strains capable of producing O2- are better adapted physiologically to utilize limited resources in the intestinal environment, leading to overgrowth of the organism. Alternatively, O2- production may enhance niche control in proximity to the intestinal epithelium. The membrane damaging effects of oxygen radicals may then potentiate the ability of the organism to translocate across a weakened epithelial barrier. The enrichment of this trait among E. faecalis infection derived isolates presents intriguing questions and warrants further study.

One of the enigmas of nosocomial enterococcal infection not easily explained is the ready colonization of an ecology already occupied by members of the same species. As noted, antibiotics lacking substantial anti-enterococcal activity (i.e. antibiotics that do not deleteriously affect indigenous enterococci) are important predisposing factors for infection. These infections are frequently caused by multiply resistant enterococcal isolates that have been exogenously acquired and appear to have out competed indigenous enterococci in the absence of direct selection. The numbers of exogenously acquired, multiply resistant enterococci would be expected to be minuscule compared to the numbers of indigenous enterococci that are present and well positioned to occupy any niche suitable for enterococcal colonization. The fact that exogenous, multiply resistant, nosocomially transmitted enterococci efficiently colonize the gastrointestinal tract suggests that they may not compete directly for the same niche as indigenous strains. A novel surface protein capable of enabling enterococci to colonize a new area of the gastrointestinal tract, an area perhaps less endowed with immune clearance mechanisms, may explain the ability of these outbreak strains to efficiently colonize and cause disease. Another mechanism that could render colonization by exogenous strains noncompetitive would be an ability to utilize nutrients in a new or enhanced way. For instance, an enhanced ability to utilize mammalian intestinal mucin as an energy source may enable outbreak strains to colonize deeper layers of the mucosa in more intimate association with intestinal epithelial cells. Few studies have comprehensively examined and compared the physiology of commensal strains and enterococcal strains that caused multiple infections, and so at present, these prospects remain completely speculative. However, a new surface protein of novel structure has been described, which is enriched among endocarditis (40%) and bacteremia isolates (29%), but is rare among fecal isolates (<3%)>

Bacteremia

Nosocomial surveillance data for the period October 1986-April 1997 list enterococci as the third most common cause of nosocomial bacteremia, accounting for 12.8% of all isolates (56). The translocation of enterococci across an intact intestinal epithelial barrier is thought to lead to many bacteremias with no identifiable source (38, 76). Other identifiable sources for enterococcal bacteremia include intravenous lines, abscesses, and urinary tract infections (38). The risk factors for mortality associated with enterococcal bacteremia include severity of illness, patient age, and use of broad spectrum antibiotics, such as third-generation cephalosporins or metronidazole (68). Huycke et al. (34) showed that patients infected with hemolytic, gentamicin- resistant E . faecalis strains had a fivefold-increased risk for death within three weeks compared to patients infected with nonhemolytic, gentamicin-susceptible strains. Moreover, mode of treatment was not associated with outcome, discounting the contribution of aminoglycoside resistance to this enhanced lethality of infection. In a more recent study, Caballero-Granado et al. (7) analyzed the clinical outcome, including mortality, for bacteremia caused by Enterococcus spp. with and without high-level gentamicin resistance. Mortality associated with high-level gentamicin resistance (29%) was not significantly different from gentamicin-susceptible strains (28%). In addition, these workers found no significant difference in the length of hospitalization after acquisition of enterococcal bacteremia. Taken together, these studies suggest that high-level aminoglycoside resistance does not affect clinical outcome, and that the presence of the E. faecalis cytolysin (hemolysin) may enhance the severity of the infection. A number of well controlled independent animal studies confirm the toxicity of the enterococcal cytolysin. Cytolysin significantly lowers the 50% lethal dose (LD50) of the infecting strain for mice (13, 35, 50). As discussed below, cytolysin also contributes to the acute toxicity of lupine endocarditis and endophthalmitis models (35, 39).

Urinary Tract

Enterococci have been estimated to account for 110,000 urinary tract infections (UTI) annually in the United States (33). A few studies have been aimed at understanding the interaction of enterococci with uroepithelial tissue (25, 41, 73). Kreft et al. (41) showed a potential role for the plasmid-encoded aggregation substance in the adhesion of enterococci to renal epithelial cells. E. faecalis harboring the pheromone responsive plasmid pAD1, or various isogenic derivatives, were better able to bind to the cultured pig renal tubular cell line, LLC-PK, than plasmid free cells. Their findings also showed that a synthetic peptide containing the fibronectin motif, Arg-Gly-Asp-Ser, could inhibit binding. This structural motif mediates the interaction between fibronectin and eucaryotic surface receptors of the integrin family (20).

Guzman and coworkers (25) analyzed strains of E. faecalis isolated from either urinary tract infections or endocarditis, for their ability to adhere to urinary tract (UT) epithelial cells and the Girardi heart cell line. UTI isolates adhered to the UT epithelial cells in vitro, whereas strains from endocarditis adhered efficiently to the Girardi heart cell line. A key observation from these experiments was that growth in pooled human serum enhanced the binding of UTI isolates to the Girardi heart cell line (8-fold increase). The authors noted that the serum-dependent alterations to cell adhesion were lost by several sub-cultures in brain heart infusion broth (25). In a later study, E. faecalis adherence was found to be mediated by carbohydrate antigens present on the cell surface (26). Thus, the nature of the interaction of enterococci with uroepithelial tissue appears to be quite complex, involving surface adhesins of protein and/or carbohydrate nature.

Endocarditis

Of the diverse infections caused by enterococci, infective endocarditis (IE) is one of the most therapeutically challenging (49). Enterococci are the third leading cause of infective endocarditis, accounting for 5-20% of cases of native valve IE, and 6-7% of prosthetic valve endocarditis (49). As noted above, enterococci cultured in serum exhibit enhanced binding to Girardi heart cells. This interaction is inhibited by periodate treatment of the bacterial cell as well as competitive inhibition of binding, by prior incubation of the target cells with specific sugar residues, including D-galactose and L-fucose (26). This suggests that a carbohydrate antigen mediates the adherence of enterococci to cultured heart cells which were derived from the right auricular appendage (Girardi heart).
The presence of the pheromone-responsive plasmid pAD1 enhances vegetation formation in enterococcal endocarditis (9). By comparing endocarditis caused by isogenic mutants in either cytolysin (hemolysin) production or aggregation substance, which are encoded on pAD1, it was observed that the presence of the cytolysin contributed to overall lethality (6/11 animals killed compared to 2/13 in the non-cytolytic mutant, p<0.01), whereas the presence of aggregation substance led to a 2-fold increase in mean vegetation weight. It was noted, however, that all strains tested were able to cause endocarditis, even the plasmid-free controls. This data suggests that the virulence traits encoded by auxiliary genetic elements can enhance the pathogenicity of the organism, but may not be essential in establishing infection.

Serum from a patient with E. faecalis endocarditis was used to identify an E. faecalis antigen selectively expressed in serum but not in broth culture (44). This protein antigen, designated EfaA, had a predicted molecular weight of 34,768. Database homology searches revealed extensive sequence similarity with several streptococcal adhesins. The authors hypothesized that this surface antigen might function as an important adhesin in endocarditis, but there is no published data to support this.

Endophthalmitis

Colonization of host tissue may play a role in the pathogenesis of endophthalmitis. Enterococci are among the the most destructive agents that cause this post-operative complication of cataract surgery (27, 39). Experiments designed to determine whether aggregation substance targeted E. faecalis to alternate anatomical structures within the eye showed that enterococci attach to membranous structures in the vitreous, but that such adherence is not dependent on the presence of aggregation substance (37). In summary, the preponderance of data indicates that E. faecalis adhesion to host tissues is complex and involves multiple adhesins including surface carbohydrates as well as proteins.

Immune Evasion

For enterococci to maintain an infection, they must successfully evade both specific and nonspecific host defense mechanisms. Other gram-positive pathogens possess attributes which allow them to survive in the host in spite of powerful nonspecific host defenses mediated primarily by professional phagocytes, i.e. neutrophils, monocytes, and macrophages. These factors include antiphagocytic polysaccharide capsules, antiphagocytic surface proteins, such as the group A streptococcal M protein, and various secreted toxins with direct toxicity for phagocytic cells.

Studies designed to characterize the host response to enterococcal infection have been conducted (2, 19, 28, 58). Harvey et al. (28) concluded that "neutrophil mediated killing of enterococci was largely a function of complement with antibody playing a less essential but potentially important role." Arduino et al. (2) reached similar conclusions with regard to the role of complement in the clearance of enterococci by polymorphonuclear cells (PMNs). The latter study also tested several defined virulence traits, which included gelatinase, cytolysin, and aggregation substance of E. faecalis and found no significant correlation between a given trait and resistance to phagocytosis. However, these phagocytosis assays were performed under conditions unlikely to support cytolysin expression (72), and production of the other traits in this environment was similarly not controlled. Although cytolysin is not made at appreciable levels in standard laboratory media, it can be detected when organisms are cultured in serum (unpublished data), so it may be of value to reexamine the roles of these factors under more physiologic conditions.

In the course of studying neutrophil-mediated phagocytosis, Arduino et al. (1) identified a strain of E. faecium that exhibited increased resistance to phagocytosis. They were able to detect electron-dense clumps adjacent to the cell wall consistent with the presence of capsular material. It was noted, however, that similar electron-dense clumps surrounded the cell wall of strains of E. faecalis that appeared to be sensitive to PMN-mediated clearance. The nature of the material providing protection to phagocytosis for the E. faecium strain was shown to be protease resistant and periodate sensitive, implicating a carbohydrate. Further characterization of this material has not been reported. In a recent case report, Bottone and colleagues (6) isolated three highly mucoid-encapsulated strains of E. faecalis from patients with urinary tract infections. Whether these encapsulated strains are more resistant to phagocytic killing by neutrophils remains to be demonstrated.

Additional evidence for the importance of anti-enterococcal antibodies in promoting clearance by opsonophagocytic killing was recently reported by Gaglani et al. (19). These authors compared killing efficacy by neutrophils using normal human serum, hypogammaglobulinemic serum, or normal human serum adsorbed with the homologous bacterial strain. Their findings suggest that normal human serum has sufficient anti-enterococcal antibodies to promote > 90% reduction of the bacterial inoculum with serum concentrations as low as 0.5%. Hypogammaglobulinemic serum also promoted > 90% reduction of the bacterial inoculum, but only at serum concentrations above 5%. Adsorption with the homologous strain significantly reduced bactericidal activity of the normal human serum. These findings indicate that the normal human host possesses antibodies to enterococci that aid in opsonophagocytic killing, which might be expected for a normal bowel organism in constant association with the host. The protective role of anti-enterococcal antibodies should be examined to determine whether such protection extends from the strain level to either genus or species. Work in progress is examining these issues (60, 67).

In 1992, Maekawa et al. (47) proposed a new serologic typing scheme for E. faecalis, in which E. faecalis isolates were classified into 21 distinct serotypes, but 4 serotypes accounted for 72% of all typable strains, indicating that certain serotypes are more prevalent among clinical isolates. The exact nature of the serotype antigens is not yet known, and could be protein (such as M protein in the case of group A streptococci), or a polysaccharide (as is the case for group B streptococci and Streptococcus pneumoniae).

More recently it has been observed that enterococci possess the ability to survive within professional phagocytes (21, 70). Preliminary evidence (70), indicates an important role for aggregation substance in the adherence, entry, and survival in macrophages. Further studies into the basis for the survival of enterococci within phagocytes will add to our understanding of how enterococci escape immune surveillance.

Pathologic Tissue Damage

Following adhesion to host cell surfaces, and evasion of the host immune response, the last step in the pathogenesis of infection is the production of pathologic changes in the host. Such changes can be induced by the host inflammatory cascade or by direct tissue damage as a result of secreted toxins or proteases. Both mechanisms have been observed in studies of E. faecalis pathogenesis.

Indirect Tissue Damage

Enterococcal lipoteichoic acid (LTA), also known as the group D streptococcal antigen, has been implicated in a variety of biological processes (24-26, 54). Some properties ascribed to LTA include modulation of the host immune response as well as mediating the adherence of enterococci to host cells. Bhakdi et al. (4) found the LTA from enterococci to be as inflammatory as lipopolysaccharide of gram-negative bacteria. LTA may also contribute to the ability of enterococci to exchange and rapidly disseminate genetic determinants, a subject that has been investigated extensively (12).

The role of LTA and aggregation substance (AS) in cardiac infections was recently examined (65). Strains of E. faecalis defective in AS and the enterococcal binding substance (EBS), which is at least partially derived from LTA, did not induce clinical signs of illness when injected intraventricularly at levels of 108 cfu/ml. However, EBS+AS- or EBS-AS+ strains induced signs of illness and pericardiac inflammation. All rabbits injected with the EBS+AS+ strain developed illness and died. Surprisingly little inflammation was observed in rabbits injected with the EBS+AS+ strain despite the lethality observed. The authors state that such observations are consistent with the presence of a superantigen. The presence of LTA (EBS) and AS together may mediate effects on the host immune response that differ from those seen when either component acts alone. These results warrant further investigation as one of the strains tested possessed multiple transposon insertions, and the culture fluid extract used to demonstrate superantigen behavior was crude and of unknown physiologic relevance in terms of concentration. Nevertheless, the hypothesis that aggregation substance may bind and display LTA in a conformation that promotes an enhanced inflammatory response is intriguing.

Direct Tissue Damage

The enterococcal cytolysin and the zinc metalloprotease (gelatinase) are secreted factors well suited to contribute to disease severity (9, 13, 22, 35, 39). The role of the enterococcal cytolysin in disease pathogenesis has been well established in several independent laboratories and models (9, 35, 39, 50). The cytolysin is enriched in clinical isolates, and occurs at a frequency of 45-60% (31, 34, 36). The cytolysin is a unique bacterial toxin that is distantly related to lantibiotic bacteriocins, a family of small, post-translationally modified antimicrobial peptides (5). The cytolysin possesses both toxin and bacteriocin activities, and may provide several levels of selective advantage for E. faecalis strains expressing this trait. We observed that the presence of the cytolytic phenotype promotes the appearance of enterococci in the blood when compared to a non-cytolytic isogenic mutant in a mouse model of septicemia (10). A substantial body of data supports the role for cytolysin in enterococcal infection, both in humans, (34) and animal models (9, 35, 39).

The most direct and quantitative evidence for pathologic damage attributable to the cytolysin was obtained using a rabbit model of endophthalmitis (39). This model was selected because of the natural aberrations in the intraocular immune response, allowing a robust infection to be established with as few as 10 organisms. This limited response provides the offending bacterium an opportunity to adapt to in vivo growth conditions and environmental cues. Moreover, highly sensitive and quantitative measurements of the evolution of disease can be made. A role for the cytolysin in tissue pathology was unambiguously demonstrated both by a reduction in retinal function as measured by electroretinography (B-wave response), and complete destruction of retinal architecture by 24 hours postinfection. The contribution of cytolysin to the severity of disease has also been observed in animal models of systemic disease (35) and endocarditis (9). These findings conclusively demonstrate the importance of the E. faecalis cytolysin as a major virulence factor in E. faecalis infections. However, the cytolytic phenotype is a variable trait typically encoded on pheromone-responsive plasmids (38). In about half of E. faecalis infections, the cytolytin is absent, emphasizing the importance of other traits in pathogenicity (11,31, 34, 36).

The enterococcal gelatinase may also play a measurable role in systemic disease (13), as well as in a caries model using germ-free rats (22). Dupont et al. (13) showed a reduced LD50 for mice injected with gelatinase producing (Gel+) strains. These studies were limited, however, in that the basis for comparison was a Gel- strain which was generated by chemical mutagenesis, and therefore other uncharacterized traits may have contributed to the observed attenuation.
Using germ-free rats, Gold et al. (22) showed that a proteolytic (Gel+) strain exhibited cariogenic activity, whereas three nonproteolytic strains exhibited little cariogenecity. There is some indication that clinical isolates may be enriched for this trait, as greater than 50% of isolates from both endocarditis and other clinical sources exhibited gelatinase activity, whereas only 27% of community fecal isolates possessed this trait (11). In this study, highly virulent lineages that caused multiple infections were discounted by study design, skewing the correlation between phenotype and disease incidence (11).

Although demonstration of the involvement of gelatinase in tissue pathology and virulence requires the comparison of isogenic mutants, in vitro targets of this enzyme do provide clues for a potential role (69). The gene for gelatinase, gelE, encodes an enzyme that shares significant homology with neutral proteinases from Bacillus species and elastase from Pseudomonas aeruginosa (69). The proposed targets of this enzyme include gelatin, casein, hemoglobin, and other bioactive peptides, including the E. faecalis sex pheromones. The observation that enterococcal pheromones are potent chemoattractants (62), and that gelatinase can cleave these and other bioactive peptides, indicates that gelatinase at least has the potential to modulate the host response to enterococcal infection.

CONCLUSIONS AND FUTURE PERSPECTIVES

Enterococci are well adapted for survival and persistence in a variety of adverse environments, including sites of infection and inanimate hospital surfaces. The rapid emergence of antimicrobial resistance among enterococci undoubtedly also contributes to their emergence as prominent nosocomial pathogens, making them among the most difficult to treat. An understanding of the molecular pathogenesis of enterococcal infection, however, is in its infancy, largely because rogue commensals do not fit the mold of what has emerged as the modern conception of "pathogenesis". These organisms are not highly toxigenic, highly invasive, or highly infectious by most measures. They do, nevertheless, cause a substantial amount of human disease, highlighting the inadequacy of existing pathogenesis precepts. Additional study on the pathogenesis of enterococcal infection is urgently needed to reverse the trend toward larger numbers of refractory infections caused by these organisms, for which we have limited understanding.

Acknowledgments

The authors wish to thank Viswanathan Shankar, Mark Huycke, Wolfgang Haas, Pravina Srinivas, Phil Coburn, Brett Shepard, Michelle Callegan, and Mary Booth for helpful discussions and comments. Portions of the work described were supported by PHS grants AI41108 and EY08289.

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Wednesday, November 15, 2006

How it started / how it's been treated

It all started after having been out of work for close to a year last September (2005). I wasn't coping very well and had pretty much ceased all of my usual physical activity for several months (I was previously a VERY active badminton player). I had begun putting on enough pounds that I was motivated to start an exercise regimen. I lived in a 19 floor apartment building, so I started climbing to the roof everyday. I gradually built up from one climb a day with several stops to four times daily with no stops. A couple of times, I had a sharp pain in the testicles that stopped me cold, but after about 5 seconds it went away. I chalked it up to "yet another weird thing my body does occasionally". Then one day, they started feeling funny, as if they were heavier than normal. Over the course of a week, they just became more and more noticeable. Then one morning, it was suddenly painful to even walk across the room, and my upper inner thighs were numb and tingling. An ultrasound at the local hospital left docs unsure of whether it was a varicocele or epididymitis, so they gave me a week of Levofloxacin. I came back a week later with no improvement and saw a different doc, who said the first doc didn't know what he was talking about, and immediately placed me on an IV (cefotaxime) for 5 hours, saying that if I felt any better the next morning, I should come back for IV treatment for the next 7 days. IV treatment is a miserable affair in China, and since I lived just across the border from Hong Kong at that time, I hopped on over the next day to see my doctor there. He referred me to a urologist who quickly concluded via manual / visual examination that I had a varicocele; RX: take acetaminophen as needed and lay down with legs raised. "It's nothing serious".

Within a week, things DID improve. Pain ceased to be a constant companion - as long as I didn't walk or stand for too long. All the symptoms did seem to point to a varicocele. I figured I'd just have to live with it until I found work again.

I took a job in
Shanghai in March 2006 and quit a month later because the travel requirements made my two little companions unbearable. The first urologist I saw in Shanghai did a manual exam, said "Epididymitis!", threw some antibiotics at me, and rushed me out the door. The second was a little more thorough, doing testicular and prostate ultrasounds. The testicular showed no abnormalities, and the prostate showed none either although something about an echo was a little off. This doc concluded I had prostatitis (despite the lack of urinary or perianal symptoms) and gave me some pills (English name was Prostat) which are some kind of pollen primarily. I took those for 4 days, but from the very first day developed urethral irritation (felt like there was sand in there) and a slight burning sensation at the tip similar to what I get if I urinate too soon after ejaculating. Once I quit the Prostat, that problem went away.

I then saw an internal medicine specialist who said that epididymitis and prostatitis were related and not much was known about either; he thought my case could be caused by my stair-climbing. He gave me ibuprofen and said if that didn't work to try diclofenac. Beyond that, he said, suggested that I consider going to Hong Kong or back to the US for treatment, as he didn't know of any urologists here that are up to the task. I saw a previous urologist again not long after, and he gave me tramadol, which doesn't really kill pain but makes me just not give a damn about it. Unfortunately, it also half-zombifies me for about 24 hours and gives me arrhythmia, which in turn sometimes makes me nauseous. I use it only as a last resort.

Around this time I started to develop a severe case of what I now believe was reactive arthritis in my hands. It got so bad I couldn't even type. I got desperate and went to a TCM doctor who said my problem had to do with diet. He put me on a very foul diet of nuts and beans for a week. It didn't work, so I went back and he put me on a couple of different herb balls. Within a week, my arthritis cleared up completely, but it had no effect on my testicular pain.

Not long after this, my copy of Headache In The Pelvis arrived, and reading it prompted me to look around for a good physical therapist. Somehow I managed to get referred to a hospital here to see a
Hong Kong based sports medicine doctor in late July who found a hip problem that could possibly be the cause of my pain. Here's an exerpt from his report:

On examination: Positive findings: irritable right hip on flexion with adduction and internal rotation. Negative findings: normal FABER tests both hips. Normal gait. Normal testes. No significant herniae. Back, SI joints and buttock muscles normal.

X-ray: AP pelvis and hips and frog laterals: show a Ganz lesion of the right proximal femur with a pistol grip (aka phalloid) deformity.

Injection: local anaesthetic and steroid to the right hip: he found the injection uncomfortable and it was not possible to place the entire injection intraarticularly, reexamination showed a slight improvement in hip impingement.

Impression: he has cam impingement, a form of femoro-acetabular impingement (FAI). This condition could certainly cause the testicular pain, however, it is possible that it could be an alternative underlying cause, such as a sports hernia. Unfortunately the local anaesthetic component of the hip injection was non-diagnostic, but I hope that the steroid component will reduce his pain over the next few weeks.

FAI is a recently recognised condition, and most likely causes arthritis of the hip.
Recommendation: hip arthroscopy to remove the Ganz lesion and deal with any secondary articular cartilage damage to the acetabular labrum.

Plan: if his pain settles with the injection, it would be reasonable to proceed directly to arthroscopy, if the pain does not settle it would be reasonable to repeat the injection or perform MRI of the hip and pelvis to rule out alternative problems such as avascular necrosis of the femoral head, musculo-skeletal pelvic tumour etc.

Information: I have asked him to visit www.hipfai.com for further information.

Physiotherapy: FAI cannot be treated by physiotherapy, but the physiotherapist may be able to relieve his, presumably secondary, muscle spasm and reinforce the importance of avoiding positions of hip impingement (i.e. flexion +/.adduction +/.internal rotation).

I must say it was a real relief to see a doctor that actually listened and was willing to explore the possibility that there may be causes outside of the urological sphere (I sure had a tough time explaining that to the nurse who was charged with conveying the general nature of my problem to the doctor before he saw me though!). After that visit, I began doing the stretches recommended in A Headache In The Pelvis, but stopped after a week or so as it seemed to be making things worse. I have not been back to see this physician since because I'm not entirely convinced that an impingement is my problem. It doesn't explain why the testicles are tender to the touch when flare-ups occur.

In early August, I saw yet another TCM doctor who said the problem was that too much heat and dampness was trapped down there. He prescribed some herbs that were, in the end, profoundly foul tasting but ineffective. I went back again a week later and he changed the prescription a bit. A week later nothing had changed.

A strange thing happened when leaving that doctor's office the first time. My right testicle was suddenly so sensitive that with each step, I had a horrible dull pain as it rubbed against my thigh. I almost could not make it to the curb outside to get a taxi. Sitting at home later that night feeling terribly depressed, I tried watching old Jackass episodes to lighten my mood, and I found that laughing caused the same intense pain. It occurred to me that this was a hernia symptom, so I spent some time reading about it. I found what I believed to be the left inguinal canal, explored it a bit, and then went to the right one, where I felt no difference. The surprising thing was that after I did this, I stood up without really thinking about it and started walking around – and experienced no pain! This got me excited enough to go the next day to Huashan hospital to get checked specifically for a hernia.

I saw a general physician who felt around and found nothing. He started telling me the same things most of the others have, and he kept resisting the idea of having an x-ray or CT scan, yet he would not say why (I know now that both of these are ineffective for hernia detection - what I should have asked for was a dynamic ultrasound). My insistence flustered him enough that he called in a urologist to consult. The urologist was no different than the others, ultimately saying that the idea of a hernia in my case was ridiculous because there was nothing palpable. He wound up prescribing levofloxacin for six weeks along with a TCM herbal tablet called Wenglitong Jiaonang. I took the levo for two weeks and felt no improvement.

At the end of August, I saw yet another TCM doctor closer to home and poured out the whole story to him. He gave a little speech about how he was going to be different, and how my pain would be gone in a week after taking these herbs he prescribed, etc. He wanted me to have a digital prostate exam, but I refused - Chinese people seem to have a very different idea of what constitutes significant pain, and thus medical staff here can be a bit rough! Anyway, he pronounced it as 'probably prostatitis' and sent me on my way. It didn't work.

After two weeks week of fennel+fenugreek tea (another combination that has helped some on the boards), I flew to Hong Kong hoping to not only see my regular physician, but be referred to some specialists. I had a dynamic ultrasound which points to several possible causes; here are the findings:

Both of the testicles are of normal size and echogenicity. (Measurements omitted) The echotexture is homogenous although there are small clusters of hyperechoic nodules measuring approximately 0.1cm at the inferior pole of both testes. These are most likely foci of calcification indicating previous inflammation. There is no increased vascularity elicited within either testes.

There is a 0.4cm x 0.2cm epididymal cyst at the head of the right epididymis. The rest of the right epididymis is unremarkable. There is a similar cyst measuring 0.4cm at the head of the left epididymis with a smaller 0.2cm cyst at the tail. Some calcification is noted within the body of the left epididymis which is also midly thickened. However, no increased vascularity is found on colour doppler. The overall appearances may therefore indicate post infective change.

There is no evidence of varicocele in the right scrotum but the veins in the left testis are distended particularly after Valsalva maneuver measuring more than 0.3cm, suggestive of a varicocele.

In addition, there is a small right inguinal hernia elicited on increased intra-abdominal pressure (remember the doctors who ridiculed the idea that I might have a hernia!).
The left inguinal orifice is intact.

Both kidneys are of normal size and appearance. (Measurements omitted) There is an echogenic lesion at the left upper pole measuring 1cm without acoustic shadowing which is most likely haemangioma.

Impression:
1. Foci of calcification within inferior pole of both testicles suggestive of previous inflammation/infection.
2. Small bilateral epididymal cysts with mildly thickened left epididymis suggestive of previous epididymitis.
3. Right inguinal hernia
4. Left varicocele

5. Probable angiomyolipoma in the left kidney


A manual prostate check and blood/urine tests turned up nothing. The doctor said he didn't think referral to any specialists was necessary and instead wanted me to try gabapentin. It's been over month since that visit, and I have stopped taking the gabapentin. I wasn't feeling any better with it, and it was causing loads of abdominal pain.

Tuesday, November 14, 2006

My symptoms

- Dull pain (sometimes right testicle, sometimes left, sometimes both) if I walk very long (usually more than 5-10 minutes, but occasionally I can walk much longer), and if I push it too far, I will suffer much discomfort for a week or two after.

- Sitting generally eases the pain to the point of being non-existent - except in cases where I've pushed myself too far as mentioned above

- Hot baths used to help, but now they seem to make things worse.

- When the scrotal sack is not pulled up tight, I can feel a pea-sized lump on the bottom of the left testicle. I have a larger, nickel-sized lump on the top right-hand side of the right testicle that seems to get bigger after walking a bit and has occasionally increased in size after sex. I suspect this larger lump is either a spermatocele or a really angry epididymis...but it's not excessively tender.

- Manual examination by physicians is always an unpleasant ordeal, as are ultrasound scans.

- Testicles seem to hurt much less or not at all when the scrotal sac is pulled up tight against my body (this isn't so true lately).

- Sexual activity definitely results in increased pain within 12-24 hours and remains that way for 2-4 days.

- Recently (since October 2006) I (and my wife) have noticed a very pronounced increase in the length of time it takes my erections to subside after orgasm. We're now talking 10 - 15 minutes.

- Intense anger can negate pain completely and enable me to walk for hours with no repercussions. This has happened twice in the last 12 months.

- Psychologically, this problem has nearly destroyed me. I feel like I am on indefinite house arrest, and it has made a complete mess of my entire life. I'm generally a fairly optimistic person, but lately thoughts of jumping off the highest building I can find are a daily occurrence. I cannot live like this much longer. Compounding the problem is that I am currently unemployed because of this issue, and I am thus uninsured.

About me

I am a western expatriate who has lived in China for the last five years. I was hired as a marketing/business development manager and relocated to China by a medical device manufacturer in 2002. At the end of 2004, I and many others lost their jobs in a merger. Because I loved living in China so much, I opted to stay here.

In September of 2005, unemployed and uninsured, I managed to contract epididymitis - a crippling condition that few doctors seem to take seriously or know anything about. I have now spent thousands on doctors who have done nothing to earn that money, and there is no cure in sight. I also now know more about my condition and its possible causes than any doctor I've met thus far, yet only one has taken me seriously and listened. After all, I'm not a doctor; how could
I possibly know anything they don't?