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Humans exist in complex milieus, and their association with disease is affected both by the environment in which they live and by their genetic susceptibility to particular diseases. People live in concert with microbial agents that may or may not cause disease in particular individuals, depending on their environment and their genetics.
There are substantial obstacles to identifying organisms associated with a particular chronic disease. First, organisms can act in a "hit and run" manner, in which they cause disease initially but then are either resolved due to natural immunity or are successfully eliminated with antibiotics. The damage has been done, however, resulting in chronic disease. For some chronic diseases of this type, such as Reiter's syndrome, Guillain-Barré syndrome, or rheumatic heart disease, it is very difficult to find a fingerprint of the organism in the disease tissue. Second, organisms can be latent at the time of diagnosis. They may not be actively replicating, so there is no active RNA transcription. Third, chronic latent or recurrent infection may be involved in the pathogenesis so that, again, the organism may not be active at the time of diagnosis. Fourth, organisms may need a particular predisposing environment or a host with a particular genetic susceptibility, so the simple presence or absence of the organism may be misleading.
To address these problems, evidence is assembled in a number of ways: from epidemiological studies, from microbiological assessment of pathogenesis and etiology, from studies that mimic the disease process in vitro or in animals, and from clinical treatment trials.
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Obstacles and Opportunities for Framing Future Research
Humans exist in complex milieus, and their association with disease is affected both by the environment in which they live and by their genetic susceptibility to particular diseases. People live in concert with microbial agents that may or may not cause disease in particular individuals, depending on their environment and their genetics.
There are substantial obstacles to identifying organisms associated with a particular chronic disease. First, organisms can act in a "hit and run" manner, in which they cause disease initially but then are either resolved due to natural immunity or are successfully eliminated with antibiotics. The damage has been done, however, resulting in chronic disease. For some chronic diseases of this type, such as Reiter's syndrome, Guillain-Barré syndrome, or rheumatic heart disease, it is very difficult to find a fingerprint of the organism in the disease tissue. Second, organisms can be latent at the time of diagnosis. They may not be actively replicating, so there is no active RNA transcription. Third, chronic latent or recurrent infection may be involved in the pathogenesis so that, again, the organism may not be active at the time of diagnosis. Fourth, organisms may need a particular predisposing environment or a host with a particular genetic susceptibility, so the simple presence or absence of the organism may be misleading.
To address these problems, evidence is assembled in a number of ways: from epidemiological studies, from microbiological assessment of pathogenesis and etiology, from studies that mimic the disease process in vitro or in animals, and from clinical treatment trials.
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Patrick Moore described how the discovery of new pathogens will require the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology. Moore used the example of the identification of the virus that causes Kaposi's sarcoma, which often strikes gay men, to discuss general issues in causality and to illustrate the limits of current approaches for determining causality for a newly discovered agent and disease. The causative agent, named Kaposi's sarcoma-associated herpesvirus (KSHV), was identified using a genetic technique called representational difference analysis. Once the virus was identified, in 1994, events moved rather quickly—a fact that speaks to the importance of new pathogen discovery. The virus's genome has been sequenced, serologic tests have been developed, and studies have been initiated to understand its epidemiology and to test possible treatments. Moreover, the virus has since been found to cause at least two other types of disease. Based on this experience, Moore pointed to the need for researchers to move beyond Koch's postulates or other traditional guidelines in their efforts to determine disease causality for suspect microbes. Researchers are attempting to do this by applying various new techniques emerging from molecular biology and biotechnology. It seems clear as well that epidemiologists developing new criteria for causality will have to incorporate new pathogenic mechanisms that are not accounted for in current disease models.
Mikhail Pletnikov discussed the importance of expanding research to better understand the interplay of genetic and environmental factors in the causation of a number of important developmental behavioral disorders. Among methodological problems of studying the gene-environment interplay is the difficulty in firmly defining environmental factors and making them quantifiable. In this context, virus infections provide a promising research avenue, because of their etiologic connection to several neurodevelopmental disorders, including autism and schizophrenia, and because of the reliability of quantification of viral effects on brain and behavior. In particular, Pletnikov described work using an animal model to study gene-environmental interactions that occur during neonatal infection with Borna disease virus (BDV). Neonatal BDV infection in rats has been shown to produce distinct neuroanatomical, neurochemical, and behavioral abnormalities that resemble pathological and clinical features of some human developmental disorders. The significance of studying neonatal exposure derives from the fact that the effects of many genetic and environmental risk factors are evident either prior to or around the time of birth, and the interaction between them often is apparent well before the onset or diagnosis of the chronic disease condition. Thus, studying the effects of neonatal BDV infection across the entire postnatal period in genetically different strains of rats will aid in understanding the course and time-dependent character of the interaction of genetic background features and the virus infection. In this way, the model system may allow study of some tremendously complex mechanisms relevant to developmental disorders.
David Persing provided an overview of recent research in the area of infec-
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tion, cancer, and the immune response. Current evidence suggests that inherited predisposition to cancer probably accounts for only a subset of total cancer patients, and in most models of the development of neoplasia, an underlying assumption is the contribution of an array of intrinsic and extrinsic factors within a multistep process. A basic prerequisite of many models is an increase in the baseline proliferation rates of essentially normal cell populations that leads to dysregulation of normal growth control mechanisms. Since many infectious processes often lead, directly or indirectly, to increased cell turnover and proliferation, certain agents are now widely regarded as carcinogens. Some of the pathogens that have been linked to cancer include human papillomaviruses (cervical cancer and other skin cancers), human T-cell leukemia viruses (adult T-cell leukemias and lymphomas in endemic areas), hepatitis B virus (liver cancer), Epstein-Barr virus (Burkitt's lymphoma and nasopharyngeal carcinoma), and Helicobacter pylori infection (gastric carcinoma and MALT lymphoma).In addition, new disease associations are being made with respect to previously known pathogens, such as the association of chronic hepatitis C virus infection with non-Hodgkin's lymphoma in certain populations.
In a separate presentation, Persing described recent and continuing advances in the development and application of techniques for identifying pathogens that cause chronic diseases. Although a paper on these subjects does not appear in this chapter, the following paragraph notes the highlights.
The ability to detect and manipulate nucleic acid molecules in microorganisms has created a powerful means for identifying previously unknown microbial pathogens and for studying the host-pathogen relationship. Although a paper on these subjects does not appear in the ensuing text, the highlights of his presentation are discussed here. Among the new technologies that Persing described is broad-range polymerase chain reaction, which has proved instrumental in linking a growing number of pathogens with chronic diseases, and representational difference analysis, which is an efficient means for finding differences between complex genomes and for identifying specific DNA sequences from the genomes of unknown pathogens. Researchers also are making use of sophisticated new DNA microarrays and biosensors that, among other things, can monitor host response as an indicator of the presence of infection or inflammation. In addition, new methods for generating "libraries" of genetic information from very small amounts of material are making it easier to conduct very specific and sensitive serologic tests. Equipped with these and other advanced tools, researchers are becoming better able to move beyond the limitations of Koch's postulates and to link infectious agents with chronic diseases more precisely and with greater confidence than ever before.
In the ensuing discussions, participants began to sketch in some of the characteristics of a comprehensive and coordinated effort that would enhance efforts both to identify links between infectious microorganisms and chronic diseases and to develop and implement interventions to minimize their health conse-
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quences. The goal was not to set specific priorities, but to identify opportunities. Highlighting a selection of the traits identified may provide a glimpse of the overall picture envisioned.
Participants agreed, for example, on the need to develop standardized definitions of infections and disease, to enable comparisons across studies and conclusions about causality, and on the need to ensure that laboratory assays maintain universally high standards of specificity, sensitivity, and reproducibility. New laboratory technology also is needed that can meet such performance standards while handling high throughput rates, in order to handle analyses of large cohorts in a reasonable amount of time, a trait that likely will be required in many future projects. Comparable efforts are needed to ensure that epidemiological studies are conducted with vigor and in an appropriate manner. One step will involve linking of databases that are designed (or modified) to be compatible. Peer review journals can reinforce performance standards if publication depends on the use of sound laboratory assays and epidemiologic design capable of supporting the conclusions.
Continued studies are needed to define temporal relationships between infections and disease—that is, what stage of infection determines outcome (e.g., first infection, reinfection, persistent infection, coinfection, or subsequent cross-reacting infection). Studies also are needed to clarify at which stage infection must be prevented or treated in order to minimize or eliminate chronic sequelae. It will be important to determine the expected benefit of actions, to ensure that the benefits will outweigh any possible risks. In other words, intervention should decrease chronic disease burden without unduly endangering the people who receive care.
There is a need to better understand the natural history, especially the earliest stages, of chronic diseases of unknown or incompletely known origins. What makes this task especially important is the hit-and-run nature of some diseases in which microbes set adverse events in motion and then disappear, the increased difficulty of imputing causation to microbes detected late in the course of disease, and the increased ease of treating or preventing disease at early time points. Toward this aim, clinicians should be increasingly encouraged to identify patients who have recently developed or seem to be developing various suspect chronic diseases, to collect in an orderly manner a range of clinical specimens, and then to follow the course of the disease in order to identify tell-tale early clinical features.
Calls were made for more effort devoted to developing animal models of chronic diseases, and to teaching health professionals about their value and their limitations. Animal models can be powerful tools when the etiology or pathogenesis of a disorder is unknown. Psychiatric modeling with animals may present an especially ripe area for probing a variety of important questions, yet many practitioners in the field are not accustomed to working with such models.
Increased emphasis should be placed on longitudinal studies, as well as on follow-up studies and "look back" studies of cohorts and surveillance results that have been generated in the past. Longitudinal studies may prove particularly valu-
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able given that rapid advances in the field may mean that we might not know today which pieces of evidence will be needed in the future. Human specimen collections, such as the National Children's Study that will begin in 2004, may be especially important for longitudinal research.
Participants identified a number of specific populations that should receive additional attention. One such group includes people who move from rural areas into cities, both in the developing and the developed world. Studies are needed to see whether they bring new infections with them, or whether they prove to be susceptible to new infections that they previously had not encountered. With the world's changing demographics, gathering such information may provide a window into pathogenesis of a number of chronic diseases.
Efforts are needed to address problems related to informed consent. Many workshop participants expressed concern that current regulations and guidelines are too complex, too uncertain, or too restrictive to allow for meaningful sharing of data—and sometimes all three. There was general agreement that informed consent is and must remain an important part of research involving human subjects. But participants also agreed that all parties—from government, academia, and private funding agencies—need to work together to develop a more standardized method for gaining patient consent, for gathering identifying information, and for being able to use this identifying information in the future. This may be an opportunity for multiple institutions and multiple governments, domestic and foreign, to cooperate in devising a system of patient consent that operates more smoothly, protects patient rights, and allows for expanded research on infections and chronic diseases.
Given the magnitude of the outstanding scientific questions, and of the health consequences at stake, an increasing share of future research likely will involve groups of investigators representing a variety of disciplines, or groups of institutions working collaboratively. Although there remains a clear role for individual investigators, it is becoming apparent that large multidisciplinary projects often can best marshal the critical mass needed to address the thorniest biological problems. In many cases, these large projects will include a multinational component, in order to ensure that sufficient attention is paid to multiracial, multiethnic, and multicultural differences.
Participants called on the overall scientific community to evaluate whether it is organized and structured properly to address these issues, and whether its various components communicate effectively. The community also should mount a concerted effort to identify gaps in current knowledge about the etiology of chronic diseases, pinpoint what needs to be done to close those gaps, chart the obstacles that stand in the way, and then identify and provide the necessary financial resources (monetary and human) to drive progress.
Government can play an important role by reorienting its funding priorities. Indeed, the time is ripe. The government is now investing nearly $1 billion in rebuilding the nation's public health system, and part of the money will go to-
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ward linking state health departments more closely with local health departments than has historically been the case. At the same time, government research centers are launching major new interdisciplinary projects, and universities, which often have been in competition with one another, are beginning to join in collaborations. Thus, foundations are beginning to be built for bridges linking public health, clinical medicine, and research. But these promising efforts need to be nurtured to ensure continued cooperation.
Patrick S. Moore
University of Pittsburgh
Pittsburgh, PA
Successful new pathogen discovery requires the talents of multiple disciplines, including epidemiology, clinical medicine, molecular biology, and pathology. In this paper, the identification of Kaposi's sarcoma-associated herpesvirus (KSHV) illustrates general issues in causality and shows the limits on our ability to determine a causality for a newly discovered agent and disease (Moore and Chang, 1998).
The mysterious outbreak of Kaposi's sarcoma among gay men was the harbinger of the AIDS epidemic. It is now clear, however, that the AIDS-associated Kaposi's sarcoma epidemic was actually due to the collision of two independent viruses in a susceptible population: HIV and a new virus, KSHV or HHV8, which was found using molecular techniques (O'Brien et al., 1999).
Over 20 different agents had been put forward as the cause of KS before 1994. To look for the "KS agent" (Beral et al., 1990), Yuan Chang used representational difference analysis (RDA) to compare DNA from a Kaposi's sarcoma lesion to uninvolved, sterile-site tissue from the same patient on the assumption that the two samples would be genetically identical except for the presence of the putative agent's genome (Chang et al., 1994).
As shown in Figure 3-1, RDA is a subtractive hybridization technique in which PCR adapters are ligated onto digested DNA from the KS tissue (tester) (Lisitsyn et al., 1993). The tester DNA was then rehybridized back to a ten-fold excess of uninvolved sample DNA (driver) that had been identically digested. For human genomic fragments present in the KS sample, 90 percent of these fragments will form pairs with the corresponding antisense strand lacking the adapter from the normal tissue DNA. PCR with a primer specific to this adapter linearly amplifies these common sequences and, of course, there was no amplification of the DNA rehybridized from the driver alone. Sequences that were unique to the KS lesion, however, reanneal to each other and have adaptors on both ends, so that amplification occurs exponentially. The initial PCR products are then
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FIGURE 3-1 Representational differential analysis comparing DNA from a Kaposi's sarcoma lesion to sterile-site tissue from the same patient.
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rehybridized again to the adapter-less healthy tissue DNA and the process is repeated, each time selectively enriching for the unique sequences found only in the KS lesion (Gao and Moore, 1996).
Four RDA fragments were generated by this process, two of which were found to be specific for the KS agent. Although these two fragments account for less than 1 percent of the entire 145-kilobase viral genome, the few base-pairs worth of unique information they provided made it possible to develop enough tools to identify the agent.
The two fragments were used as Southern hybridization probes and tested against KS lesions, showing that about three-quarters of the KS lesions were positive for viral DNA. Using internal specific primers from the KS 330 band, a PCR assay was developed that showed 25 out of 27, or 93 percent, of the initial KS lesions tested positive. Moreover, the negative samples were equally telling: one of the two negatives had degraded DNA and was not amplifiable by using cellular primers, and the other one was mislabeled normal human kidney.
KSHV is a gamma herpesvirus belonging to the same class as Epstein-Barr virus (EBV). It is associated with three different major proliferative diseases: Kaposi's sarcoma, primary effusion lymphoma (PEL) (Cesarman et al., 1995a), a monoclonal B cell lymphoma, and multicentric Castleman's disease (Soulier et al., 1995), which is a polyclonal hyperplasia caused by a virus-encoded cytokine expressed by KSHV (Parravicini et al., 1997). Nearly all KS and PEL patients have KSHV infection, but only about half of HIV-negative, multicentric Castleman's disease patients are positive for KSHV infection indicating that this disease has a heterogeneous pathogenesis.
The two aforementioned RDA fragments of the KSHV genome facilitated the identification of infected cell lines to serve as source material for viral DNA and as a reagent for biologic studies (Cesarman et al., 1995b). Genomic library walking was performed using cosmid and lambda libraries from one of these cell lines allowing sequencing of the remainder of the genome (Russo et al., 1996). Using this information, various techniques were used to identify likely antigens and generate serologic tests (Gao et al., 1996a,b; Kedes et al., 1996; Simpson et al., 1996). While identification of high-titered infected cell lines sped up this process, isolating the agent was not essential for developing tools to detect it. Molecular biology has reached the point where it is straightforward to identify a new agent, sequence its genome and develop serologic tests for it without ever having actually purified, living sample of the agent. The virus does not have to be grown in order to apply traditional techniques for determining whether or not an agent is present.
The virus itself is a tremendously interesting scientific problem. It has a long unique coding region containing all of the viral open reading frames. Unlike most viruses, KSHV has pirated cellular genes over its evolution and the viral genes are recognizable homologues to cellular genes of known function. Many of these
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genes provide new insights into tumor virology through their control of the cell cycle, prevention of apoptosis, or immune evasion properties.
One might conclude that this virus is completely different from other viruses and not much can be learned from it to extend to other viruses. In fact, the opposite is true. EBV, for example, induces cellular cyclin D2 to drive the cell through the G1/S cell cycle checkpoint; KSHV encodes its own version of a cyclin D with an analogous function. Other examples of functional correspondence between the KSHV homologues and viral genes encoded by even distantly related viruses can be readily seen (Moore and Chang, 1998a, 2001). For this reason KSHV might be considered something like a molecular Rosetta stone because by using it, we can begin to interpret the language of molecular virology in terms of cell biology for many different viruses.
The importance of new pathogen discovery is illustrated by a timeline of KS research. This would be equally true also for hepatocellular carcinoma and hepatitis C or a wide range of diseases where a new pathogen has been found. The point is that things change quite rapidly once the agent is finally found. Moritz Kaposi initially described the disorder in 1873, but not until 70 years later was there a suggestion of an infectious etiology. In 1981, the onset of the AIDS epidemic brought a tremendous increase in scientific interest in this cancer. There was still, however, little known about the pathogenesis of this disorder in 1993 when there were over 200,000 cases of AIDS in the United States. At that time over 20 different agents had been proposed at one time or another as the causal agent for Kaposi's sarcoma.
The description of KSHV was first published in 1994 and within two years its viral genome was completely sequenced (Neipel et al., 1997; Russo et al., 1996). By that time it was known that the virus was found in all forms of Kaposi's sarcoma (Boshoff et al., 1995; Chang et al., 1996; Moore and Chang, 1995), serologic tests had been developed (Gao et al., 1996a,b; Kedes et al., 1996; Miller et al., 1996; Simpson et al., 1996) and studies initiated to understand the epidemiology of this virus in KS (Moore et al., 1996; Whitby et al., 1995). Shortly thereafter, studies were performed to see whether ganciclovir, a specific antiviral agent, could be used to treat KS (Martin et al., 1999). At the present, there have been over 2,000 papers published on KSHV and its role in malignancy.
Finding a new pathogen also can benefit other fields. When KSHV was first described, only two other related rhadinoviruses had been described in new world primates. Although we live in North America, humans are still considered old world apes. One was herpesvirus saimiri from squirrel monkeys and the other herpesvirus ateles from spider monkeys. Researchers at the University of Washington began to look for other primate KSHV-like viruses (Rose et al., 1997). Using consensus PCR, two were found in rhesus macaques, and subsequently in all the various branches of the primates, both lower and higher primates. This suggests that the viral ancestor of KSHV evolved with us over time. Even more
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interesting, another group found a closely-related but distinctly different virus in rhesus macaques (Desrosiers et al., 1997). It was named rhesus rhadinovirus (RRV) and belongs to a second lineage of rhadinoviruses. RRV was initially only found in the lower primates, but last year an RRV was found in chimps (Greensill et al., 2000; Lacoste et al., 2000; Lacoste et al., 2001). The implication is that there is an ancestral KSHV/RRV-like virus split off in the primate evolution and has followed through with the different primate lineages, probably including humans. Thus, it is almost certain that there is an undiscovered HHV 9.
An issue in new pathogen discovery is making the step from finding a new DNA sequence to determining whether or not it causes a specific disease. Applying Koch's postulates (Koch, 1942) can elucidate the process:
The agent occurs in every case of disease.
The agent never occurs as a fortuitous or non-pathogenic strain.
The agent can be isolated from the lesion, grown in pure culture, induce disease in a susceptible host and can be re-isolated from an infected susceptible host.
These were postulates that Koch developed for determining the cause of tuberculosis at a time when not much was known of viruses or the carrier state. This was a brilliant attempt to develop a scientific rationale for determining whether an agent is causal for disease or not.
Bradford Hill also developed epidemiologic criteria for causality which are shown here for KSHV and KS (Hill, 1965). Though developed specifically for cigarette smoking, most epidemiologists now use these criteria to determine causality:
Is the infection present in cases; do all types of the disease involve infection? Is it reproducible in multiple settings?
Does infection precede disease?
Is the infection specific to the disease or is it ubiquitous infection among humans?
Is the virus localized to the tumor (one interpretation of a biologic gradient)?
Do the epidemiologic studies make sense (are they coherent?)?
Is it biologically reasonable and do experiments confirm the relationship?
With regard to KSHV, the answers to these questions are largely true. KSHV is present in more than 95 percent of KS lesions. It can be said that the remaining negative 5 percent is probably spurious due to technical difficulties in detection or misdiagnosis, and in fact the virus is absolutely necessary for disease. Though this cannot be proven at present, it can be argued that the situation is very similar to that of papillomavirus and cervical cancer 5 years ago. Is it generalizable? Yes. All types of KS are infected as far as is known. It also appears to have the correct
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temporal association in that cohort studies show that patients are infected before developing disease, and not afterwards.
But specificity is an important question. KSHV is not singly associated with Kaposi's sarcoma. It is also associated with two other diseases. However, the epidemiology of these two diseases makes some sense in terms of Kaposi's sarcoma, so multiple outcomes are not too worrisome. Depending on the assay that is used, some researchers suggest that the infection rate in the general population for this virus is much higher than alluded to here, but careful studies suggest that less that 5 percent of Americans are infected with KSHV.
Is there a biologic gradient? Yes, there is. Are the epidemiologic findings coherent? Yes, a wide range of epidemiologic studies seem to come to exactly the same set of conclusions. Is it biologically plausible? Yes, there are multiple oncogenes in this virus, related viruses cause cancers, and there are blinded clinical trials which seem to suggest that treatment with ganciclovir prevents the development of Kaposi's sarcoma.
KSHV and KS was a relatively easy case even though it took two years and seven or eight different studies before these conclusions could be reached. Nonetheless, the case for causality was relatively easy.
Now let's consider issues where causality is more problematic. First, KSHV has been claimed not only to cause Kaposi's sarcoma, but also a wide variety of diseases that don't fit its epidemiologic pattern, such as multiple myeloma and sarcoidosis. Although studies supporting these associations were published in reputable journals, they were based on PCR or had other problems and remain questionable in terms of contemporary epidemiological knowledge. In the age of PCR, it is difficult for the casual observer to sort out what is true and what is not.
Assuming that the problem of poor laboratory technique can be solved, there are three more fundamental problems in determining causality. First, causality is relative and should not be thought of as being cast in stone. Causality depends on pathogenic assumptions. That is where Koch's postulates fall down and also where Hill's criteria fall down as well.
For example, if a virus is associated with autoimmune disorders, it can be assumed that one would have an immune response against that virus. In that case the individual may actually clear the virus, so a reverse association would be seen from what would normally be expected following Hill's criteria. The criteria simply do not apply in this case, even though it is a reasonable possibility.
Second, causality is normative. Researchers can get together and study the data but only a few agree to particular conclusions. When the studies describing KSHV as the cause of KS were completed, it was thought that the issue of causality would be resolved. However, it still required a great deal of interpretation. There were many contradictory studies that were ignored because they were not considered valid. But others might disagree, and this is true for just about any contentious issue. An agent is only considered causal for a disease when a major-
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have been directly implicated in the progression of neoplasia. Epstein-Barr virus plays an important role in the evolution of B cell lymphomas in these patients, Kaposi's sarcoma virus participates in the tumorigenesis of Kaposi's sarcoma, and human papillomavirus infection contributes to the development of carcinomas of the skin and cervix. A reduction in levels of antigen-specific cytotoxic T cell responses are associated with activation of infection or disease progression in all of these cases, and a reduction in the efficiency of immune surveillance has been proposed as a factor in tumorigenesis. Consistent with this hypothesis, patients on immunosuppressive therapy following transplantation appear to be at increased risk for the same spectrum of malignancies with the exception of a lower incidence of KS; accordingly, KSHV appears to be much less prevalent in transplant patients compared to HIV patients, presumably because of the risk factors associated with the predominantly sexual transmission of KSHV (Chang and Moore, 1996).
Hepatitis B Virus
Primary infection with hepatitis B virus usually follows an acute and convalescent course in immunocompetent hosts with ultimate resolution of disease. However, in approximately 5 to 10 percent of adults, and in most infants born to infected carrier mothers, primary infection leads to chronic active hepatitis which may progress to cirrhosis of the liver and hepatocellular carcinoma (Kew, 1996). Continuous proliferation of hepatocytes, which may be present for the life of the host, is a prominent feature of chronic active hepatitis; in such patients, the relative risk of developing hepatocelluar carcinoma is increased 20–40 fold. Because of the large number of carriers of hepatitis B virus (HBV), approximately 200 million persons worldwide, hepatocellular carcinoma is one of the most common cancers in the world and is the most common cancer in HBV-endemic areas of the Far East and sub-Saharan Africa. The development of hepatocellular carcinoma probably depends upon direct effects of certain viral determinants along with chronic persistent proliferation of hepatocytes. HBV-related hepatocellular carcinomas often contain defective HBV genomes expressing one or more viral open reading frames; the viral X gene, which is often expressed in malignant tissues, is a transcriptional transactivator of host promoter sequences including those associated with oncogene expression and integrated viral genomes can activate host proto-oncogenes. There is little doubt that continuous proliferation of hepatocytes is also an important contributor to the development of neoplastic disease, since other disorders associated with chronic hepatitis and hepatocyte turnover (such as chronic alcoholism or hereditary hemochromatosis) may also lead to an increased predisposition to liver cancer, and the effects of alcohol ingestion and viral infection may well be synergistic in this regard (Brechot et al., 1996).
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Hepatitis C Virus
A rapidly emerging association of chronic viral infection with malignancy is the development of hepatocellular carcinoma associated with chronic hepatitis C virus infection. In the United States, HCV infection is projected to become the major cause of liver cancer, due in part the large number of chronic carriers in this country, currently estimated at 3.5 million persons. In the case of HCV infection, a major determinant of development of hepatocellular cancer appears to be duration of infection and the degree of persistent liver injury (Zein and Persing, 1996). Several studies have associated certain HCV subtypes with differences in liver disease severity, interferon responsiveness, and duration of infection. Viral subtypes that appear to have been in the U.S. population for longer periods of time are dramatically overrepresented among patients with liver cancer. Specifically, subtype 1b, which is present in 15–20 percent of cases nationwide, is present in 90 percent or more of liver cancer patients in several studies conducted at different centers (Zein et al., 1996). Since presence of genotype 1b appears to be a marker of longer duration of infection in U.S. patients, it is possible that other genotypes will be more commonly implicated in cases of hepatocellular carcinoma in other countries, and that the overrepresentation of genotype 1b in the United States will decline over time. Additional factors such as alcohol consumption may contribute independently to risk of neoplasia, even in patients with more recent infections (Brechot et al., 1996). As for HPV infection, host immunogenetic or other factors may play a role in susceptibility to viral infection as well as in determining the severity of infection (see below).
Recently, chronic HCV infection has been associated with the development of B-cell non-Hodgkin's lymphomas in an Italian population (Mele et al., 2003) and with the development of cryoglobulinemia and monoclonal gammopathy in the United States (Cacoub et al., 1994). The development monoclonal gammopathy is thought to presage the development of hematologic malignancies in a significant subset of cases; it is not yet known whether HCV-associated monoclonal gammopathy or mixed cryoglobulinemia is a predisposing variable for the development of such malignancies in the United States. One recent study suggests that HCV infection-associated lymphoproliferative disease might include multiple myeloma (Montella et al. 2001). It is possible that MGUS is a marker of an underlying benign, perhaps antigen driven lymphoproliferative process, which may after many years convert to a malignant process via somatic mutation. In this respect, the genesis of neoplasia may be similar to that described for Helicobacter pylori-related MALT lymphoma. The relative disparity in the frequency of non-Hodgkin's lymphoma associated with HCV infection in the United States compared to that in Europe may conceivably reflect differences in duration of infection within the population, immunogenetic differences, or exposure to other oncoviruses including KHSV.
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Human Papillomavirus Infection
In the past decade, human papillomavirus (HPV) has emerged as the single most important risk factor for development of cervical carcinoma, and it may be associated with neoplasia in other tissues as well. To date, more than 80 HPV subtypes have been described in a wide variety of epithelial tissues, with some viral subtypes found exclusively in certain tissues; partial sequences of novel subtypes indicate that over 100 subtypes may exist in humans. It is estimated that approximately 95 percent of cervical cancers worldwide are associated with infection by certain human papillomavirus subtypes, usually types 16 or 18 but occasionally other types. HPV-associated cervical cancers typically harbor at least remnants of the HPV genome in the form of two viral oncogenes which are consistently expressed in malignant tissues. The viral E6 gene product binds to tumor suppressor protein p53, promoting its degradation, and the viral E7 product binds to the retinoblastoma gene product, resulting in a functional inactivation. In addition, the E6 and E7 oncoproteins stimulate cell proliferation by activating cyclins E and A. The combination of these effects is to immortalize keratinocytes in vitro. However, additional mutational events are apparently needed to provide the fully transformed phenotype, since immortalized keratinocytes do not form tumors in vivo (zur Hausen and Rosl, 1994). Nonetheless, the viral E6 and E7 genes and their products may become attractive diagnostic targets for monitoring metastatic disease and for the development of tumor-specific immunotherapeutic protocols.
The association of HPV infection with carcinomas of other tissues has been less clear cut, but is somewhat reminiscent of the early days of research on the association of HPV with cervical cancer in which a fundamental limitation in the detection of the large variety of HPV types led initially to great controversy. On the other hand, the inherent proneness of PCR technology to contamination problems, coupled with its ability to detect extremely small numbers of possibly incidental HPV contaminants, warrants a careful interpretation of the growing number of reports implicating this virus in malignancies of many types. Archetypal "oncogenic" subtypes of HPV appear capable of infecting different anatomical sites, and associations of HPV infection with squamous cell carcinomas of the head and neck are reasonably well established. The involvement of HPV in the pathogenesis of skin cancer, the most common malignancy in the world, was suggested recently and a new family of HPV types has now been described in recurrent squamous cell carcinomas of the skin in transplant patients (Shamanin et al., 1996). This finding seems consistent with the clinical experience in patients who are immunosuppressed by HIV infection, in which cervical dysplasia is highly prevalent (Sun et al., 1995).
The role of HPV infection in epithelial carcinomas of the bladder and lung are also being investigated. Studies of the bovine papilloma virus (BPV) have been shown to have an association with cancer of the bladder in cattle (Olson et
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al., 1965). Inoculation of BPV into newborn hamsters or mice has also been demonstrated to induce tumors (zur Hausen, 1996). Some human studies in recent years have suggested that relatively common HPV types can be detected in human transitional cell carcinoma (TCC) of the bladder in up to 34 percent of cases in certain patient populations (Smetana et al., 1995), but the presence of HPV in the neoplastic tissue has been difficult to demonstrate with consistency (Chetsanga et al., 1992). Interestingly, cases of rapidly progressive multifocal TCC of the bladder have been reported in patients following renal and cardiac transplantation, suggesting that HPV may play a more significant role in TCC of the bladder in immunosuppressed patients (Noel et al., 1994). Although smoking history is the leading risk factor in the development of squamous cell carcinoma of the lung, a recent study implicated the presence of HPV type 16 in an unexpectedly high number of cases of well-differentiated squamous cell carcinoma of the lung on the island of Okinawa (Kinoshita et al., 1995). However, although some studies have supported this finding (Hirayasu et al., 1996), others have failed to implicate HPV in lung cancer (Szabo et al., 1994). In this regard, it is interesting to note that risk of cervical cancer is linked epidemiologically to risk of carcinoma of the lung but not uterine or ovarian cancers, and that both of the former are linked to smoking (Anderson et al., 1997). Clearly, additional studies will be necessary which are designed to rule out the effects of incidental virus and DNA contamination, yet also designed to be capable of detection of the widest range of HPV types.
Recent studies of the natural history of HPV infection have suggested that the ability of the genetically heterogeneous papillomaviruses to exploit relative deficiencies in the immune response may represent an important determinant of the risk of developing chronic infection and subsequent neoplastic disease. Attention has focused recently on cytokine production in HPV-specific helper T lymphocyte populations in women with cervical cancer compared to women in whom the disease regresses spontaneously. Several studies have now indicated that failure to mount cytotoxic T cell (CTL) responses to human papillomavirus-infected cells may significantly predispose to the development of cervical cancer (Tsukui et al., 1996); this failure may be virus type-specific, such that the types represented most often in cervical cancer are those most successful at avoidance of CTL activity (Ellis et al., 1995). Conditions associated with reduced CTL activity, such as HIV and HTLV infection, oral contraceptive use, pregnancy, and immune suppression associated with transplantation have likewise been associated with increased HPV viral burden and acceleration of disease progression (Sun et al., 1995). Twin studies have suggested that risk factors for cervical cancer, as for another HPV-associated lesion, epidermoplasia verruciformis, may be inherited (Ahlbom et al., 1997). More recent studies have failed to detect an association with somatic mutations in the gene encoding p53, and have further explored associations with the immunoglobulin gene cluster (Cuzick et al., 2000). Understanding the contribution of the environmental, host somatic, and host im-
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munogenetic factors to the development of HPV-related dysplasia is an area of intense research activity which may lead to direct practical benefits to patients in the form of improved immunomodulatory approaches to early and late stage lesions. Since the prevalence of HPV infection is so high, the use of routine testing for HPV is of questionable value (Stoler, 2001), except in patients with Pap smears containing atypical features (ASCUS). Clearly, if additional immunogenetic and other host susceptibility factors can be identified, the positive predictive power of HPV testing in cervical cancer screening programs may increase to acceptable levels (Klug et al., 2001).
The Role of Humoral and Cellular Immune Responses
As illustrated vividly by HIV infection, infection with one pathogen may lead to a predisposition toward other infectious processes as well as cancer; a key feature of the immune suppression associated with HIV infection and pharmacologically-produced immunosuppression following transplantation is a reduction of cytotoxic T-cell (CTL) and related T-helper type 1 responses (Spina and Tirelli, 1992). One important theme that recurs among the above mentioned programs, and in cancer research in general, is the relationship of T cell responses to the evolving tumor. A decline in cytotoxic immunity has been associated with virus-associated tumors in immunosuppressed patients, and relative deficits in the establishment of CTL responses during the initial stages of infection are associated with progression of infection in otherwise immunocompetent hosts. Relative differences in the ability to mount cytotoxic T-cell responses have been noted among mouse strains for several years, and recent evidence suggests that immunogenetic determinants in humans may play similar roles. From a teleological perspective, it is likely that viruses and other pathogens associated with chronic infections in humans have evolved means of avoiding CTL responses in at least some hosts in order to maximize reservoir capacity. An example is the recent documentation of point mutations within a dominant HLA B7-associated CTL epitope of the human papillomavirus E6 gene product; the presence of sequence variation has implications for vaccine design and immunotherapy, and overall, viral diversity must be taken into account in the design of therapeutic strategies.
Just as the suppression of cellular immune responses may relate to development of cancer, the development of humoral immune responses may be extremely useful for determining the history of exposure to the pathogen and for the serologic surveillance necessary to establish the etiologic role of a given pathogen. Serologic studies have been critical to the understanding of the role of H. pylori as an etiologic cofactor in various malignancies; when no such assays are available for a novel infectious agent, surrogate serologic assays can be used as proposed previously (Persing, 1997). Furthermore, since IgG antibody subclasses are generated on the basis of T-cell help, measurement of IgG subclasses may lead to an understanding of the role of T-cell responses (i.e., the proportional Th1
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and Th2-type responses) in determining the resolution or persistence of a particular infection (Moro et al., 2001).
Role Reversal: The Cancer Cell as the Ultimate Eukaroytic Parasite
Independent of the etiologic roles of infectious agents in the development of human cancer, in more than one sense, the cancer cell itself represents the ultimate eukaryotic parasite. Cancer cells, like parasitic protozoa, use a variety of mechanisms to avoid immune surveillance including persistence in small numbers, active secretion of immunosuppressive substances, downregulation of MHC class 1-based recognition, and antigenic variation (Buchanan and Nieland-Fisher, 2001). Humoral immune responses to cancer-specific antigens often occur in cancer patients and are undetectable in patients without cancer (Disis et al., 1997), suggesting that immunologic tolerance can be broken and that many types of cancer-specific immune responses, in the form of tissue-specific autoimmune phenomena, can be tolerated in humans. Antibody responses in cancer patients have led to the discovery of many important cancer-specific antigens (Chen, 2000). At the same time, these studies point to the relative lack of efficacy of humoral immune responses in the control of a developing malignancy, much the same way that in chronic carriers of protozoan parasites, immune responses to pathogen-specific antigens happily coexist with the pathogens themselves. Indeed, many of the lessons learned from parasite immunology can be extrapolated to human cancer, especially in the development of new vaccine-based approaches to the treatment of both diseases.
In purely reductionistic terms, infectious diseases can be viewed as horizontally acquired genetic disorders, in which exogenously acquired nucleic acids of a pathogen integrate, either chromosomally, episomally, or extracellularly, with those of the host to disrupt normal cellular processes or produce inflammation. Developing a better understanding of the interactions of human microbial flora with their hosts, along with an understanding of other host and environmental determinants of pathogenicity, represents an increasingly important intersection of infectious disease research with the Human Genome Project. Illustrations of the latter concept are provided by the discovery of resistance to HIV infection by virtue of mutations within a gene encoding an HIV coreceptor (CCR-5) (Samson et al., 1996). Another important example is the inherited susceptibility to Mycobacterium avium-intracellulare infections in families carrying a mutant allele of the interferon-gamma (IFN-γ) receptor (Newport et al., 1996). The identification of such an allele within the human population has far-reaching implications, since it may be associated with a general reduction in the ability to mount cytotoxic T-cell responses during infections of many types. Genetic predisposition to
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papillomavirus infection appears to underlie the inherited skin disorder epideromodysplasia verruciformis (Majewski and Jablonska, 1995), in which cytotoxic T-cell responses apparently fail to develop against certain papillomavirus subtypes. Since early generation of such responses appears to be a critical step in the resolution of human papillomavirus infections, patients harboring functionally similar mutations may be uniquely predisposed to the development of cervical and other cancers linked to HPV infection. By focusing on unusually severe outcomes of relatively common infectious diseases, we may be able to identify critical immunogenetic factors in the formation of protective immune responses, and to tailor patient management and cancer chemoprevention efforts (in some cases directed against the pathogens themselves) in appropriate ways.
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Berghenheim's score 5:54 into the second period put the Panthers ahead 2-0. Eleven minutes later, he set up Boyes for a three-goal advantage.
Tomas Fleischmann also scored and Aleksander Barkov had a pair of assists as Florida stayed hot on the road.
Scott Clemmensen made 28 saves.
Mason Raymond scored for the slumping Leafs, who fell for the fourth time in five contests.
James Reimer stopped 20-of-23 shots for Toronto.

subset: commoncrawl


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Definition of Foreign body airway obstructionForeign body airway obstruction: a partial or complete blockage of the breathing tubes to the lungs due to a foreign body (for example, food, a bead, toy, etc.). The onset of respiratory distress may be sudden with cough. There is often agitation in the early stage of airway obstruction. The signs of respiratory distress include labored, ineffective breathing until the person is not longer breathing (apneic). Loss of consciousness occurs if the obstruction is not relieved. Treatment of airway obstruction due to a foreign body includes:
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text: I never use a intermediate water bath when using my 2 bath development for VC (or graded) enlarging paper. I cannot see any reason for doing so. As far as mixing the two baths together in one tray, I think that would reduce the ability to contropl contrast and basically would defeat the purpose of using 2 baths. If the point is to creat an "intermediate" developer, for whatever reason, ok, but if it's tonal control you're after, then I say keep the two baths seperate.


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Home > Find a B&B > Search by Region > The Islands Bed and Breakfasts
The Islands Bed and Breakfasts of British Columbia
Explore British Columbia Islands Bed and Breakfast Inns
Enjoy a Unique Lodging Experience during Your Stay in BC
The member bed & breakfast inns of the Islands invite you to discover our ruggedly gorgeous region of British Columbia, Canada. We welcome you to be our guest at the B&B inns across this BC region as you explore scenic, diverse locations throughout the islands and enjoy the many adventures that await you here.
Vancouver Island, largest island in the region, offers the charming culture of Victoria, "The Garden City" and capital of British Columbia, and much more. The Greater Victoria area includes the world famous Butchart Gardens and the rugged water sports of Sooke. South Island is comprised of the Chemainus and Cowichan valleys and offers fine agritourism, culinary tourism and arts communities. Central Island is home to recreation ranging from beaches to old-growth forests. The Pacific Rim area of the west coast is Vancouver Island's destination for outdoor recreation. North Central Island offers world class salt and freshwater sport fishing. North Island is known for its ruggedly charming vistas, wildlife and recreation.
The Gulf Islands, located between the major destinations of Victoria and mainland British Columbia, are a haven of arts communities, breathtaking scenery, farmers markets and recreation that ranges from biking to scuba diving.
The BC Islands Bed and Breakfast Experience
Our bed and breakfast inns of the Islands region of British Columbia are dedicated to making you feel at home away from home from the moment you arrive. Enjoy a good night's sleep in a comfortable guest room. Savor a delicious breakfast at the inn before heading out to your adventures and sightseeing all across our region. Come "home" at the end of the day and take advantage of the "personal touch" amenities offered by the B&B. Refreshed and relaxed, you will be ready for the next day's activities in the Islands of BC, Canada.
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Albion Manor Bed and Breakfast InnPhone: (250) 389-0012Toll Free: (877) 389-0012 Welcome to Victoria's Victorian Jewel just a 5 minute walk from the ferries, downtown and major attractions. Situated in a beautiful garden, Albion features delightful architectural details. Enjoy gourmet breakfasts in a tastefully decorated ambiance with antique furnishings and art. Victoria, British Columbia View Listing Go to: www.albionmanor.com View availability |
Marifield HousePhone: (250) 383-3820Toll Free: 1-866-235-3820 10 min, walk to downtown. Free wifi, off-street parking, complete breakfasts. Established in 2001. Victoria, British Columbia View Listing Go to: www.marifieldhouse.com View availability |
Beacon Inn at SidneyPhone: (250) 655-3288Toll Free: 1-877-420-5499 5-Star luxury in the heart of quaint Sidney by the Sea. Centrally located, close to Victoria, Butchart Gardens, BC and WA State ferries, marinas and Victoria Airport. Stroll to many unique local shops, eateries, coffee houses and the waterfront. Modern, mock-heritage, adult-oriented property. Sidney by the Sea, British Columbia View Listing Go to: www.thebeaconinn.com View availability |
Hammond Bay OceansidePhone: (250) 751-1409Relax and experience our beachfront B&B in Nanaimo British Columbia. Oceanside rooms w/ fireplaces, TV,dvd, queen beds, wifi,kitchen facilities, private bathrooms/entrances/patios. Close to parks,amenities,and the Nanaimo Ferry. Enjoy beautiful sunrises with your morning coffee. Nanaimo, British Columbia View Listing Go to: www.hammondbaybb.com View availability |
Fairholme ManorPhone: (250) 598-3240Toll Free: 1-877-511-3322 Fairholme Manor is a beautifully restored 5 Star Victorian mansion with private ocean/mountain view suites overlooking the inn's beautiful 1 acre gardens adjacent to Government House and gardens. Bestseller cookbook 'Fabulous Fairholme-Breakfast & Brunches' published by Whitecap Books. Victoria, British Columbia View Listing Go to: www.fairholmemanor.com View availability |
Cobble House Bed & BreakfastPhone: 250-743-2672Toll Free: 1-866-743-2672 Our Cobble Hill Bed & Breakfast is a peaceful haven in the heart of Vancouver Island's Wine region. On a forested acreage with a creek, our Cowichan Valley accommodation, halfway between Victoria and Nanaimo, makes us a great central location from which to explore southern Vancouver Island. Cobble Hill, British Columbia View Listing Go to: Www.cobble-house.com View availability |
Dayspring Farm B&BPhone: 250-592-6089Toll Free: 1-888-592-6089 Dayspring Farm is located between downtown Victoria and Sidney (airport/ferry terminal). Close to world-famous Butchart Gardens and wine country yet minutes from downtown attractions, this is country living at its best. Enjoy a delicious, customized breakfast to start your day. Let us pamper you! Victoria, British Columbia View Listing Go to: www.dayspringbb.com View availability |
Pine and PicketPhone: (250) 741-0168Located close to the Nanaimo waterfront and just a short walk from the Nanaimo Departure Bay ferry terminal. Our balconies provide incredible views of Departure Bay and Newcastle Channel and kayak and bicycle rentals are a block away. Your host is a French Chef! Nanaimo, British Columbia View Listing Go to: www.thepineandpicket.com View availability |
Heron House Waterfront B&BPhone: 250-335-0594Welcome to Heron House Waterfront Bed & Breakfast. Located on Vancouver Island, our Bed & Breakfast is located within 60 feet of the beach. You can enjoy our oceanfront balcony. Our exclusive luxury B&B has two guest bedrooms that affords our guests Union Bay, British Columbia View Listing Go to: www.heronhousewaterfront.com |
Majestic Ocean Bed and BreakfastPhone: (250) 726-2868Toll Free: 1-800-889-7644 Waterfront B&B with outdoor hot tub and deck, surrounded by nature and wildlife. Comfortable private ensuite rooms, big showers and tubs, heated floors. Home cooked breakfast for any dietary concerns. Wifi,f/p, sat/tv. Nearby National Park, beaches and trails, close to town, restaurants/shopping. Ucluelet, British Columbia View Listing Go to: www.majesticoceanbb.ca |
Cottage PirouettePhone: (250) 386-2166Toll Free: 1-877-386-2166 In a quiet residential neighbourhood, convenient to downtown Victoria, ocean side parks, walking trails, shopping and dining. Bus stop near front door, on-site parking and bicycle storage. Water feature garden for relaxation. Space for workshops, weddings & other events. Japanese also spoken. Victoria, British Columbia View Listing Go to: www.cottagepirouette.com View availability |
Ashcroft HousePhone: (250) 385-4632Toll Free: 1-866-385-4632 Rich in hospitality, Ashcroft House is a graceful 1898 heritage landmark located in the historic James Bay area of downtown Victoria. Explore our ocean pathways, beaches, or enjoy an easy 12 minute stroll along famous Beacon Hill Park placing you in the heart of Victoria's famous Inner Harbour. Victoria, British Columbia View Listing Go to: www.ashcrofthousebandb.com View availability |
Marketa's Bed & BreakfastPhone: (250) 384-9844Only 500 steps from Inner Harbor, 1912 delightful Edwardian B&B, easy walk to downtown Victoria, restaurants, parliament buildings. Comfortable rooms, budget to luxury, jacuzzis, fireplaces. Guest lounge, patio. Full gourmet breakfast of choice. Free off street parking. Ask about midweek specials. Victoria, British Columbia View Listing Go to: www.marketas.com View availability |
MGM Seashore B&BPhone: 250-729-7249Vancouver Island...a Spectacular Executive Oceanfront B&B in Nanaimo. The Coast Mountains provide a stunning backdrop for our dynamic views, gorgeous sunrises & sunsets. Modern, custom built, West Coast design, 3 level, 3 bedroom B&B is a Trip Advisor favourite. Wildlife, location, relaxation. Nanaimo, British Columbia View Listing Go to: www.mgmbandb.com |
Kidd'sBed & BreakfastPhone: (250) 749-7790Toll Free: 1-866-749-7790 Welcome. Our air conditioned home overlooks Cowichan Lake. Swim & boat in the lake or river; drive, hike or bike while exploring southern Vancouver Island. Relax in our hot tub. Choose a main floor 1 bedroom suite(separate entrance),or 2 ensuite bedrooms. We serve a full breakfast Lake Cowichan, British Columbia View Listing Go to: www.kiddsbb.com |
Birds of a Feather Victoria Oceanfront B&B and Vacation RentalPhone: (250) 391-8889Toll Free: 1-800-730-4790 Hotel Privacy. B&B Hospitality. Voted Most Loved in CityHub's Hotels & B&Bs category. Frommers Recommended. CIBC Travel Rewards Top 10 Canada B&Bs. 3 private luxury condo-like suites with fireplaces, soaker tubs, rain showers, heated floors at an affordable price on Victoria's west shore. Hot Tub. Victoria, British Columbia View Listing Go to: www.birdsofafeather.ca View availability |
Abbeymoore Manor Bed & Breakfast InnPhone: 250-370-1470Toll Free: 888-801-1811 Unwind and relax in the historic Rockland district of Victoria, British Columbia, Canada. Abbeymoore is an exquisite 1912 Edwardian mansion offering comfortably elegant accommodation in five gorgeous heritage bedrooms. Spacious, self-contained private garden suites are also available. Victoria, British Columbia View Listing Go to: www.abbeymoore.com View availability |
Long Lake Waterfront Bed & BreakfastPhone: (250)758-5010Toll Free: (877)758-5010 Top rated by Trip Advisor - Romantic private lakeside lifestyle with reflections on the water in our canoe/kayaks. Hot tub, King size beds, wifi, float plane accessible. Your day trip center for Vancouver Island. Warm hospitality and hot breakfasts served by Hospitality winners 2013 Gordie & Janice. Nanaimo, British Columbia View Listing Go to: www.lodgingnanaimo.com View availability |
Bostrom's B&B On Little Beach BayPhone: 250-726-7266Oceanfront with views that will take your breath away! Come find out why we have been awarded Trip Advisor's People's choice award listing us in the top 10 B&Bs in all of Canada. Ucluelet, British Columbia View Listing Go to: www.BostromsBandB.com |
Misty Meadows B&BPhone: 250-727-6405Be pampered in a luxurious country setting just 20 minutes from downtown and all major tourist attractions. Stay at an active farm in the Highlands of Victoria, a unique and peaceful greenbelt area. Children are welcome to share in this unique farm experience. Hike, birdwatch, golf or simply relax. Victoria, British Columbia View Listing Go to: www.mistymeadows.com |
Oak Bay Guest House B&BPhone: (250) 598-3812Toll Free: 1-800-575-3812 Steps from the sea, enjoy the best of both worlds in Victoria's most sought-after neighbourhood! We offer a quiet stay and a breakfast you can coast through the day on! For those seeking excitement, the Oak Bay Marina, the Village, Victoria's Downtown Inner Harbour are all a few minutes' walk/drive. Victoria, British Columbia View Listing Go to: www.oakbayguesthouse.com View availability |
Quarrystone HousePhone: (250) 537-5980Toll Free: 1-866-537-5980 All four rooms are located in a seperate building from the main house joined by a patio ensuring complete privacy. All rooms have their own entrance, private patio/balcony, fireplace, jacuzi tub, wii fi, tv/dvd, fridge, microwave, robes etc Full three course country breakfast. Kids and pets welcome Salt Spring Island, British Columbia View Listing Go to: www.quarrystone.com |
Dashwood Manor Seaside Bed & Breakfast InnPhone: 250-385-5517Toll Free: 1-800-667-5517 Built in 1912 this stunning Heritage Inn offering Bed & Breakfast is the perfect seaside get-away. All guest rooms have clear ocean views. Ideally located next to Beacon Hill Park & the Cook Street Village Victoria, British Columbia View Listing Go to: www.dashwoodmanor.com View availability |
Ocean Mist Guesthouse B&BPhone: 250-726-7199Toll Free: 1-877-726-6478 Open ocean/harbour view B&B close to beaches and steps to the Wild Pacific Trail lighthouse loop. Gourmet breakfast served in-room. Private, coastal decor, king & queen suites each with private entrance & deck, ensuite bathroom, kitchenette with microwave (no stove), fireplace, TV & wood floors. Ucluelet, British Columbia View Listing Go to: www.oceanmistgh.com |
Nairne House By-the-SeaPhone: 250-384-6971Toll Free: 888-214-8819 Welcome to your private B&B suite in our award-winning Victorian home. Located in the city's most historic residential neighbourhood - steps from the ocean & Beacon Hill Park and a 10 minute stroll to downtown and the Inner Harbour. Off season and extended-stay rates available. Victoria, British Columbia View Listing Go to: www.nairnehouse.com |
Fisher House Bed and BreakfastPhone: 250-386-6252Toll Free: 877-386-6252 In the heart of James Bay Village, a short walking distance to downtown and the Coho and Clipper ferries at the Inner Harbor. Enjoy the comfort of a beautiful room and warm hospitality and taste the delicious breakfasts made with fresh, local organic ingredients.Twin, Queen and King beds available. Victoria, British Columbia View Listing Go to: fisherhousevictoria.com View availability |
Artful Suite - Boutique B&BPhone: 250-667-2455Home is Where the Art Is! A Private, bright, very comfortable, self contained one bedroom B&B apartment featuring contemporary handcrafted furniture that is designed & made on site along with Artworks in various mediums by fine Local Vancouver Island Artists! Nanaimo, British Columbia View Listing Go to: www.artfulsuite.ca |
Anchor Point Bed and Breakfast SuitePhone: (250) 538-0110Toll Free: 1-800-648-2560 Relax in the Terrace Suite at the sailclub on Ganges harbour. Private self contained designer queen-size 1 bedroom suite with living/dining space,WiFi/cable/DVD/MP3.Harbour views. Island breakfasts delivered to you. The convenience of Full Service; but with total privacy. All "Yours to Enjoy" Salt Spring Island, British Columbia View Listing Go to: www.anchorpointbb.com View availability |
Abinger HousePhone: 250-590-3578Toll Free: 1-888-511-1541 Abinger House is one of the finer Victoria Bed and Breakfasts and the perfect home base for your travels in and around Victoria and southern Vancouver Island. Our Victoria Bed and Breakfast is located in the heart of one of Victoria's most beautiful and serene neighbourhoods. Victoria, British Columbia View Listing Go to: www.abingerhouse.com View availability |
Hawley PlacePhone: 250-245-4431Toll Free: 1-877-244-4431 WELCOME, you\'ve arrived at our beautiful Victorian replica home\r\nin pretty Ladysmith. You will have a well-appointed theme room with ensuite, robes, luxury linens,coffee/tea service in room, free wifi or internet station,ocean glimpses, complimentary beverages, off road parking,and pretty gardens Ladysmith, British Columbia View Listing Go to: www.hawleyplacebandb.com |
Humboldt HousePhone: (250) 383-0152Toll Free: 1-888-383-0327 1893 Victorian B&B featuring elegant rooms with large Jacuzzi baths, and wood-burning fireplaces. Conveniently located 2 blocks from Victoria's city center and inner harbour area. Reservations include a hot, gourmet in-room breakfast, and sparkling wine with homemade chocolate truffles on arrival. Victoria, British Columbia View Listing Go to: www.humboldthouse.com View availability |


text:
Garrett Harris noon, April 28
A wagon road in Plum Canyon is difficult to fathom.
Hike part of the California Riding and Hiking Trail to an overview of Shelter Valley.
Geologic processes at work in the Narrows Earth Trail and Quartz Vein Wash
The Narrows Earth Trail, located at the "Narrows" where San Felipe Creek turns abruptly northeast just east of the junction with Pinyon Wash, is the perfect place to observe geology and earth movement in action. ...
Visit a historic line shack made of rock on the vigorous Bow Willow-Rockhouse Canyon desert loop hike.
Hike where modern California began and Cahuilla Indians died.
Make your way through a lush riparian area and loop back to an overview of a historic spring.
Visit Dog Beach, take a bicycle ride on the Ocean Beach Bike Path to Mission Valley and back, or check out the waves on the pier.
Cascading waterfalls, pools, and an historic three-hinge bridge built in 1913 make this an interesting canyon to explore.
Hike into a lush desert riparian setting with waterfalls, pools, and shady trees.
Cougar Canyon is one of the delights of Coyote Canyon. It has willows, sycamores, and cottonwood trees in a lush riparian oasis where waterfalls cascade into deep pools surrounded by huge boulders and sandy beaches. ...
Colorful walls of metamorphic schist and intrusions of granite and quartz make this an interesting canyon hike.
Camp where the Kumeyaay lived in the Anza-Borrego.
Hike from a Kumeyaay seasonal village site to an elephant tree "forest" and palm groves.
Hike to a rare plant once thought to be the only one in the county.
The elephant tree (Bursera microphylla) is rarely found in the United States. It is found in the Gila Range of Arizona and, more commonly, in Baja California and Sonora, Mexico. For many years it was ...
Hike in a pristine desert wilderness where over 100 ironwood trees are found.
Ironwood Wash and Canyon are not on any map prior to March 11, 2010. That was the date that the U.S. Board on Geographic Names unanimously approved the official naming of this wash and canyon, ...
Hike to Raptor Ridge and see many species of raptors from this viewpoint.
Kumeyaays' "valley of the eagles" still worthy of the name.
View Kumeyaay rock art, a rock shelter, and bedrock mortars in a cultural preserve.
The Morteros Trail is part of the 4757-acre Little Blair Valley Cultural Preserve that was created in December 2010 in Anza-Borrego Desert State Park. The area was a seasonal home for the Kumeyaay people who ...
A bird's eye view of Borrego Valley and the surrounding desert and mountains from a mountaintop.
Sunset Mountain takes its name from the last rays of sunshine that enshroud the top with the setting sun. The 3657-foot peak is located south of SR-78 between Pinyon Wash and Harper Canyon. From the ...
Hike along a bubbling creek and beside a towering riparian forest festooned with native grape vines.
The Lower Santa Ysabel Trail, now reserved for hikers and equestrians, takes you beside a lush riparian forest of towering sycamores, willows cottonwoods, and spreading oaks, draped with native grape vines as it travels beside ...
Hike from lake to lake while passing through shady oak woodlands and lush chaparral.
Lake Poway Recreation Area is a convenient starting point since it provides abundant free parking during much of the year. The lake also provides numerous additional recreational opportunities. The hike to Lake Ramona offers a ...
Hikers have wide open views of the peak in the aftermath of the Cedar Fire.
In 1907, General Land Office (GLO) survey records note "Mid Peak" as the peak between North and Cuyamaca peaks. It was not until 1970 that "Middle" Peak appeared on forest maps. Middle Peak used to ...
Ascend and sign the peak register at the top of San Diego's "Half Dome."
Bring friends, as this is a trail less traveled. The route averages a 7 percent steady climb with short sections of 60 percent (stairs) at the 4588 peak before reaching the plateau to Corte Madera ...
Walk, jog, or bike in this friendly community park that has a pond.
East Shepherd, or Greenbelt, trail is interesting in all seasons, with a combination of native coastal sage scrub and nonnative plants in the canyon. Walk north on Santo Road for about 160 feet, where the ...
This hike offers a serpentine slot canyon and a forever view.
This is one of the most popular hikes in the Anza-Borrego Desert. From the top, there is an almost 360-degree view that includes a major part of both the state park and the state vehicular ...
Hike through a narrow desert canyon with lush vegetation.
This is one of the most popular hiking trails in the Anza-Borrego Desert. Where else can you camp in comfort with full facilities, including hot showers, and soak in pools of geothermally heated mineral water ...
The Highland Valley Trail travels east along the grasslands.
The Highland Valley Trail is part of the San Dieguito River Park trail system. Eventually it will extend 55 miles from Volcan Mountain near Julian to the Pacific Ocean at Del Mar. The Highland Valley ...
Hike down to a canyon floor through scrub oak "tunnels."
This is the only trail that accesses Los Peñasquitos Canyon Preserve from the south rim between Black Mountain Road and the West End parking lot off Sorrento Valley Blvd. Before the Camino Ruiz Trailhead was ...
Views to Mt. San Jacinto and the San Bernardino Mountains on this scenic hike.
You are unlikely to encounter any horses, wild or tame, on this trail, but it offers a chance to hike through beautiful oak and sycamore-shaded canyons and lush chaparral that can be ablaze with color ...
Explore San Diego's backcountry history on this hike.
Julian's Old Banner Road, now a hiking trail, starts in a suburban-like setting among Coulter pines and black oaks and descends through lush chaparral, providing a chance to explore a fascinating bit of San Diego's ...
Take this hike for dramatic views of the Anza-Borrego Desert and a different view of Borrego Valley.
One of the best scenic rides in San Diego, which includes a trip on the ferry
This ride offers scenic views of San Diego Bay from downtown to the South Bay, and up to Coronado. There are sweeping views of the ocean along the Silver Strand and of downtown San Diego ...
Waaay bigger than the other one
Excellent panoramic view of Ramona's wilderness area.
Trail to past tragedy in the Cuyamacas
Hike this year-round trail through chaparral and oak woodland to stunning views and to see a mounted 12-cylinder aircraft engine.
Get a good workout and avoid the crowd on Cowles Mountain
Kwaay Paay Peak is a good alternative to Cowles Mountain for anyone who wants a good climbing hike without a crowd. It is the fourth highest peak in Mission Trails Regional Park, at an elevation ...
Encounter several natural habitats and an Indian acorn-grinding area on this short trail.
The nation's largest urban natural park, right off I-8
Encounter several natural habitats and an Indian acorn-grinding area on this short trail.
Discover a Kumeyaay dwelling nestled in a shady oak grove.
The highlights of this short hike include the transition from grasslands and coastal sage scrub habitats to small shaded oak woodland with majestic coast live oaks and rare Engelmann oaks found along a stream where ...
Tijuana Estuary's endangered annual hemiparasite, only found in ten locations.
Reddish egrets and yellow-headed night herons are sometimes seen in this section of the Pacific Flyway.
Early morning or late afternoons are the best times for birding on this section of the Pacific Flyway.
Enjoy great views of San Diego all the way up to the top of Viejas Mountain, which is green again after the Cedar Fire in 2003.
Stroll through one of San Diego's more scenic oak woodlands and experience a diversity of vegetation types on your way up to the top of Mt. Woodson where rock climbers may be seen.
Anza-Borrego's high elevation multiuse trails appeal to hikers, bikers, and equestrians.
Find two rare plants on the Torrey Pines Loop Trail — bush rue when descending into Gonzales Canyon and Torrey pine trees when ascending to the mesa top.
This short hike and visitor center are perfect introductions to coastal birds and marsh habitat.
Easily accessible falls and multiple crossings of the Sweetwater River through chaparral, riparian, and meadow habitats.
Unusual rock formations, views, and a variety of landscapes and habitats make this one of the better hikes in the county.
Panoramic views of Lakeside and East County mountains from "God's Hill"
This ridge climb to a historic site has panoramic views of Lakeside and East County mountains.
Discover a hidden treasure in the heart of Ramona.
This hike includes trails beneath an old oak canopy, morteros, open meadows, two creeks, and a small pond with a stone weir.
Hike from a tree-shaded riparian area to a mountain peak
The varied topography and ecosystems of Louis A. Stelzer County Park make this 420-acre reserve a delight to visit. It is situated along Wildcat Canyon Creek and includes the rocky hillsides, ridgeline, and a peak ...
Indian Creek Trail does not give up surprises easily. Hike this trail for woodlands, streams, and panoramic views in the Laguna Mountains.
Aromas of butterscotch and grape soda in Cleveland National Forest
Pines, oaks, and incense cedar on this six-mile loop of the Gatos Big Laguna Trail Spur.
Water birds on the lake and chaparral vegetation on the slopes make this a pleasant walk.
Sand mine becomes riparian willow forest in Lakeside.
This hike features the work of a local conservancy to restore this section of the San Diego River.


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Parents caught in middle — DPAC43 president
As the ongoing labour dispute between the province and the BC Teachers' Federation threatens a harmonious back-to-school, many parents are wondering what the future holds, says the president of the local District Parent Advisory Council.
"Parent comments are wide ranged; but, the common theme is frustration. Inconvenience varies from family to family. Yet, most parents are being remarkably patient, because learning conditions are as important to them as working conditions are to teachers," stated Chuck Denision DPAC43 president in an email statement.
Denison said the unsettled court case remains a stumbling block and parents would like the issues set aside while they deal with other concerns.
"Parents would like the two parties to temporarily set aside class size and composition issues without prejudicing their positions, whether this is achieved through contract wording or a cease fire agreement.
Government has the upper hand, holding the money, seemingly intent to starve teachers into submission. That would hold more weight for the few sympathetic parents if the money saved were redirected within our education system." Denison further stated.
Currently, the province intends to put strike savings into a $40 per day per child Temporary Education Support for Parents (TESP), which parents with children in school 12 and under can register for here.
Meanwhile, Denison said he plans to join a rally this Saturday at Spirit Square in Coquitlam from 1 p.m. to 4 p.m. It's called "Defend Our Public Education, Defend Our Future", and is hosted by a student group called Tri-Cities Leadnow Youth Connections.
"I am excited to see our older students growing their leadership skills," he said.
More information about the rally is available here.
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text:
John Barkai Professor of Law
"Let's Stop Spreading Rumors About Settlement and Litigation:
A Comparative Study of Settlement and Litigation in Hawaii Courts"
29 Ohio St. J. on Disp. Res. 85 (2014).
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