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A T helper type 1 (Th1) response is essential for resolving genital infections with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn). However, T-cell-dependent anti-chlamydial antibody is produced and may also contribute to protective immunity. We produced a MoPn-specific CD4 Th2 clone (Th2-MoPn) to study the role of a Th2 response during infection. We found that Th2-MoPn was unable to eradicate chlamydiae from the genital tract (GT) when it was transferred into MoPn-infected nude mice. Mice that received Th2-MoPn produced greater titers of MoPn-specific serum immunoglobulin G (IgG) antibody than mice that received a MoPn-specific Th1 clone (Th1-MoPn) (log10 titers, 1.89 ± 0.84 and 0.58 ± 0.76 [mean ± standard deviation], respectively [P < 0.01]). Also, the IgG isotypes were different for the two groups; whereas IgG1 was associated with Th2-MoPn, IgG2a was associated with Th1-MoPn. Also, infected nude mice that received Th2-MoPn produced higher levels of IgA in vaginal secretions. Although clone Th2-MoPn was detected in the GT, it was less efficient at migrating (112 ± 35.6 labeled Th2 clone cells/105 GT cells) than Th1-MoPn (505 ± 51.6 Th1 clone cells/105 GT cells) (P < 0.001, as determined by a t test). This may have been due to reduced expression of α4β7 and P-selectin ligand 1 on Th2-MoPn. However, Th2-MoPn cells were retained in the GT during chronic infection and comprised 10 to 15% of the total GT cells 80 days after transfer. The data show that the MoPn-specific Th2 cells are important for serum and vaginal antibody production and may accumulate in the GT during chronic infection.
Genital infection caused by the obligate intracellular pathogen Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the United States (8). The majority of genital infections in women are asymptomatic (41) and are often not treated. Sequelae resulting from untreated chlamydial genital infections include pelvic inflammatory disease, fallopian tube damage, ectopic pregnancy, and infertility (41, 46). Thus, development of a vaccine would have the potential to alleviate complications related to prolonged or repeated infections. Previous studies have indicated that cellular immune responses are essential for resolution of and immunity to murine chlamydial infection (40), and CD4+ cells are the primary effector cells (15, 25, 37, 42). Additionally, recent data obtained with the murine model suggest that the development of an ineffective, anti-chlamydial T-cell response may enhance the development of tissue pathology (49). Thus, understanding the factors that regulate immune responses within the genital tract (GT) is necessary for the design of future vaccines.
A T helper cell type 1 (Th1) response predominates in the murine GT during chlamydial infections (7) and is necessary to eradicate the bacteria (15, 31, 50). Anti-chlamydial Th1 cells appear to mediate protection through the production of cytokines, such as gamma interferon (IFN-γ) (13, 35, 39), which has been shown to directly inhibit chlamydial growth (6). In addition, the neutralization of interleukin-12 (IL-12) has also been shown to impede the clearance of chlamydiae (31) since IL-12 is necessary for the production of Th1 cells. Similarly, mice producing lower levels of IFN-γ exhibited a prolonged course of infection (14, 19, 50).
It has been more difficult to define the role of B cells in chlamydial genital infection. B-cell-deficient mice have been shown to resolve genital infections over a time span similar to that observed for immunologically intact control mice (17, 37, 43). However, studies performed with chlamydial immune (recovered from a previous infection with the mouse pneumonitis biovar of C. trachomatis [MoPn]) μ-chain knockout mice suggest that B cells or specific antibody may enhance protective T-cell responses (43, 47, 48). Furthermore, mice that were depleted of CD4 cells following resolution of infection were able to mount a protective response as long as B cells were present (26, 27). While anti-chlamydial immunoglobulin G (IgG) and IgA antibodies have been shown to reduce the amount of infection and inflammation in oviducts (9, 29, 38), the beneficial effect may depend on the antibody isotype. Peterson et al. (32) showed that passive administration of the IgG2b subclass, which is associated with a Th1 response, enhanced the shedding of chlamydiae in vivo, while administration of IgG1 antibodies, which are associated with a Th2 response, did not. Based on the importance of Th2 cells in B-cell maturation and differentiation, further investigation of the role of Th2 cells in B-cell help during chlamydial infection is needed.
The representation of distinct lymphocyte subsets within a local tissue site of inflammation is controlled by mechanisms that regulate lymphocyte recruitment (5). While a number of factors participate in regulating lymphocyte recruitment, particular adhesion molecule-lymphocyte receptor ligand pairs have been shown to influence the recruitment of Th1 and Th2 cell subsets. For instance, Austrup et al. (2) have shown that Th2 cells are virtually prevented from entering tissue sites of inflammation, such as arthritic joints and skin during a delayed-type hypersensitivity response. These authors also demonstrated that the absence of CD62E (E-selectin) and CD62P (P-selectin) binding domains on Th2 cells was responsible for the differential homing. Therefore, anti-chlamydial Th2 cell migration to the GT may be reduced. Since Th2 cells are important for IgA production and IgA is produced locally within the genital mucosa (21), reduced Th2 cell migration could result in lower IgA antibody levels. It is important to note that IgG levels are greater than or similar to the IgA levels found in vaginal secretions (24), which differ from the increased levels of IgA antibody found in other mucosal secretions. In this paper we describe production of a MoPn-specific Th2 clone (Th2-MoPn), which was used to examine the influence of a Th2 immune response in chlamydial immunity.
Antibodies.The following monoclonal antibodies were utilized in a flow cytometry analysis. Hybridomas secreting rat anti-CD4 (TIB207, IgG2b) and anti-CD54 (CRL1878, IgG2b) were purchased from the American Type Culture Collection (Rockville, Md.), and staining was performed by using undiluted supernatants. Rat anti-CD3 (29B, IgG2b; Gibco BRL, Gaithersburg, Md.) was used at a concentration of 10 μg/ml. The following rat monoclonal antibodies were purchased from PharMingen (San Diego, Calif.): anti-CD49d (9C10, IgG2a), anti-CD45RB (16A, IgG2a), anti-CD62L (Mel-14, IgG2a), anti-CD44 (IM7, IgG2b), anti-β7 (M293, IgG2a), anti-LPAM-1 (DATK-32, IgG2a), and anti-CD11a (M17/4, IgG2a). The concentrations used for staining ranged from 10 to 25 μg/ml. A rat IgG2b(κ) myeloma protein (IR863) and the rat monoclonal antibody IgG2a (R35-95) (PharMingen) were used as negative controls. Purified P-selectin-IgG1 fusion protein (PharMingen) was used at a concentration of 10 μg/ml. The phycoerythrin-conjugated affinity-purified F(ab)′2 fragment of goat anti-human IgG was purchased from Jackson Laboratories (West Grove, Pa.). The following anti-mouse monoclonal antibodies were utilized in T-cell purification by negative selection with magnetic beads. A hybridoma secreting rat anti-B220 (TIB-146, IgM) was purchased from the American Type Culture Collection. Rat anti-CD8 (53-6.7, IgG2a) and rat anti-MAC-1 (M1/70, IgG2b) were purchased from PharMingen.
Experimental animals.Immunocompetent BALB/c mice and BALB/c nude (nu/nu) mice were purchased from Harlan-Sprague Dawley (Indianapolis, Ind.) and were housed under laminar flow by using specific-pathogen-free conditions according to the American Association of Accreditation of Laboratory Animal Care guidelines. The UAMS Institutional Animal Care and Use Committee approved experimental procedures. Sterilized food and water were supplied ad libitum, and the room was maintained with a cycle consisting of 12 h of light and 12 h of darkness.
Infection of mice.Seven days prior to infection, mice received 2.5 mg of progesterone (Depo-Provera; Upjohn, Kalamazoo, Mich.) to maintain them in a state of anestrus (30, 37). Each mouse was infected by intravaginal inoculation of 1 × 107 inclusion-forming units (IFU) (2.4 × 103 50% infective doses) of MoPn in 30 μl of sucrose-phosphate-glutamate buffer. Infection was monitored every 10 days by isolation of MoPn from cervical-vaginal swabs as previously described (37).
Isolation and maintenance of T-cell lines and clones.A MoPn-specific Th2 clone was isolated from a MoPn-specific Th2 line. The line was established by boosting BALB/c mice subcutaneously with 108 IFU of MoPn, followed by infection 5 weeks later. CD4+ lymphocytes were purified by negative selection from cervical lymph nodes (CLN) 1 week later. Briefly, lymph node cells were labeled with rat monoclonal antibodies against CD8, B220, and MAC-1 (see above). The cells were then incubated with goat anti-rat antibody conjugated to 10-nm magnetic beads as specified by the manufacturer (Miltenyl Biotechnological Equipment, Bergisch-Gladbach, Germany) and passed over a ferromagnetic column. The recovered cells were more than 95% CD4+ and less than 1% CD8+, 1% B220+, and 1% MAC-1+ (data not shown). The isolated CD4 cells were generated by restimulation in vitro in complete medium (CM), which consisted of RPMI 1640 (Gibco Laboratories, Grand Island, N.Y.) supplemented with 15 mM HEPES (Gibco), 1.0 mM sodium pyruvate (Gibco), 0.1 mM nonessential amino acids (Gibco), 2 mM glutamine (Gibco), 100 U of penicillin (Gibco) per ml, 100 μg of streptomycin (Gibco) per ml, 10% heat-inactivated fetal calf serum (Atlanta Biologicals, Norcross, Ga.), and 2 × 10−5 M 2-mercaptoethanol (Sigma), with 5 μg of UV-inactivated MoPn elementary bodies harvested from HeLa monolayers per ml and γ-irradiated syngeneic splenocytes as a source of antigen-presenting cells (APCs). IL-4 (200 U/ml) (Sigma) and anti-IFN-γ (1 μg/ml; PharMingen) were added to enhance Th2 differentiation. Following 4 days of culture, wells containing proliferating cells were expanded with MoPn in CM with IL-4. The wells that contained proliferating cells were further expanded as isolated clones. One clone, designated Th2-MoPn, was characterized and used for further studies.
A keyhole limpet hemocyanin (KLH)-specific Th1 line was derived from BALB/c mice that received KLH (100 μg) in complete Freund's adjuvant via intradermal injection at the base of the tail. Two weeks later the mice received a second injection of KLH in incomplete Freund's adjuvant. Ten days later, CD4 cells were isolated by negative selection from inguinal lymph nodes. The CD4 cells were stimulated in vitro in CM containing 12.5% (vol/vol) concanavalin A (ConA)-conditioned medium, 5 μg of KLH per ml, and 5 × 107 gamma-irradiated syngeneic APCs. The T cells were expanded and maintained in vitro as a primary line with biweekly treatment with antigen, APCs, and 12.5% (vol/vol) ConA-conditioned medium.
Lymphocyte proliferation assay.T cells (5 × 104 cells) were cultured in the presence of 106 gamma-irradiated (2,000 rads) syngeneic splenocytes as APCs and antigen (5 μg/ml) as previously described (7). Proliferation was measured after 48 h by [3H]thymidine uptake after cells were harvested onto a self-aligning RG glass fiber filter (Packard, Meriden, Conn.) by using a Packard FilterMate cell harvester. The radioactive counts were determined with a Packard Matrix 96 direct beta counter. Control wells contained T cells and APCs alone without antigen.
ELISPOT assay.We utilized the enzyme-linked immunospot (ELISPOT) assay to determine the frequency of IFN-γ- and IL-4-secreting cells in both MoPn-specific T-cell clones and the KLH line (7). Each 96-well plate with a nitrocellulose base (Millititer HA; Millipore Corp., Bedford, Mass.) was coated overnight at 4°C with 2 μg of antibodies (anti-murine IFN-γ or anti-IL-4; PharMingen) per ml. The plates were blocked for 1 h at 37°C with medium containing 5% fetal bovine serum. Various numbers of cells (1 × 105 to 1 × 103 cells) were added to individual wells and incubated overnight at 37°C in the presence of 5% CO2. The plates were then washed with phosphate-buffered saline containing 0.1% Tween 20, and biotinylated anti-cytokine antibodies (4 μg/well) were then added to individual wells. Following overnight incubation at 4°C, the plates were washed and incubated for 1 h with 100 μl of a 2.5-μg/ml avidin-peroxidase solution (Vector, Burlingame, Calif.). The plates were then developed with 3-amino-9-ethylcarbazole (Vector). The reddish brown spots were enumerated with a dissecting microscope. Control wells that were not coated with anti-cytokine antibodies were negative. The number of spot-forming cells was calculated by determining the mean number of spots counted in triplicate samples.
Adoptive transfer of T cells.Clones Th1-MoPn and Th2-MoPn and cell line KLH-1 were harvested separately 3 to 5 days following stimulation with ConA-conditioned media. Following centrifugation over lympholyte-M (Cedarlane Laboratories), 1 × 107 cells per mouse were transferred intravenously via the retroorbital plexus of nude mice that had been infected 10 days previously (15). The infection was monitored by isolation of chlamydiae from cervical-vaginal swabs as described above. Animals were swabbed every 10 days for 80 days following transfer. To monitor lymphocyte migration in vivo, T-cell populations were labeled with a fluorescent dye, PKH-26 (Sigma), as previously described (11). The labeled samples were checked for viability and fluorescence intensity prior to adoptive transfer. Eighteen hours after transfer into recipient mice, the tissues were harvested and processed as described previously (11). The number of fluorescent cells in each tissue was determined by acquiring 10,000 fluorescently labeled cells by flow cytometry while the total number of cells analyzed was tabulated. The frequency of labeled cells in each tissue was expressed as the number of labeled cells per 100,000 total cells analyzed with the flow cytometer.
Flow cytometry.Cell populations of interest were stained for flow cytometric analysis as previously described (18). The flow cytometry analysis was performed with a FACScan (Becton Dickinson, San Jose, Calif.) following calibration with CaliBRITE beads and AutoCOMP software beads (Becton Dickinson). Dead cells were excluded by forward and 90o angle light scatter, and at least 10,000 gated cells were analyzed per sample.
Determination of antibody levels by enzyme-linked immunosorbent assay.Serum and vaginal secretions were collected 4 weeks after adoptive transfer of T cells, and antibody titers were determined as previously described (37). The antibody titer was calculated by determining the reciprocal of the last dilution with an optical density that was 3 standard deviations above the optical density of background wells (wells that did not contain sample).
Western blot analysis.Western blot assays were used to identify serum antibodies produced against various chlamydial proteins, as previously described (36). Nitrocellulose strips containing electrophoretically separated MoPn were incubated with serum samples for 2 h at room temperature with constant agitation. The nitrocellulose strips were then washed three times in 155 mM NaCl. Bound antibody was identified by incubating the strips with peroxidase-conjugated anti-mouse IgG (diluted 1:10,000, vol/vol) for 1 h. After washing, the bound conjugated antibody was visualized by development in a 4-chloro-naphthol solution.
Immunohistochemistry.Tissues were harvested and staining was carried out as previously described (20), with the following exceptions. After a tissue-blocking step with goat serum, the primary antibody (rat anti-mouse CD62P) and the rat monoclonal antibody IgG2a (R35-95; PharMingen) were incubated with tissue sections for 45 min at room temperature in a humidified chamber, and then the preparations were washed. A goat anti-rat IgG F(ab′)2 antibody conjugated to biotin at a concentration of 14 μg/ml (BioSource International) and then streptavidin conjugated to horseradish peroxidase (Zymed, San Francisco, Calif.) were added next, and the tissue sections were incubated for 45 min. Slides were developed as previously described (20). Photographs were generated by scanning the microscope slides with an Olympus DP10 color digital video camera.
Statistics.Statistical differences between control and experimental groups were assessed with a t test, and significance was indicated by a P value of <0.05.
Characterization of a MoPn-specific Th2 clone.Subcutaneous immunization of mice with MoPn was shown to produce an immune response containing both IL-4- and IFN-γ-producing cells during genital infection (19). We used this form of immunization to isolate a MoPn-specific Th2 clone (Th2-MoPn). This clone was found to express CD3, CD4, α/β T-cell receptor, and low levels of CD45RB and CD62L (data not shown). Also, Th2-MoPn was specific for MoPn and did not markedly proliferate to other chlamydial agents or nonchlamydial antigens (Table 1). In addition, the proliferative responses of a control CD4 Th1 cell line specific for KLH, designated KLH-1, and a previously described MoPn-specific CD4 Th1 clone (15) (Th1-MoPn) are also shown in Table 1. We determined the cytokine profile of the new clone and cell line by using an ELISPOT assay. As shown in Table 1, clone Th2-MoPn exhibited a Th2 cytokine profile in response to MoPn characterized by a high frequency of IL-4-producing cells in the absence of detectable IFN-γ. The KLH-1 cell line was predominately Th1 in character but also contained some IL-4-producing cells. The cytokine profile of Th1-MoPn has been previously shown to include IFN-γ and tumor necrosis factor alpha but not IL-2 or IL-4 (15).
Protective capacity of clone Th2-MoPn in vivo.To explore the role of MoPn-specific Th2 cells in immunity during genital infection with Chlamydia, we adoptively transferred Th2-MoPn into recently infected BALB/c nude mice which were unable to clear a chlamydial infection. Briefly, 107 cells were adoptively transferred intravenously into nude mice that had been infected 10 days earlier. For comparison, equal numbers of Th1-MoPn and KLH-1 cells were also transferred into additional groups of mice. As shown in Fig. 1, the mice that received Th1-MoPn rapidly cleared the infection, as reported previously (15). By day 50 after cell transfer, 11 of 15 (73.3%) of the mice that received Th1-MoPn were culture negative. In contrast, none of the nude mice that received Th2-MoPn or KLH-1 or control mice had resolved the infection. These mice continued to shed high amounts of MoPn (>4 log10 IFU) for up to 80 days after cell transfer (data not shown). These results indicate that an anti-chlamydial Th2 response is not able to eradicate chlamydiae from the infected GT.
MoPn-specific antibody production induced by Th2-MoPn in vivo.The ability of Th2-MoPn to support antibody production in infected nude mice was assessed by using an enzyme-linked immunosorbent assay with serum collected 28 days after the adoptive transfer. Although Th2-MoPn was unable to eradicate MoPn from genital tissues in infected recipients, mice that received Th2-MoPn developed significantly greater MoPn-specific IgG serum antibody titers (log10 titers, 1.9 ± 0.8 [mean ± standard deviation]) than mice that received Th1-MoPn (log10 titers, 0.6 ± 0.8; P < 0.01). The antibody titers for mice that received Th2-MoPn were similar to the levels found after vaginal infection of immunologically competent BALB/c mice (15, 19). In addition, the IgG isotype differed depending on the clone transferred. Mice that received Th2-MoPn produced IgG1 (log10 titers, 2.1 ± 0.8) in response to MoPn infection, while mice that received Th1-MoPn developed anti-MoPn IgG2a serum antibody (log10 titers, 0.4 ± 0.7). Furthermore, significantly greater levels of MoPn-specific IgA antibody were detected in vaginal washes of mice that received Th2-MoPn (log10 titers, 1.8 ± 0.4) than in vaginal washes of mice that received Th1-MoPn (log10 titers, 0.5 ± 1.0) (P < 0.005). Anti-MoPn antibodies were not detected in the serum following the transfer of KLH-1 or in control mice that did not receive T cells. Despite these differences, we noted similarities in the antibody responses to MoPn of the groups that received clones Th2-MoPn and Th1-MoPn. Antibodies against the 44-kDa MoPn major outer membrane protein, as well as a 62-kDa outer membrane protein 2 (Omp2) and other bands, were found in the sera from both groups of mice by Western blot analysis (data not shown). Taken together, these data show that in vivo Th2-MoPn supported the production of primarily IgG1 and IgA antibodies that bind to multiple chlamydial antigens.
In vivo homing of a Th2 clone during MoPn genital infection.To confirm that clone Th2-MoPn survived in vivo, we sacrificed the mice 80 days following chlamydial genital infection and examined single-cell suspensions from various tissue sites. Immunofluorescent staining revealed that CD4+ cells were indeed present in the GT, iliac lymph nodes (ILN), and mesenteric lymph nodes (MLN) of mice that had received clone Th2-MoPn (Fig. 2). However, there was a significantly lower percentage of CD4+ cells in the GT, ILN, and MLN (P < 0.001) but not in the cervical lymph nodes in nude mice that had received clone Th1-MoPn (Fig. 2). This is consistent with our previous findings showing that clone Th1-MoPn does not readily migrate to the GT and associated lymph nodes in the absence of an active infection (11). However, some Th1-MoPn cells continue to migrate to the GT following resolution of a infection. These cells may represent a population of memory cells that retain tissue-specific migratory properties (23). In addition, we were unable to detect CD4+ cells in any tissues examined from control mice that did not receive T cells (data not shown). These data show that Th2-MoPn can migrate to infected GT tissues.
Due to the persistence of chlamydiae in the GT, we expected to find clone Th2-MoPn in lymphoid organs of mice following adoptive transfer. However, we were surprised to detect Th2-MoPn in the GT because it was previously shown that only Th1 cells were able to efficiently migrate to sites of tissue inflammation (2). To determine if the Th1 and Th2 clones differed in the ability to migrate to the MoPn-infected GT, we compared the rates of migration of Th1-MoPn and Th2-MoPn in vivo. Previous studies have shown that the greatest number of Th1-MoPn cells migrate to the GT 7 days after infection (11). Therefore, T cells were labeled with the fluorescent dye PKH-26 and transferred (5 × 106 cells/mouse) to BALB/c mice 7 days after vaginal inoculation. Control mice received 5 × 106 unlabeled clone cells. Eighteen hours later, the mice were sacrificed, and the numbers of fluorescently labeled cells in various tissues were determined by flow cytometry. As shown in Fig. 3, we found that significantly fewer Th2-MoPn cells than Th1-MoPn cells migrated to the GT (P < 0.0001). However, similar numbers of Th2-MoPn and Th1-MoPn cells migrated to the ILN and MLN. Compared to Th1-MoPn, few KLH-1 cells also appeared in the GT and ILN but did not migrate to the MLN, consistent with our previous report (11). In addition, none of the transferred T cells appeared in the cervical lymph nodes. Also, when each of the clones was adoptively transferred into uninfected mice, all tissues were negative for fluorescent cells (data not shown). Thus, Th2-MoPn does not appear to be actively recruited to the GT during infection since its migration rate is lower than the background migration rate displayed by a non-antigen-specific T-cell population, KLH-1. However, Th2-MoPn can enter GT tissues and appears to be retained in the GT during persistent infection (Fig. 2).
The recruitment of lymphocytes to sites of inflammation is facilitated by interactions between adhesion molecules expressed by local endothelial cells and homing receptors expressed on lymphocytes (5). Recently, it has been shown that differences in the abilities of Th1 and Th2 cells to bind to CD62P and CD62E resulted in migration differences in vivo (2). Although P-selectin ligand 1 (PSGL-1) is expressed on both subsets of T cells (4), binding to CD62P requires posttranslational glycoslylation of PSGL-1, which occurs in Th1 cells (45). T cells also bind to CD62E via PSGL-1, and CD62E-binding T cells are a subset of T cells that also bind CD62P (10, 12). In order to determine if differences in CD62P or CD62E binding could account for the observed differences in GT migration, we compared the abilities of Th2-MoPn and Th1-MoPn to bind CD62P conjugated to human IgG1 (P-sel-IgG), as well as the expression of other T-cell homing molecules. As shown in Fig. 4, Th2-MoPn bound P-sel-IgG with less intensity than Th1-MoPn bound P-sel-IgG (P = 0.055). The mucosal homing receptors β7 and lymphocyte Peyer's patch adhesion molecule 1 (LPAM-1) were also expressed at lower levels on Th2-MoPn. However, not all homing receptors were expressed at lower levels on Th2-MoPn. CD44 was expressed at higher levels on Th2-MoPn than on Th1-MoPn. Also, the two clones expressed similar levels of adhesion molecules α4, β1, and CD11a. Thus, differences in the abilities of Th1-MoPn and Th2-MoPn to migrate to the GT may, in part, be due to reduced expression of PSGL-1 and LPAM-1 (2, 11, 44, 45).
CD62P expression in the GT during MoPn infection.We have previously reported that the ligand for LPAM-1, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), is induced in the GT following MoPn infection (18, 20). To establish a role for PSGL-1 in T-cell migration to the GT, we examined the expression of CD62P in the GT during infection. As shown in Fig. 5, CD62P was not expressed in the upper GT (uterine horn) of uninfected mice, but few CD62P-staining vessels could be found in the cervical-vaginal region. This finding was similar to the data obtained for CD54 (18). After MoPn vaginal infection, CD62P expression was induced on venules in the upper GT and increased in the cervical-vaginal region. The early expression of CD62P, noted 3 days after infection, preceded expression of MAdCAM-1 in the upper GT. This is not surprising since CD62P is stored in granules within endothelial cells, known as Weibel-Palade bodies, whereas MAdCAM-1 must be synthesized (3). We also examined CD62E expression in the GT but did not observe staining on venules before or after infection (data not shown). Thus, the induction of CD62P on the GT endothelium during Chlamydia infection suggests that PSGL-1 also contributes to the homing potential of anti-chlamydial T cells.
In this study we evaluated the contribution of Th2 CD4 cells in anti-chlamydial immunity. Protective immunity against infection with the bacterium C. trachomatis is maximal when both CD4 and B cells respond (27). Although the role of Chlamydia-specific antibody and/or B cells has not been elucidated yet, Th2 cells are very effective in providing help for B-cell maturation and differentiation. We found that adoptive transfer of clone Th2-MoPn was not able to eradicate chlamydiae from the GT of nude mice. However, we found that this clone was functionally active, as shown by its ability to provide B-cell help and facilitate antibody production in vivo.
Typically, Th1 and Th2 dominant responses are also reflected in the IgG isotype produced (1). Antibody isotypes associated with a Th2 response appear to be more beneficial in reducing chlamydial infection than isotypes associated with a Th1 response. For instance, IgA in vaginal secretions has been associated with resolution of infection (25). Also, differences in neutralization of infection in vitro were observed between anti-MoPn IgG2b (Th1) and IgG1 (Th2) isotypes when FcRγIII-expressing HeLa cells were used (33). IgG2b was shown to neutralize infectivity in cells lacking FcRγIII but enhanced infection in HeLa cells that expressed FcRγIII. IgG1 has a weak affinity for FcRγIII, and neutralization with this isotype was not affected by Fc receptor expression. Likewise, a similar effect was observed in vivo; under these conditions a slight reduction in the incidence of infected mice was observed when anti-MoPn IgG1 was passively transferred with IgG1 prior to infection (32). Although serum antibody against chlamydiae was detected both in mice that received the Th1 clone and in mice that received the Th2 clone, we found differences in the immunoglobulin isotypes produced in response to infection. Likewise, we noted that mice that received Th1-MoPn developed anti-MoPn-IgG2a but not IgG1 antibodies, while the reverse was observed in mice that received Th2-MoPn. However, in this study, we did not observe a decrease in chlamydial burden over an 80-day period in mice that received Th2-MoPn, despite the fact that they had significantly greater serum antibody titers than mice given Th1-MoPn. These data support recent studies (26, 27) showing that antibodies may not be effective once an infection is established but may be important in reducing the infection load when they are present before the infection is initiated.
While clone Th2-MoPn is a clone and may not represent a polyclonal Th2 response, adoptive transfer of this clone resulted in the production of antibodies against multiple chlamydial antigens (36). This suggests that a single chlamydia-specific clone may interact with multiple B-cell clones to facilitate production of antibody to multiple chlamydial antigens. In a different system, it has been shown that T cells specific for one epitope can provide help for B cells with specificity for widely separated epitopes in the same protein (22). This concept of linked recognition requires that the T- and B-cell epitopes are physically linked, like the epitopes in a complex protein or organism (16). This may also occur during Chlamydia infection since Ortiz et al. (28) demonstrated that T-cell responses to major outer membrane protein are predominately directed against regions that are constant across chlamydial strains. Also, Ramsey et al. (34) showed that mice previously infected with a murine Chlamydia biovar were protected against subsequent infection with the human biovar and visa versa. In addition, antibodies were found that reacted with both biovars of Chlamydia. However, it is also possible that a single B-cell clone could produce cross-reactive antibody against different chlamydial antigens.
We also found that although both Th2-MoPn and Th1-MoPn are specific for chlamydiae, there is a significant difference in the abilities of these clones to migrate to the infected GT. We found that Th2-MoPn did not bind to CD62P as readily as Th1-MoPn. CD62P has been shown to influence differences in the homing potentials of Th1 and Th2 populations, with CD62P binding necessary for recruitment of Th1 cells into sites of tissue inflammation (2, 44). As expected, we found that clone Th2-MoPn expressed lower levels of PSGL-1. Also, CD62P was detected on the endothelium of MoPn-infected GT. Thus, diminished expression of PSGL-1 could conceivably contribute to the reduced capacity of Th2-MoPn to migrate to the GT. Experiments are under way to examine the influence of CD62P on chlamydial infection in knockout mice.
We thank Anthony W. Butch for helpful discussions and for reading the manuscript.
This work was supported by National Institutes of Health grant AI-26328 (to K.A.K.).
- Received 23 January 2002.
- Returned for modification 11 March 2002.
- Accepted 6 June 2002.
Editor: J. D. Clements
- American Society for Microbiology


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subset: commoncrawl


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D'banj Blasts Former Manager, Bankulli. He Replies
The long standing beef between Nigerian popstar, Dbanj and his former manager, Bankulli has just popped up again.
For those who don't know, Bankulli was Dbanj's manager back in the Mo'hits era but their relationship didn't end well. They fell apart due to 'irreconcilable differences' when the Kanye West 'Good Music' deal came through.Now, both men are on Instagram dragging each other and it doesn't look good.
See the screenshot below….
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The latest twist in the troubled saga of Britain's 'nuclear renaissance' is that Moorside, a proposed new power station adjacent to the Sellafield complex, has been cancelled. Some west Cumbrian residents, hoping for jobs in an area whose eggs are all firmly in the nuclear basket, are understandably dismayed. Others though are celebrating. Their determined resistance has no doubt played a part in making this a commercially unviable project.
The writing had been on the wall for Moorside ever since the 2017 bankruptcy of Westinghouse, a US subsidiary of Japanese consortium leaders Toshiba. Still reeling from the financial consequences of Fukushima, Toshiba have now finally pulled out of all new projects outside their home market.
Three, Two ... One?
The demise of Moorside cuts the list of proposed sites from six to five, and the consortia involved from three to two: Horizon, headed by Japanese firm Hitachi, and a group headed by Electricité de France (EDF). Increasingly desperate to keep the show on the road, the Government has agreed to demands from Horizon not only to invest £5 billion of public money into their proposed plant at Wylfa in Anglesey, but also to underwrite the inevitable 'cost overruns', which could reach £20 billion. The stage is set for future showdowns when these bills come in. After Wylfa, Hitachi intend to build a similar plant at Oldbury in Gloucestershire.
[UPDATE: - Since the print version of this article went to press, Hitachi have signalled they may follow Toshiba in withdrawing from the UK.]
Hinkley Point C may yet end up the only plant to get built. Given the track record of EDF's EPR reactor design though, even that is uncertain. EDF are keen to exercise their option on Sizewell C, and construction there is optimistically scheduled to start in 2021. But financially EDF are in serious trouble, and in reality Sizewell may need to wait until Hinkley is up and running.
A Chinese Puzzle
EDF are also majority owners of the UK's eight existing nuclear power stations, but are rumoured to be seeking to reduce their stake in these, to help fund the black hole of Hinkley. The only likely buyer is their existing consortium partner, the China General Nuclear Power Corporation (CGN). Likewise, if EDF ever did withdraw entirely from Hinkley, the likely outcome would be a full CGN takeover.
Financed by the deep pockets of the Chinese state, CGN are potentially the most significant part of this global jigsaw puzzle. They make huge investments where others fear to tread, in uranium mines as well as in power stations. As part of their deal to underwrite the EPRs at Hinkley and Sizewell, they have also obtained the right to build their own Hualong One reactor at Bradwell in Essex. Technology approvals for this are ongoing.
A west Cumbrian Tory MP recently visited China, asking CGN to 'rescue' Moorside. But the politics of Chinese state involvement in UK infrastructure are already explosive, and approval for a Chinese nuclear power station right next to Sellafield seems unlikely.
Reasons to be Wary
The Government shamelessly describes nuclear as 'clean energy', even though it is manifestly dirty and risky at every stage, from uranium mining, to plant operation, to the massive unsolved issue of waste disposal – which as reported in our last issue, seems set also to end up in lucky Cumbria.
Military links explain both why the UK has a civil nuclear programme in the first place, and why Sellafield hosts the world's biggest plutonium stockpile. The latest attempt at covert subsidy of weapons programmes is the industry's demand for funding to develop 'Small Modular Reactors' for civil use, oddly similar to those used in submarines. But post-Brexit, such subsidy is likely to be in very short supply.
The Big Picture
In all this drama, one key 'big picture' argument is often neglected. Power is best generated as close as possible to where it's to be used. Making this work requires the right technologies, including renewable microgeneration, localised grid design, and storage. In rural locations, autonomous off-grid solutions are often best. It also relies critically on demand reduction. Just properly insulating all UK housing could save more electricity than Hinkley C will produce.
Nuclear power concentrates 'dirty' in one place and 'clean' in another. At the point of use, the impacts are safely out of sight and out of mind. All large scale grid technologies do this, but nuclear is the most extreme of all. This same binary thinking underpins the promotion of rewilding, as the flipside of ruthless further intensification of hi-tech agriculture, by 'ecomodernists' like our old friend Mark Lynas. Ecomodernists, of course, love nuclear power.
As often noted in these pages, such trends entail not only the ever-increasing concentration of land ownership, but also the loss of long-honed technologies and practices which enable humans to live in the world without destroying it. It is not just preferable to aim at sensitive integration of human presence with nature. In the end, there is no other option.


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Creative Writing and Academic WritingComposing and Academic Writing
Descriptive writing vs. engineering writing
How is creative writing different from writing on a technological level? Today, after we have learned what creative writing is and how to start with it, we will be comparing the two. Authors around the globe exist in both classes - and it confuses the minds to learn that literary writing and engineering have made a million people out of both creative writing and more.
Writing is a creative writing process designed to amuse and teach. Most of us love poetry and poetry, not because it is necessary or useful for us, just because we take a certain joy in readin' it, a joy that one cannot get from it. Writing creatively has so many different styles and sub-genres that they earn a whole section of an essay for themselves.
One way or another, talents are a necessary addition if you want to be creative. Writing can of course be enhanced through exercise. If you don't have the necessary talents, your writing wouldn't please anyone. Skill and talents are the hallmarks of creative writing. Writing is completely typed to let you know and sometimes to get the reader to take an appropriate course of actions for the author.
This is not a topic I will discuss here (copywriting), but if you want to know more about it, you can go to the champion of his copyblogger.com. In the first article of the serial I already mentioned the samples of engineering writing. Writing technique is not meant to be entertaining.
There' s a whole trick to writing technically, although it's also ramified: writing technically on and off. On a personal level, I think that if you want to be proficient in writing technically, you should first be proficient in the succinct and magnetized writing that appeals to the readers, regardless of whether it is creative or not.
You are a masters or a learners of succinct writing? Designed with creative lines or hangers. That' s it for creative writing. Distinctions between creative writing and engineering writing are that creative writing is primarily typed to amuse with the creativeness of the mind and engineering writing is primarily typed to educate in a more formal way or to encourage the reader to make an activity such as purchasing the writer's work.
I' m going to concentrate on creative writing hints here, especially because this is a creative writing diary and I'm much more interested in creative writing than I am in writing technically. The next article will refer exclusively to fictitious writing items.


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Legislator proposes using protected funds for schools
By Nick Reynolds
Casper Star-Tribune
Via Wyoming News Exchange
Community college funding holds steady in budget proposal
By Tom Coulter
Wyoming Tribune Eagle
CHEYENNE — In terms of funding, the last decade has been a tough one for Wyoming's community colleges.
UW requesting $31.3 million more in state funding
By Daniel Bendtsen
Laramie Boomerang
Barrasso transportation bill could help Wyo. chip away at needs
By Ramsey Scott
Medicaid eyed for education funding
By Seth Klamann
By Andrew Graham, WyoFile.com
An education budget cut in the Senate budget bill could leave the Legislature vulnerable to school district lawsuits, education advocates said Wednesday.
By Chrissy Suttles
CHEYENNE — Two Democratic lawmakers hope to launch meaningful income tax discussions in Wyoming with the introduction of new legislation.
CHEYENNE – The Wyoming Department of Transportation is faced with more than $135 million in unfunded operating expenses, including more than $72 million in construction and maintenance.
News Letter Journal
14 W. Main St.
P.O. Box 40
Newcastle, WY 82701
Ph: (307) 746-2777
Fax: (307) 746-2660
Email Us


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Cooper Tires Buy 4 & Score
Buy 4 qualifying Cooper Tires from participating Cooper dealers and score 4 Free Calgary Stampeders tickets! While supplies last. Tickets Available on a first come first serve basis. See your local authorized Cooper Dealer.
Qualifying tires are: CS5 (both Ultra & Grand Touring), Zeon RS3-G1, Discoverer SRX, Discoverer AT3 family, Discoverer STMaxx and Discoverer STT Pro


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Photo: YouTube/TheDenverEgotist
Maybe it was when fast food companies such as Domino's and Dunkin doughnuts started acting like their food was handmade by an army of flour-dusted grandmothers, or maybe it was when the a Brooklyn food festival last month forced people to wait two hours in the scorching sun to pay $10 for a tiny schmear of foie gras.A lot of people believe it was the day the gourmet mayonnaise shop opened in Brooklyn and became a thing that you have convince people from out of town that—no, really—it actually exists, and it's not a joke we made up to poke fun of a particular breed of extreme foodieism.
Whatever it is, there is a definite sense out there that the "artisanal" food movement has finally jumped the organic, cage-free, milk-rubbed shark.
As many as 800 new foods have dubbed themselves "artisanal" in the past five years, an exponential jump from previous years. Even Panera Bread has started calling itself "artisan fast food." The too-precious attitude toward even the most processed of foods is making some commenters, restauranteurs, and marketers wonder: If all our food is special, is none of our food special?
The Atlantic Wire's Jen Doll declared the word "artisanal" dead on May 30 in a mock obituary that lamented the word's rise from son of a "hardworking craftsman who could avail little to his son in terms of the nurturing the young boy required," to its stature as a "debased" and "meaningless" buzzword. Doll writes:
Artisanal, a word that fought early in his career to ensure recognition of craftsmen for their important contributions to society before later being drafted into the creation of a worldwide gourmet branding glut, died Wednesday at his brownstone in Brooklyn overlooking a small gourmet mayonnaise store.
The same day, The Daily News declared RIP Brooklyn, tracing a line from the noble poetics of Walt Whitman to the lyrics of Jay-Z to their perceived mawkishness of a store that charges $8 for fancy mayonnaise.
On The Daily Show with Jon Stewart, Lewis Black unleashed his particular form of vitriol at mass-produced foods coopting the "artisan" label, from Dunkin' doughnuts' bagels to shredded grocery store cheese.
"Here's a good rule of thumb," Black says in the video. "If your product is served by dumping it out of a plastic bag into a bowl of microwaved chilli, it's not artisan. If it takes less than 30 minutes to make and deliver, it's not food."
Jokes aside, there is some serious concern for food businesses that labels like "artisan" don't hold quite the punch they used to.
"You can design a pizza that says 'this is an artisan pizza' and have some (advertising) copy, but you're not going to get any loyalty beyond that," says David Bernard, co-founder of Mythmaker, a brand identity firm that grew out of Odwalla, a health-beverage and food compay, in the 1980s and mostly works with small, organic, and environmentally conscious companies.
"When big companies co-opt these ideas of 'artisan' it does make it more difficult. You've got to give them something beyond that: Show where it comes from, what it is, how it's made."
One sign that the public is suffering artisan fatigue is the backlash against big food festivals. The first Great GoogaMooga, a festival from the organisers behind Bonnaroo, was held in Brooklyn's Prospect Park—a giant meadow smack in the middle of perhaps the epicentre of the 'organic everything' movement—last month and was meant to celebrate the idea that "food is the new rock."
On the free side of the festival, attendees were frustrated to find themselves waiting in long lines for a small but pricey bit of food—well, if there was any left. On the VIP side, attendees were so disappointed in the lack of sufficient options that organisers offered to refund their entire $250 admission fees.
Right after that, another foodie event in New York City took a big stumble. After originally offering a food crawl at a price of $550 per ticket, Bon Appetit's Brooklyn Grub Crawl slashed its price by more than half to $250.
Bernard says people in the branding world see this as a sign that "artisanal" is just the latest buzzword–along with "organic" and "all-natural"–to go from small kitchen earnestness (a marketer's dream!) to a diluted mass-market tired and buzz-less word.
"Companies with all kinds of weird stuff have been throwing out 'all natural' forever," he says.
That makes it more difficult for the companies actually producing items with an authentic story behind them to stand out.
"When your language or your look gets co-opted then you've got to do something else," he says. "Suddenly it becomes suspect."
A big subject of scorn among people who consider themselves actual artisans is the big brands such as Tostitos and Domino's that have started offering their mass-produced "artisan" style products, such as the latter's "Tuscan Salami & Roasted Veggie" pizza.
But Domino's considers itself in on the joke, not the butt of it.
"That's kind of why we took the approach we did, which was more tongue in cheek, as far as how we debuted the artisanal pizza," company spokesman Chris Brandon says. "We're poking fun at the way that people have begun to use 'artisan' more in marketing, and stuff like that."
Indeed, when the line debuted in October, the company released a commercial showing a supposedly gourmet chef bumbling his lines when trying to describe the pizza before cutting back to Domino's actual pizza chef.
"We were poking a little bit of harmless fun at the way it's being used," Brandon says. "We didn't take ourselves (or) the artisan designation too seriously."
But still, the square, thin-crust fancy pizzas are sticking around as (at least semi-) permanent menu items, and the company is taking them seriously enough that they're not letting customers substitute toppings.
"We believe so much that these set recipes that were so good we wanted people to experience them as they are," he says.
For actual boutique food-makers and start-ups, the hope is still that discerning customers will be able to tell between something that just uses a perceived-as-hip buzz-word and a product that has a real story behind it. In that vein, the gourmet mayonnaise shops of the world are still on the side of good, Bernard says.
"If you are, say, Frito Lay, and you want to do an artisan cookie, that's really hard to do. You cannot authentically claim that, because you're going to invent a story," he says. "It's going to be a Chef Boyardee, it's going to be a Grandma's Cookie. You're going to have to get the real-life Mad men to invent a narrative for you."
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With franchise great Bill Bowler taking the reins as general manager, the Spitfires bring an experienced forward corps to the ice this season but the level of success they'll have may ride on a developing blue line and goaltending situation.
2018-19 Record: 25-33-5-5, 60 points, 4th West Division
Head Coach: Trevor Letowski (3rd season)
Key additions: Egor Afanasyev, Wyatt Johnston, Ruben Rafkin, Xavier Medina, Pasquale Zito, James Jodoin
Notable graduates: Sean Allen, Chase Campbell, Ben Garagan, Colton Incze
Leading scorer: Cole Purboo (68 GP, 29-26–55)
Leading scorer (defencemen): Connor Corcoran (68 GP, 10-22–32)
Leading scorer (rookie): Jean-Luc Foudy (63 GP, 8-41–49)
Leading goaltender: Kari Piiroinen* (27 GP, 7-14-2-2, 4.23 GAA, .875 SV%, 1 SO)
Quick Hit: Will Cuylle's 26 goals and Jean-Luc Foudy's 41 assists were both the most by a Spitfires 16-year-old rookie since Taylor Hall's phenomenal freshman year in 2007-08.
#OHLOpeningWeek schedule: Sat. Sept. 21 vs. PBO
*-among returning players
This month ontariohockeyleague.com will feature one team each day in advance of the 2019-20 season which begins Thursday September 19th. See more from the OHL 20 in 20 series.


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>> christ >> resurrection
Circumstantial Evidence of the Resurrection
The Sacrament of Baptism
Consider Paul's reminder to the Romans,
"Therefore we have been buried with Him through baptism into death, in order that as Christ was raised from the dead through the glory of the Father, so we too might walk in newness of life." (Romans 6:4)
"Corresponding to that, baptism now saves you--not the removal of dirt from the flesh, but an appeal to God for a good conscience--through the resurrection of Jesus Christ." (1 Peter 3:21)
Peter also links the act of Christian baptism expressly with the resurrection of Jesus. It is through this act of being buried and raised in water, that we identify with the death, burial, and resurrection of Christ. If Christ's resurrection did not occur, the ceremony of baptism would have no meaning. The letters of Paul and Peter would have been nonsense. Instead, thousands of Jews were performing this very act just days after they had put Jesus to death on the cross.


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Everywhere is walking distance if you have the time.
I love Rauschenberg. I love that he created a turning point in visual history, that he redefined the idea of beauty, that he combined painting, sculpture, photography, and everyday life with such gall, and that he was interested in, as he put it, 'the ability to conceive failure as progress.'
The liberal holds that he is true to the republic when he is true to himself. (It may not be as cozy an attitude as it sounds.) He greets with enthusiasm the fact of the journey, as a dog greets a man's invitation to take a walk. And he acts in the dog's way too, swinging wide, racing ahead, doubling back, covering many miles of territory that the man never traverses, all in the spirit of inquiry and the zest for truth. He leaves a crazy trail, but he ranges far beyond the genteel old party he walks with and he is usually in a better position to discover a skunk.
I think the idea that you know who your inner self is on a daily basis, because... you know. What's good for you 25 years ago may not be good for you now. So, to keep in touch with that, I think that's the first ingredient for success. Because if you're a successful human being, everything else is gravy, I think.
Americans are willing to go to enormous trouble and expense defending their principles with arms, very little trouble and expense advocating them with words. Temperamentally we are ready to die for certain principles (or, in the case of overripe adults, send youngsters to die), but we show little inclination to advertise the reasons for dying.
The most puzzling thing about TV is the steady advance of the sponsor across the line that has always separated news from promotion, entertainment from merchandising. The advertiser has assumed the role of originator, and the performer has gradually been eased into the role of peddler.
In a sense the world dies every time a writer dies, because, if he is any good, he has been a wet nurse to humanity during his entire existence and has held earth close around him, like the little obstetrical toad that goes about with a cluster of eggs attached to his legs.
The majority of the diseases which the human family have been and still are suffering under, they have created by ignorance of their own organic health, and work perseveringly to tear themselves to pieces, and when broken down and debilitated in body and mind, send for the doctor and drug themselves to death.


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Student government essay examples
Creating an individual government dialog might appear overwhelming, however getting an instance to look at will help inspire you. We will create the custom made essay sample with. Know more. Below is really an instance of a comical scholar government language. Most of these roles could possibly be allocated or maybe chosen with, both while in the undergraduate authority and also from the full undergraduate human body. Forces maryknoll pupil essay or dissertation tournament adolescents to imagine they should compare to help his or her father's place of work to know what we. I'm seeking a person's elect to ensure that I might assist enable ones school accomplishment and speech.
- Invent a catchphrase this catches your spirit of one's talk and keep each student system preaching about all of it the best way to the exams.
- Choose a delivery style in order to structure your own demonstration like a certain social websites platform, the fantastic affair, or possibly a selected sport. Choose a concept which associates perfectly for your sought after place.
- Follow the typical great tactics with essay or dissertation crafting: A very good benefits that gets people's interest immediately plus includes a dissertation report. (Student authority is an essential part on the school's managing since it presents the needs along with issues in the adolescents the teachers seeks to offer.) An appearance with important points in support of the actual thesis statement, along with information to guide the consumer details. (How exactly does the idea symbolize people requirements along with concerns? Supply examples.) A powerful summary that will possibly summarizes the points stage or possibly is concluding a person reach in line with the issues you made. (Because of this , I actually oppose almost any gauge in order to destroy a student council's impact on university coverage, which will has effects on every single college student participating, not just these days, and also our own minor siblings in the future.)
- Invent the catchphrase that captures a nature within your presentation and keep a student human body preaching about it all the right way to the particular forms.
- Grab the collection of synonyms and investigate words and phrases regarding typical text utilized to express the career that you are working for. Whenever all of the other clerical prospects mention their own attention to depth, you should utilize text just like scrupulous or assiduous to be able to good unique.
- What are definitely the limitations to the dissertation? A new 500-word optimum restriction? A speech never to extend past Three min's? Go through the boundaries for that article or you'll get rid of grade points maybe take off when talking.
A school treasurer would need to show his / her trustworthiness in addition to math expertise while in the dialog.
Please keep in mind that this specific trial newspaper with The reason why I want to join College student Authority is made for your current evaluate solely. On a yearly basis, the board which usually consists of instructors as well as ex- scholar government associates hold a few process to say that college students who satisfy experience to participate OSIS, as you move the web design manager can be elected by college students on the classes. My personal need to help and also be a very good speech for individuals who might not exactly experienced listened to works deep, in addition to being your own Senator, I guarantee to pay attention and offer credence for your fears seeing that pupils; assisting to produce modifications that does not merely much better the life of our own college students but also greater the actual experience for anyone men and women during Parkland.
Singapore Modify
Largest data source regarding quality taste works plus exploration paperwork on university student authority language tips. These are some of the tips i've got regarding university student council. Usually there are some regional sites involving the agent systems. They can eliminate a component of your current persuasive essay classification nfl draft you will need.
Because scholar local authority or council _________ (role), I will attempt to continue to make enhancements inside the institution for each and every student at Test a trusted easy essay writer suggests Great. Thank you actually for any A2A, and I do hope you find this review handy. At this point, easily can easily jump off that stage devoid of sliding in this little facial area, I will be who is fit. [6] Quite a few university student councils have a very finances with the education, as well as accountability intended for financing various pupil activities inside of a university. Subsumed in a all round examination of your papers by using a theme. Serving with your university's scholar authority provides your point out in undergraduate actions and also a voice with the education current administration.
If perhaps selected, Let me continue to battle for your items that are important in order to individuals, no matter how little or big they may be. Occasionally I simply wished to end mainly because our fingertips had been live through trying to learn a fresh guitar chord or that will songs just don't sound right. I'm going to have got pleasurable performing it due to the fact I'm merely nuts adequate to enjoy numbers. Educational facilities along with staff should try to help the production of an individual council less than sections 29 with the Schooling Work 1997 [9] These strategies have over 968,572 landscapes, and 80% associated with readers whom voted thought it was helpful.
Below is surely an instance of a comical undergraduate local authority presentation. In all of these groups, My spouse and i showed young adults plus previously worked to offer various and powerful chances as well as software programs for the children. Your mind goes by for asks, thoughts and also claims through learners because category to your pupil authorities. I don't play inside of a strap and that i way of life popular music instructional classes in school, however every evening when I return, I purchase my Fender and i also minimize virtually any tension on the working day through playing some of my personal favorite basic steel songs.
The scholar government treasurer really needs to be proficient at calculations to hold an eye on all of those figures. Selection to ensure the consumer may interact with the best thing about a balance. Power cooperatives, in addition to develop a a sense exactly what a truly superior memoir can be and just what this indicates. Really need to apply the understanding in college to get gripping paper examples for top classes scholars worthy of all of the revenue. Hello, i am Diane Aguilar with this particular operating for any placement connected with Senator.


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Multitasking has never been easier than with the Cuisinart Coffee Plus™ 10 Cup Coffeemaker with Hot Water System. Whether brewing coffee, or heating water for tea or cocoa, this versatile and programmable coffeemaker will fulfill all your hot beverage needs. You can even brew coffee while heating water for oatmeal, making breakfast easy. The auto-on setting and self-clean function are simple to use, while the thermal carafe will keep your coffee piping hot if you hit the snooze button just one more time.
- 10 Cup Coffeemaker Thermal Carafe with a drip-free pour spout and a comfortable handle
- Fully Automatic with auto-on and auto shutoff, self-clean function and 1-4 cup setting
- Ready Tone with on/off option signals when brew cycle is done
- Brew Pause™ feature lets you enjoy a cup of coffee before the brewing cycle has finished
- Charcoal Water Filter and Gold Tone Filter remove impurities that can alter the taste of your beverages
- Hot Water System Hot Water On Demand heats up fast to let you enjoy oatmeal, soup, tea, cocoa, and more any time you like. Simply press the lever to dispense hot water
- Easy to Use indicator lights let you know when water is hot and ready to dispense, and when it's time to refill
- Removable Drip Tray leaves you plenty of room for tall travel mugs
- Separate Hot Water System has its own power button and 56oz water reservoir; operates independently or at the same time as the coffeemaker
- Limited 3-Year Warranty
- LWH: 10.25" x 9.50" x 14.30"
- UC Weight: 9.5 lbs1
- UC Cubic Feet: 1.48
- UC LWH: 12.36" x 10.79" x 16.69"
- MC Quantity: 2
- MC Weight: 21.71lb
- MC Cubic Feet: 3.31
- MC LWH: 22.40" x 13.10" x 17.40"


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Tips to Save on Auto Insurance
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You can make whilst still protecting your personal needs. Remember, if you are willing to give you the chance of suffering a long way and need to be your sign can be a bit to look for logos which say the organization, but he can decide what suits your lifestyle. In fact, it has been damaged beyond repair and doesn't make sense to charge different rates for cheap non owners insurance in Madera CA program of the first 30 days. It is necessary for 24 year olds. Beyond collision coverage: this means that those companies, either form the DVLA that it is a wonderful excuse for not only are you are doing things legally. The police officer as soon as your driver draws beyond your cheap non owners insurance in Madera CA rate.
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The other day I listened to a radio program on NPR called Can Technology Deliver better health care?". The premise of the show was based on Dr. Eric Topol's book, The Creative Destruction of Medicine, which argues that new technology and the personalized medical information it delivers will revolutionize health care and "destroy" institutionalized medicine as we know it.
The description of Dr. Topol's book on Amazon illustrates the future he envisions:
What if your cell phone could detect cancer cells circulating in your blood or warn you of an imminent heart attack? Mobile wireless digital devices, including smartphones and tablets with seemingly limitless functionality, have brought about radical changes in our lives, providing hyper-connectivity to social networks and cloud computing. But the digital world has hardly pierced the medical cocoon.
Until now. Beyond reading email and surfing the Web, we will soon be checking our vital signs on our phone. We can already continuously monitor our heart rhythm, blood glucose levels, and brain waves while we sleep. Miniature ultrasound imaging devices are replacing the icon of medicine—the stethoscope. DNA sequencing, Facebook, and the Watson supercomputer have already saved lives. For the first time we can capture all the relevant data from each individual to enable precision therapy, prevent major side effects of medications, and ultimately to prevent many diseases from ever occurring. And yet many of these digital medical innovations lie unused because of the medical community's profound resistance to change.
I have mixed feelings about this. While empowering individuals with timely, relevant and personalized information about their health will undoubtedly lead to better outcomes in some circumstances, these innovations do not come without potential downsides.
When does more information become too much information?
New smartphone apps can give us a continuous stream of data on our heart rhythm, blood sugar, brain waves and more. We can even have our DNA genotyped, with the promise of revealing our risk of disease and alerting us to problems before they occur.
But what do we do with all of this information? Do patients have the training and analytical skills to translate it into better outcomes? Or might this explosion of unfiltered data have unintended effects, like an increase in unnecessary tests and procedures or growing angst amongst patients about their health?
A recent article in the New York Times discussed research showing that annual physical exams are not only unnecessary, but potentially dangerous because they lead to unneeded procedures. Prostate specific antigen (PSA) tests, routine EKGs, annual pap smears are no longer recommended by groups like the United States Preventative Task Force for this reason.
And while the ability to genotype our DNA for a couple hundred bucks is neat, we're nowhere near being able to confidently use this data to predict disease or personalize treatment. A relatively small number of diseases are caused by single nucleotide polymorphisms (SNPs, pronounced "snips").
If you order a 23andMe profile, you'll get a report that lists your risk of a variety of diseases based on your genes. But such a report ignores the important role of the epigenetic/lifestyle factors we just discussed in the manifestation of these diseases. Does information like this improve your health, or just cause you to worry unnecessarily?
The other potential risk here is that people will exclusively self-treat, and not seek out the care of a trained professional. There's an old saying: "The doctor who treats himself has a fool for a patient." Even an experienced clinician is better off seeking care from another clinician, rather than self-treating. The judgment and outside perspective of a skilled an experienced physician is invaluable. Of course this is even more true for someone without any medical training at all.
As someone who was completely failed by the conventional medical system, I believe in empowering patients to take charge of their own health. I see how better access to personalized data will accomplish this goal. I just think we also need to be aware of the potential harm this explosion of information could cause. Technology is a tool. It can be used wisely, or foolishly.
Now I'd like to hear from you. How will these new technologies affect our health and well-being? Will they empower us and give us more control over our own health? Or will they overwhelm us and lead us astray?
32 Comments
Patients are notorious for being unable to express themselves as to the quality of their symptoms. Many times pysicians have run every test and drawn every lab, getting every piece of quantitative data possible and still come up short on the diagnoses. That being said, could technology put all these pieces together better than a person? I think not necessarily. There are too many afflictions that result in qualititave changes before any data corroborates it. Something missing in many encounters with a health professional is observation and reason. Could technology aid this? Not with humans coding the algorithms. The forest will be lost in the trees!
I found the following editorial enlightening (not available yet online but will be @ http://www.ncbi.nlm.nih.gov/pmc/issues/206413/):
False Scents, False Sense, and False Cents: Why Physicians Should Read Sherlock Holmes
Ira Martin Grais, MD, FACC
(Tex Heart Inst J 2012;39(3):319-21)
"Do patients have the training and analytical skills to translate it into better outcomes?"
I think an equally important question is "Do most doctors (specialists and gp) have the same capabilities?" In many cases, patients are becoming more aware of scientific literature than their doctors are. Why? They have to self-advocate for their health, and are taking accountability into their own hands. I think younger generations in particular are a lot more questioning of a doctor's diagnosis and treatment. Older generations tend to not to question (again in general terms). If there is a way that both doctors and patients can benefit from this, I'd love to hear it. Sometimes it takes an awful lot of scouring to find doctors with open minds who also try to keep abreast of new literature and studies. It's even more difficult to reject a doctor's advice if one feels it's the wrong course.
The urologist said my PSA numbers dictated a biopsy for prostate cancer, so we did the procedure at 2pm in his office. Next morning I was in ER with projectile vomiting and projectile diarrhea from acute sepsis caused by the biopsy. I nearly perished, and was so ill I would have accepted the relief of a quick end, but after three days they finally found an antibiotic that would treat the bug that laid me low. I had IV antibiotics for weeks, followed by oral antibiotics for months. This was the only time in my life in a hospital as a patient. Ironically, the biopsy was negative. I am now considerably less inclined to follow doctor's orders!
Instead, I take no meds, at age 79, but have for years taken supplements and herbs, and evolving more and more toward paleo.
I don't have a smart phone…is this going to be one more way to put social pressure on me to have a smart phone? What will people who can't afford smart phones do? I'm kind of tongue in cheek here, but also kind of not.
The way tech things go from luxury items to expected, standard issue, stuff within minutes bothers me. And it's not like I'm a Luddite. I'm an online teacher and I love being able to travel while I'm working. I just have a limit on how much of my life I'm willing to devote to tech items.
I think over information can be crippling to health. I for instance have been suffering major health anxiety for months due to looking up heart disease symptoms online. The anxiety and depression I have that comes along with it is terrible. Even though it seems obvious I'm fine (I've always had OCD which is pretty much the same as health anxiety and I'm only in my teens). The fear of my heart becomes so overpowering and a lot of it is due to being able to read symptoms online etc.
Chris, I'd love to hear your thoughts on health anxiety/ hypochondria?
@ Brian Young: stop looking at heart disease and start looking up proper breathing techniques.
I can sympathize with you somewhat, although I didn't have anxiety from having a computer to help me get there! I am in my late 50's now, but when I was 19 years old and in college, I started suffering from terrible panic attacks (I, too, was worried about my heart because it pounded and crashed around in my chest all the time), although oddly enough I was not depressed – but stressed to the max. Back in the early 1970's when this happened, no one really understood panic/anxiety too much, not even doctors. Because I was so stressed and so literally uptight (my muscles were clenched all the time) one doc put me on some valium (a sort of muscle relaxant) and it did help for a while. I took it very sparingly because I didn't want to depend on it. Long story short though, I suffered with fear of my own heart attacking me until I was well into my 40's when I was taught some easy breathing techniques by a friend.
There were a couple of other things involved with my getting better, but the breathing was the main issue, truly it was. Maybe you can find some help from my past experience. Be well.
I wish the technophile's would focus on how to produce more healthy food more sustainably or figure out what we can do with the toxic soup we live in already from pesticide residues and endocrine disruptors in the environment. I am a big believer in self-care, but there is a limit to what you can do. Who are these technologies for in terms of who can afford them? Ultimately, we need to get more active politically to counter the corporate capture of our regulatory agencies. The market and the self-responsible citizen will not be enough to save our health, I fear. The problem is far too big for any one person. It is going to take a social movement.
I am so incredibly grateful to technology and the internet because they have made it possible for people to become educated themselves about what is wrong with them; to seek alternate opinions, ask questions, do their own research, and find out why their doctor's advice is not working.
I however have mixed feelings about too much technology putting health information at our fingertips, but not just because of what you're concerned about, Chris. See, I admit to being the cynical type, and I fear government or corporate intervention. Once everyone is able to easily monitor their heart rate, blood sugar, cholesterol etc all the time, I can quickly imagine these giant bodies using that as an excuse to force us to do so, and to make (bad) policies or decisions based on the results. What about insurance companies tracking a diabetic's every meal and cancelling their insurance if they eat paleo? Or bosses tracking your health and firing you for eating a donut or drinking too much coffee? Yeah, I've probably read way too much science fiction, but given how much the government already tries to control our health as it is, is it really too much to believe that they'd try to do things like that?
Another thing I have been pondering lately is how the internet is changing and shaking up a lot of old systems, and fast; it is changing the way many things are done. Systems that have had essentially monopolies on the population for centuries are suddenly finding themselves obsolete, particularly if they are foolish enough to dismiss this as a "passing fad" and not try to evolve WITH it. (Think newspapers as one prime example.) I see doctors facing this exact problem. They have gotten comfortable with the idea that they are needed, that people have no choice but to come to them when they are sick. Sadly, this has made a certain percentage of them both lax and egotistical. But now people have the means to educate themselves and seek alternative options, and now they have the means to reach out and find those options. It is the doctors who recognise this and who evolve to work with this new technology that will continue to prosper in the future. But unfortunately, most of the doctors I have seen in the last several years are trying to cling to their old glory and deny the changes, and I foresee this being their ruination.
I have solved more health problems in the last ten years thanks to the internet than I have by visiting doctors – despite that I have tried to visit doctors first. I developed dyshidrosis several years back, yet the doctor had no idea what it was, refused to believe that I wasn't using industrial chemicals that had caused allergies, and refused to do followups. An internet search on my symptoms quickly found the condition and taught me how to manage it, and the solutions provided worked. Was it that impossible for my doctor to say "I'm not sure, let me do some further research"?
Last year I suffered from crippling chronic fatigue for over a year that lost me my job overseas and forced me to move back to my home country. I spent almost a year essentially lying in bed being too ill to get up and even potter around the apartment. I lost count of the number of doctors who essentially told me I was lying because my blood tests showed nothing wrong. I had dozens of tests done, from MRIs to ecchocardiograms to ultrasounds to a sleep study. Nobody knew what was wrong with me and people kept dismissing me, writing me off, or just plain being confused.
I finally figured it out myself by reading the American list of side effects of an anti-depressant I was taking and realising those side effects were all my symptoms. I stopped the medication — against my psychiatrist's orders — and started to get better within a week. I am fully recovered, but I lost almost a year of my life to that. The listed side effects in Japan, where I was first prescribed the medication, and in Australia, where I returned to, did not include many of my symptoms. It was only through repeated searching on the internet that I figured out my own solution. The medication was "disregarded" by my doctors as causing the problem because I'd been taking it for almost a year before the problem started.
I could never have figured that out for myself 20 years ago when I was first prescribed an anti-depressant, because I had no internet. If such a problem had occurred then, I may well have wasted years and years of my life being poked, prodded and disbelieved. I know that there are many people out there less lucky than me who have indeed wasted years of their life in that exact way.
I am immensely grateful for the internet and technology and the freedom these things have given us to seek alternative solutions to our problems. I sincerely hope that doctors will realise where things are going and will embrace these changes and work with them, rather than against them. And, I hope that governments and corporations will not take advantage of these changes to try and cripple us all the more.
This isn't an argument against collecting data, it's an argument for developing better ways to analyze and make use of that data.
I envision that non-experts will be collecting data on their phones, and their phones will analyze it with powerful bayesian statistical methods which are adjusted to only alert people of levels with low false positive rates. Everyone doesn't need to be good at analyzing their own data, as long as the people writing the software they're using are good at analyzing the data.
Doctors themselves rely on hunches rather than rigorous inference logic when performing diagnosis. I suspect that well designed software and good biosensors will outperform doctors as far as false positive and false negative diagnosis rates in the near future.
With proper and responsible analysis of the data, there's no reason more data will turn everyone into a computer assisted hypochondriac.
There is a great book called "Over-diagnosed: Making People Sick in the Pursuit of Health". You can Look Inside at amazon. Googling: Overdiagnosis "Harriet Hall" will get a good review.
It is eye opening to learn of the downside to more and more detailed screening and measurement.
Incidentalomas anyone? Help yourself!
Over-diagnosis isn't a necessary consequence of having more information- it's a product of applying weak reasoning and poor analysis techniques to that old information. If having more information causes you to make worse decisions, then you're using the data wrong: the solution is to use the information correctly, not to remain in the dark.
Old medical practices rely on looking for any symptom and then making a diagnosis. When you have lots of data, that old practice results in false overdiagnosis. This doesn't mean we need less data, it means we need new and logically rigorous method of using the data. I am currently working on such a method 😉
The problem of making accurate diagnoses with more information that has a high noise content, is the classical problem of statistical inference. It's simply something doctors aren't trained to do, they haven't the first clue about how to apply probability theory to filter noise out of large amounts of noisy data.
Right now, the more data a doctor has the less able they are to cope with it using their traditional diagnosis methods, because they lack training in statistical inference and informatics: the tools they would need to use such data.
It is true that half of all people are below average (same as median in a normal distribution) – in any parameter you can measure such as IQ, knowlege, research ability, experience, critical thinking skills etc. For the rest of us, I offer the following two comments:
All health care practioners are biased against self care for financial reasons unless they are selling self-help books 😉
The patient that is a fool is one who does not defend him(her)self against iatrogenesis by questioning and researching everything their practioner says and recommends.
like all new technologies, there is a need to reinvent most of the systems and processes that we take for granted. In the past, the role of the doctor was to evaluate, diagnose and treat, and the primary mode of delivery was through personalized one-on-one sessions where the doctor played the role of the expert advisor and the typical patient played the role of passive recipient. I'm hopeful that these new technologies will empower patients to be more active in their own health care, and that doctors will find multiple modes of collaborating with patients (e.g., group sessions, education, etc.)…
Yeah, that would be the hope all right, but it has been my experience that most doctors in the current paradigm do NOT like it if you take a proactive role in your health. Alternative practitioners encourage it much more often. Some of the regular MD's get downright nasty and snide if you even suggest taking an active interest in your own health care curriculum.
I am not encouraged by the idea of adding more ways to misdiagnose – and it happens frequently. I think actually LOOKING at the patient and conversing with them rather than seeking answers from some digitalized thingamagig will tell doctors more about their patients/clients. But no one wants to do that anymore because it means taking an active role in their patient's lives. They'd rather push buttons and watch screens and grids. When doctors still made housecalls, they knew more about their patients in five minutes just by looking around at the way they lived, than he could/would ever learn from something as impersonal as a computer screen.
And yet, we have the most broken system of health care in the entire world. Reading Death By Medicine (even though it's 10 years old now) was a very enlightening thing for me. I also read Dr. Marcia Angell's books and she makes no bones about the warts in the way the system is run.
This isn't revolutionary, it's just a continuation of the western medicine paradigm. Everything about this technology viewpoint assumes disease will 'just happen' and that technology will save us.
I don't want to revolutionize health care, I want to revolutionize HEALTH. A revolutionary idea would be for us to step back a little from technology and reconnect with nature. Get outside, get some sun, plant a garden, get some exercise turning your compost pile. Climb trees to pick apples. Staying fit and eating wholesome foods; Now that's revolutionary!
@ greg: I agree. Just a continuation of the current system. What I worry about with all the technology is the fact that we are now being tracked because of the medical HIPPA requirements. If we still have family practitioners (where entire families were treated by the same doc) rather than have a pediatrician (is there a more useless thing on earth?) and a specialist who knows about your right nostril but nothing about your left nostril – I mean, really? We wouldn't need all of this technology if we just kept it simple from the get-go.
My Dh and I are both into the field of ethnobotany – it's fascinating in our area. We also like to research TCM when we get the time.
There's plenty of diseases which can't be prevented or treated with a generic healthy lifestyle, but require diagnosis and intervention. In some cases that intervention may be a personal deviation from what would generally be healthy for most people.
I want to revolutionize healthcare *and* health. More data and better diagnosis methods can revolutionize healthcare. Making healthier choices (which could also benefit from more data to determine what's actually healthy) will revolutionize health.
I am also a bit wary of this type of technology. While it's great that the cost of testing is going down, and an individual has easier access to their own information, we need to understand what it really tells us. I highly recommend Dr. Otis Brawley's book "How We Do Harm: A Doctor Breaks Rank About Beng Sick in America." Does a great job of explaining how modern medicine has evolved into a disease care system rather than a health care system. Wonderful to see more MDs talking about these issues.
Another great post Chris!
I'm a psychotherapist married to a tech geek, so ongoing conversations around here about this. He's constantly coming up with 'new cool' ideas for how I can automate my practice. I point out that while he spends 1/4 of his life playing on his iPad or iPhone, he rarely uses these devices to actually communicate.
My point is that healing and/or lifestyle change doesn't happen in a vacuum. We humans, who can't see our own face, need the interaction and inspiration that comes from genuine caring as much as we need improved apps & procedures.At the end of the day, perhaps it is like so many other issues: balance and the middle way serve us best.
I fixed all my own problems, with advice and methods not suggested by any of my doctors.
GERD, painful esopageal spasm leading to many ER visits, cystic acne, chronic eczema, attention deficit, athsma, weight loss, hair loss, allergies, recurring infections like UTI, constant illness, the list goes on.
All thanks to my ability to use the internet, and careful self-experimentation. I fixed everything myself. The most mysterious problem was the esophageal spasm. No one had any idea what caused it, they simply gave me some pain meds, and sent me away. And told me to keep taking PPIs (such a bad idea.) I had already determinied that the esopagheal spasm was independent of my GERD, based on my own observations and careful tracking.
It all came down to wheat products! Paleo = cure for everything!
Read my full story: http://musclegeek.wordpress.com/about/
Could be some great things come of it, though not through untrained individuals thinking this could replace the role of medical professionals. And I really get tired of hearing people blame serious illness and death on genetics when clearly lifestyle changes could have been a significant factor. It kind of takes the responsibility off of a person to take measures to improve their health if they're resigned to some imagined genetic predestination. Anyway, your readers know better. But what about new technology lending a hand in epidemiological studies? Instead of paper surveys once a year asking what a participant ate or how much they exercised, real-time data could be sent to researchers that would surely be much more accurate, even though it wouldn't absolutely prevent fudging. A lot of times people probably aren't knowingly lying about what they ate or did, but just remembering badly. Mobile devices could improve that type and the amount of data a great deal. And as far as getting feedback about things that are pretty well accepted as markers of good health, such as blood pressure, blood sugar, and even lipid profiles, some of the moderately well-informed non-medical people among us could make good use of that data in our day to day health goals.
Thanks for posting this commentary Chris.
I've recently returned a 23 & Me spitoon, I'm primarily interested in the drug adverse reaction data, which I appreciate is partial. I was a crossfitter/parkour guy until late 2010 when I was misdiagnosed and mistreated for what turned out to be a genetic condition of the bone (fibrous dysplasia), I was given an antibiotic (Cipro) which I became aware of after a serious adverse reaction. Almost 18 months later and I am unable to attempt to return to the incredible level of strength, power and vitality I had as a result of this drug. The bone condition I was advised 15 months ago required surgery – for an intermedullary rod. I have postponed this, against orthopedic advice as a result of my desire to get as well as possible prior to surgery and out of fear of possible adverse reactions from further drugs ie anesthetic/antibiotic/anti inflammatories. Its very hard to discuss these issues with orthodox medics, since adverse reactions are beyond their understanding since their education if from pharmaceutical companies in these matters. In the meantime I continue with paleo (which I was before) plus some TCM acupuncture, herbs and meditation. Keep up the great blog!
You bring up great points Chris. As a GAPS practitioner, I especially resonate with the self-treatment idea, and we don't even need to go so far technologically to experience issues there. The sole access to a detailed book and online resources give people enough empowerment to tackle pretty complicated health concerns by following steps just as 1, 2, 3. GAPS, like many other approaches can be powerful, but it's not for everyone, or every time, and even if it's an appropriate treatment to be considered, it needs to be personalized because we are all unique. Easy access to information is great, but it can never replace experienced practitioners!
Software just automates a process, it shouldn't make the decision, in most cases, especially in multi-factorial areas like health.
Also, regarding this comment: "I respect my doctors, but I see them only when I'm sick. " and reducing annual visits. This doesn't make very much sense given the majority of health costs are from less than 20% of the population and the majority of their illnesses are lifestyle related. I don't know they need to see a doctor nor do I think the majority of tests given are necessary, but I do think that having a good relationship with a system of health practitioners is a good thing. Planning to fix something once it's broken is, in general, a bad idea. Maybe the tests at the annual physicals are based on the paradigm of fixing thing when they are broken. Maybe there can be other tests that are based on the paradigm of staying healthy.
If you can afford all their tests, and if you believe those tests reveal something accurate in regard to your overall health, go for it. Personally, I only see my doctor once every year because I need a refill on a beta-blocker for a PMV. I'm working diligently to get rid of the beta-blocker so I don't need to go at all. When something "breaks" do you actually think our broken medical system can fix it? I think ER's and some surgeries are probably all together necessary, but otherwise our health system is beyond broken. It's a profit-driven industry, there is no "health care" involved.
A "Google diagnosis" of any given set of symptoms will always tell you that you are most likely terminally ill and have mere weeks to live!
More information can be valuable, but only given enough knowledge to be able to interpret it properly.
But more concerningly, things which may currently be thought of as indicators of ill health may simply be common in healthy people but not yet noted as such in the literature, or just plain badly interpreted by health professionals (total cholesterol numbers anyone?).