Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. FUNDING: National Institutes of Health.

Clinical Pharmacogenetics Implementation Consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update.

Cytochrome P450 (CYP)2C19 catalyzes the bioactivation of the antiplatelet prodrug clopidogrel, and CYP2C19 loss-of-function alleles impair formation of active metabolites, resulting in reduced platelet inhibition. In addition, CYP2C19 loss-of-function alleles confer increased risks for serious adverse cardiovascular (CV) events among clopidogrel-treated patients with acute coronary syndromes (ACSs) undergoing percutaneous coronary intervention (PCI). Guideline updates include emphasis on appropriate indication for CYP2C19 genotype-directed antiplatelet therapy, refined recommendations for specific CYP2C19 alleles, and additional evidence from an expanded literature review (updates at http://www.pharmgkb.org).

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

A revision of Megalonchos Baer & Euzet, 1962 (Tetraphyllidea: Onchobothriidae), with the description of two new species and transfer of two species to Biloculuncus Nasin, Caira & Euzet, 1997.

The onchobothriid tapeworm genus Megalonchos Baer & Euzet, 1962 is revised and the generic diagnosis amended based on the examination of some of Southwell's material of M. mandleyi (Southwell, 1927) Baer & Euzet, 1962, the type-specimens of M. dubius Prudhoe, 1969 and M. musteli Prudhoe, 1969, and material of two new species, M. sumansinghai n. sp. and M. shawae n. sp., collected from the snaggletooth shark Hemipristis elongatus off northern Australia. Based on their possession of two pairs of uni-pronged hooks (rather than one pair of bi-pronged hooks) and possession of, rather than lack of, post-vaginal testes, M. dubius and M. musteli are transferred to Biloculuncus Nasin, Caira & Euzet, 1997 as B. dubius (Prudhoe, 1969) n. comb. and B. musteli (Prudhoe, 1969) n. comb. Both new species of Megalonchos differ from M. mandleyi in their possession of conspicuously smaller hooks and shorter cephalic peduncles. The new species are readily distinguished from one another in that, whereas the pores of the axial prongs of the medial and lateral hooks are located well anterior to the middle of the prong in M. sumansinghai n. sp., they are well posterior to the middle of the prongs in M. shawae n. sp. In addition, the base of the lateral hook is longer relative to that of the medial hook in the latter species than it is in the former species. The proglottid anatomy of valid species of Megalonchos is described for the first time, and the lack of post-vaginal testes is confirmed for the genus. In addition, members of this genus appear to be characterised by a sacciform uterus that extends only to the level of the cirrus-sac and an ovary that is H-shaped in frontal view and bilobed in cross-section. Species of Megalonchos have now been reported from two of the eight known species of hemigaleid sharks.

An unusual blood sequestering tapeworm (Sanguilevator yearsleyi n. gen., n. sp.) from Borneo with description of Cathetocephalus resendezi n. sp. from Mexico and molecular support for the recognition of the order Cathetocephalidea (Platyhelminthes: Eucestoda).

Sanguilevator yearsleyi n. gen., n. sp. and Cathetocephalus resendezi n. sp. are described from the Broadfin shark, Lamiopsis temmincki, in Malaysian Borneo and Carcharhinus leucas in Mexico, respectively. The new genus is unusual in its possession of internal chambers and channels in its scolex that appear to house extensive quantities of host white and red blood cells, respectively. Histology reveals an extremely intimate association between host tissue and the surface of the apical pad of the scolex. Positive staining with periodic acid-Schiff of the surface of the pad of the scolex and the linings of the chambers and channels suggests that an adhesive substance may be produced in these regions. However, explanations for how and why host blood cells come to reside within the scolex remain elusive. Cathetocephalus resendezi n. sp. is distinctive in the form of the papillae in the papillate band of the scolex and also in the inconspicuous nature of the rugose base of the scolex. Scanning electron microscopy of both new taxa as well as Cathetocephalus thatcheri, Cathetocephalus australis and an undescribed species of Cathetocephalus collected from Carcharhinus amboinensis in Australia, suggests that the papillae surrounding the pad of the scolex are of significant taxonomic utility in distinguishing among species in these groups. Parsimony and Bayesian analyses of sequence data (766 bases of 18S rDNA and 405 bases of 28S rDNA) generated from ethanol preserved specimens of C. thatcheri and S. yearsleyi, when compared with equivalent data available for 40 cestode species in GenBank, resulted in trees that support previous propositions that Cathetocephalus should be placed in the order Cathetocephalidea. The results suggest that Sanguilevator should also be considered to belong to this order.

Enhancement of plasminogen activator activity stimulated by LPS in gingival fibroblasts of individuals with Down syndrome.

Individuals with Down syndrome (DS) have a high prevalence of periodontal disease, which develops early and progressed rapidly and extensively, in comparison with healthy controls. The severe periodontal disease in individuals with DS has been considered to result from abnormal factors in their host responses. The mechanisms involved in the periodontal inflammatory processes in individuals with DS are not fully understood. Plasminogen activators (PA) are serine proteases that are well known for their part in the initiation of the fibrinolytic cascade leading to the generation of plasmin in periodontal homeostasis, including fibrinolysis and connective tissue remodeling. The PA-plasmin system affects the progression of periodontal disease. In the present study, we examined the effects of the levels of PA activity stimulated with lipopolysaccharide (LPS) in the gingival fibroblasts from donors with DS (DGF). The levels of PA activity without LPS were low in the DGFs, the same as that in the gingival fibroblasts from donors of healthy controls (NDGF). In contrast, the levels of PA activity with LPS in DGFs were significantly higher than that in the NDGFs. These results suggested that PA plays an important role in inducing extensive and rapid inflammation in the periodontal disease in individuals with DS.

Protective immunity to Streptococcus mutans induced by nasal vaccination with surface protein antigen and mutant cholera toxin adjuvant.

In this study, mice were immunized nasally with surface protein antigen of Streptococcus mutans serotype c (PAc) and a nontoxic A subunit mutant of cholera toxin (mCT) E112K, as a mucosal adjuvant. Immunization with PAc and mCT elicited significant PAc-specific secretory IgA in saliva and in nasal secretions. Antibody-forming cell (AFC) analysis confirmed the antibody (Ab) titers by revealing significant numbers of PAc-specific IgA AFCs in the submandibular gland and nasal passages. Furthermore, CD4(+) T cells from cervical lymph nodes exhibited significant proliferative responses when restimulated with PAc in vitro. Importantly, mice that were nasally immunized with PAc plus mCT E112K exhibited significantly reduced oral colonization by S. mutans. These results show that nasal administration of PAc and mCT E112K is potentially an effective mucosal vaccine against dental caries and reduces the colonization of S. mutans in the oral cavity.

Brainwashing and battering fatigue. Psychological abuse in domestic violence.

Intimate partner violence occurs often in the United States; it involves an interrelated combination of physical, sexual, and psychological abuse, usually directed against women. The psychological aspect deserves special attention because victims who lose their independence, self-esteem, and dignity tend to remain in abusive situations. The abuse is perpetrated by a domestic partner to maintain power and control in the relationship. To assert control, the abuser uses "brainwashing tactics" similar to those used on prisoners of war, hostages, or members of a cult. Common features of brainwashing include isolation, humiliation, accusation, and unpredictable attacks. The abusive environment produces real and anticipated fear, which contributes to the battered woman's belief that her situation is hopeless and that she must depend on her abuser. She develops coping strategies to deal with her oppressive environment, but eventually exhibits symptoms of "battering fatigue," similar to the battle fatigue of soldiers in combat who, like battered women, live in fear of being killed or severely injured. Recognizing the state of mind of these women can help us understand why it is difficult for them to flee their traumatic environment and why they may resort to suicide or homicide. For healthcare providers to screen and treat their patients adequately, it is imperative that they appreciate the complex and devastating psychological aspects of domestic violence.

Tamoxifen-induced regression of breast cysts.

The use of Tamoxifen as treatment for breast cancer is well established and its use experimentally as prophylaxis is promising, but little has been written about mammographically detected changes in breast parenchyma as a result of Tamoxifen therapy. We report two cases of spontaneous regression of breast cysts after Tamoxifen therapy for premenopausal breast cancer in the contralateral breast.

Characterization of cytokine producing T cells, TCR expression, and IgA plasma cells in salivary gland-associated tissues.

In this study, SMG, PGLN, and CLN from murine SGAT were employed in order to understand immunological characteristics of mononuclear cells that reside in these tissues for IgA responses. Based on our results, SMG harbor characteristics of IgA effector tissues. Further, PGLN has immunological features of both IgA effector tissue and systemic LN. On the other hand, CLN possesses classical characteristics of an organized systemic LN. Several important and unique features of T cells in SMG were demonstrated by this study. For example, approximately 40-50% of MC in SMG were CD3+ T cells which consisted of an equal distribution of CD4+, CD8- and CD4-, CD8+ T cell subsets. This can be considered as a unique feature of SMG since the other effector tissues usually have 2 to 3 times higher frequencies of CD4+ T cells over CD8+ T cells. Most interestingly, CD4-, CD8+ T cell subset contains both alpha beta TCR+ and gamma delta TCR+ T cells. Other than SMG, IELs possess significant number of gamma delta TCR bearing CD4-, CD8+ T cells. In terms of cytokine producing T cells, SMG contain significant numbers of CD4+ T cells which are capable of producing IL-5 and IFN-gamma. In addition, higher numbers of IL-5 producing Th 2-type cells was always seen in SMG when compared with IFN-gamma secreting Th1-type cells. Therefore, the occurrence of predominant IgA producing cells is associated with the appearance of a higher frequency of IL-5 secreting Th 2-type cells.

Swinglock removable partial denture and biting forces in partially edentulous patients. Comparison of individual biting forces with and without swinglock removable partial denture.

Several studies have shown that swinglock removable partial dentures are effective for stability of the abutment teeth and the surrounding tissues including alveolar bone. This efficacy has been thought to be due to the dynamic structure of the swinglock attachment. Individual biting force was measured to determine the physiological efficacy of teeth splints by use of the attachment. The results showed that individual biting forces with the swinglock removable partial denture were 10-25% higher than those without the denture. Furthermore, statistical analysis showed that the individual biting forces with the swinglock removable partial denture were significantly higher. The swinglock attachment can stabilize partially edentulous dentition by splinting all residual teeth. In addition, when physical forces are applied to the abutment teeth and the artificial teeth, this attachment can deliver and distribute the stress to the other abutment teeth and alveolar mucosa. The present findings suggest that the swinglock attachment augments the ability to withstand physical forces such as those occurring during biting and mastication.

Cytokine- and Ig-producing T cells in mucosal effector tissues: analysis of IL-5- and IFN-gamma-producing T cells, T cell receptor expression, and IgA plasma cells from mouse salivary gland-associated tissues.

The present study has focused on the analysis of cytokine- and Ig-producing mononuclear cells (MC) that reside in the salivary glands and their associated tissues (SGAT) in the oral region. The SGAT are located under the mandibular area and consist of submandibular glands, periglandular lymph nodes, and cervical lymph nodes. MC were isolated from individual SGAT and examined for T cell subsets and TCR expression, in comparison with T cells obtained from other mucosa-associated and systemic tissues. Forty to fifty percent of MC in submandibular glands were CD3+ T cells, equally divided into CD4+ CD8- and CD4- CD8+ T cell subsets. On the other hand, the intestinal lamina propria and Peyer's patches possessed a approximately 2 to 3:1 ratio of CD4+ CD8- to CD4- T cells. A high frequency of CD4- CD8- (double negative) (DN) T cells (approximately 6 to 10%) was also isolated from submandibular glands. In contrast, approximately 70 to 90% of MC in periglandular lymph nodes and cervical lymph nodes were CD3+ T cells and like the peripheral lymph nodes consisted of fivefold higher numbers of CD4+ CD8- than CD4- CD8+ T cells, with low numbers of DN cells (less than 5%). When expression of gamma/delta and alpha/beta TCR was examined in individual T cell subsets of submandibular glands, the CD4- CD8+ and DN T cell fractions contained 25% and 100% gamma/delta TCR+ cells, respectively. On the other hand, essentially all CD4+ CD8- T cells in SGAT as well as CD4- CD8+ cells in periglandular lymph nodes and cervical lymph nodes were alpha/beta TCR+ T cells. When cytokine production was examined by using IFN-gamma- and IL-5-specific enzyme-linked immunospot assays, the CD3+ CD4+ CD8- T cells in submandibular glands contained T cells spontaneously producing IFN-gamma and IL-5. Further, IL-5 spot-forming cells (SFC) were two- to threefold greater in number, compared with IFN-gamma SFC. The periglandular lymph node T cells contained cytokine producing cells with a ratio of 2:1 for IL-5 and IFN-gamma SFC cells, whereas cervical lymph node T cells did not produce cytokines unless stimulated with T cell mitogens. When the isotype distribution of Ig-producing cells was examined among SGAT, submandibular glands contained large numbers of IgA-producing cells, with few IgM- and IgG-producing cells, a pattern similar to that of the lamina propria. Further, elevated numbers of IgA-secreting cells were also seen in periglandular lymph nodes but not in cervical lymph nodes.(ABSTRACT TRUNCATED AT 400 WORDS)

Enhanced generation of free radicals from phagocytes induced by mineral dusts.

Several studies have suggested that pulmonary toxicity to asbestos and silica may be mediated through oxidant-induced cell injury. We have reported recently that surface radicals associated with freshly fractured silica may be an important factor in cell injury and induction of pulmonary disease. Although the generation of oxygenated radicals in dust-cell interactions has been demonstrated, there are no data correlating the toxicity of a dust with the level of oxygen radical generation by the dust during its interaction with phagocytic cells. In the present study, we have investigated the in vitro generation of oxygen free radicals from human neutrophils and rat alveolar macrophages stimulated with freshly fractured silica, aged silica, amosite, crocidolite, chrysotile, and nontoxic dust, barite. Electron spin resonance (ESR) with the aid of a spin trap phenyl-N-tert-butyl nitrone (PBN) was used to measure the oxygen radicals generated during phagocytosis of the dusts. The relative toxicity index and ESR peak heights, on an equal surface area basis and normalized to barite as one, showed a direct relationship. The normalized toxicity indices and peak heights were: silica, 3.5 versus 2; chrysotile, 4 versus 2; crocidolite, 11 versus 8; and amosite, 26 versus 13. Addition of hydroxyl radical scavengers such as catalase, dimethyl sulfoxide, 1,3 dimethyl-2-thiourea (DMTU), sodium benzoate, and mannitol prevented the radical generation. Carmustine, a glutathione reductase-glutathione peroxidase inhibitor, caused a 5-fold increase in the radical generation. These results indicate that a nontoxic dust such as barite generates toxic oxygen radicals at a minimal level that can be quenched by the normal cellular defense system. For toxic dusts such as silica, amosite, chrysotile, and crocidolite, the potential for oxygen radical generation is enhanced by their surface properties, physical dimensions, and the surface-based radical-generating redox sites. The enhanced radical generation may impair the cellular defense system, resulting in cell injury. Use of scavengers, chelators, and potentiating agents suggests the membrane-based oxidase system as the probable primary source of the radical-generating system. The data presented herein suggest the generation of oxygen free radicals as an important primary event in silica- as well as asbestos-induced cell injury.

Regulation of mucosal immune responses by T lymphocytes: the effect of chronic CD4+ T cell deficiency on IgA synthesis.

Mechanisms of immune defence at the mucosal surface has been elucidated by recent advances in molecular and cellular immunology. IgA is undoubtedly the most important defense factor in the mucosal immune system. It has been shown that T cells are essential for the induction and regulation of IgA synthesis. In T cell regulation of IgA synthesis, various cytokines (e.g., TGF-beta, IL-2, IL-5, and IL-6) which are secreted by CD4+ T cells, play important roles for the induction and regulation of IgA isotype switching and terminal differentiation of sIgA+ B cells to become IgA producing cells. The chronic treatment of mice with anti-CD4 mAb induced a market deficiency of CD4+ T cells in both mucosal and systemic tissues. IgA plasma cells were significantly reduced in treated mice when compared with normal mice (greater than 80% reduction), while the numbers of sIgA+ B cells in IgA inductive sites (e.g., PP) remained normal. CD4+ Th cells are a critical element for the induction of appropriate IgA responses in mucosal associated tissues. Elucidation of the precise cellular and molecular network for the regulation of mucosal immune defense system is important and useful for the consideration of prevention of infectious diseases. In this regard, the effective and sophisticated mucosal administration of vaccines using the concept of the common mucosal immune system should induce effective immune responses which prevent the pathogen from entering the host through large surface areas of mucosal membranes. This goal cannot be achieved without a more complete understanding of regulatory T cells and cytokines for mucosal immune responses.

Induction of T helper cells and cytokines for mucosal IgA responses.

CD4+ Th cells and their derived cytokines play an important role in the regulation of IgA responses in the mucosal immune system. Th1 and Th2 cells induce different Ig isotype and IgG-subclass responses. Further, cytokines produced by Th2-type cells (e.g., IL-5 and IL-6) have been shown to induce PP sIgA+ B cells to secrete IgA. Our studies have now shown that oral immunization with SRBC selectively induces Th2-type cells in PP while systemic (I.P.) immunization with SRBC predominantly induces Th1-type cells. It is tempting to suggest that Th2 cells which produce IL-5 and IL-6 tend to be predominant in mucosal effector regions, such as the salivary glands and LP tissues and account for the predominant IgA responses which characterize these tissues. The PP contain B cell subsets which respond to IL-5 and IL-6, and these are largely restricted to the PNALo non-GC (memory) sIgA+ B cells. The importance of CD4+ Th cells in the regulation of IgA responses has also been shown by the depletion of CD4+ Th cells in anti-L3T4 (CD4)-treated mice. Loss of CD4+ Th cells from mucosal tissues resulted in dramatically decreased numbers of IgA plasma cells in the small intestine and led to a reduction in IgA SFC in isolated LP cells. The overall size of PP was reduced and the GCs were absent; however, the relative frequency of sIgA+ B cells in PP did not change, possibly suggesting that CD4+ Th cells do not influence switches to IgA.

Cytokine production and T cell receptor expression by salivary gland T cells and intraepithelial T lymphocytes for the regulation of the IgA response.

The IgA effector sites such as the salivary glands and the intestinal tract contain several distinct T cell subsets which possess unique biologic characteristics. Freshly isolated CD3+ T cells from the salivary glands, the LP region of the small intestine and IELs all harbor T cells which spontaneously produce Th1 (IFN-gamma)- and Th2 (IL-5 and IL-6)-type cytokines. Interestingly, a high frequency of IL-5-producing Th2-type cells is always associated with the occurrence of increased numbers of IgA plasma cells (e.g., the salivary glands and the LP region of the small intestine). Further, the salivary gland CD3+ T cells can be divided into three distinct subsets including those of CD4+, CD8- (12-23%), CD4-, CD8+ (18-25%) and DN (6-16%) T cells. In terms of TCR expression, CD4+, CD8- and DN T cells exclusively expressed alpha/beta TCR and gamma/delta TCR, respectively. One of the unique features of the salivary gland T cells is that like IELs, relatively high numbers of gamma/delta TCR-bearing cells are seen in the CD4-, CD8+ T cell fraction. Since our study has provided important new evidence that these gamma/delta TCR-bearing T cells from IELs of mice orally immunized with TD antigen possess the capability of abrogating oral tolerance to antigen-specific immune responses including the IgA isotype, one can visualize that gamma/delta TCR+ T cells can be essential regulatory T cells which protect (or enhance) alpha/beta TCR+, CD4+ Th cells for maximum IgA responses at IgA effector tissues including the salivary glands, and the gastrointestinal tract in the presence of an active state of systemic unresponsiveness or oral tolerance.

Regulation of mucosal responses by CD4+ T lymphocytes: effects of anti-L3T4 treatment on the gastrointestinal immune system.

The role of CD4+ T cells in the gastrointestinal (GI) immune system in vivo was studied in mice selectively depleted of this subset by treatment with monoclonal anti-L3T4 (GK1.5) mAb. Treatment of young BALB/c mice with weekly injections of anti-L3T4 mAb resulted in a selective depletion of CD4+ T cells in both IgA effector (lamina propria regions of the intestine; LP) and inductive (Peyer's patch; PP) sites. However, levels of CD3+CD4-CD8+ and CD4-CD8- (double negative) T cells remained constant or increased. When sections of small intestine were assessed for the isotype of Ig-containing cells, normal mice contained predominantly IgA plasma cells with small numbers of IgM and IgG plasma cells while anti-L3T4 treatment dramatically reduced the numbers of IgA plasma cells. When numbers of IgA-producing cells were assessed by the isotype-specific ELISPOT assay, the LPL of anti-L3T4 mAb-treated mice showed an 80% reduction in the number of IgA spot-forming cells. The effect of anti-L3T4 mAb treatment on IgA inductive sites was also studied and this treatment reduced the overall size of PP as well as the germinal centers in this tissue. Although anti-L3T4 treatment depleted CD3+CD4+ T cells in PP, the relative frequency of surface IgA-positive (slgA+) B cells in this tissue did not change. These results show that repeated injection of anti-L3T4 mAb results in a CD4+ T cell deficiency in both IgA inductive (PP) and effector (LP) sites. The depletion of CD4+ T cells resulted in reductions in the numbers of mature IgA plasma cells present in the LP of gut-associated tissues, and reduced the overall size of PP including germinal centers, but did not affect the frequency of sIgA+ B cells in this IgA inductive site.

[Root fracture after crown prosthesis--observation and analysis with EDS].

Root fractures in the teeth under or after the crown prosthetic treatment after occur intra-alveolary. In the many cases, these teeth will be diagnosed to be extracted. Therefore, root fracture is one of the clinical problems for clinicians. There are many clinical and descriptive reports on root fractures after crown prosthesis. But more fundamental studies should be done for the prevention of root fractures. We observed the sampled tooth with scanning electron microscopy and analytical electron microscopy. The tooth with root fractures after the treatment of crown prosthesis was used in this study. The following were the results of this investigations: 1) The cohesional substances, which are regarded as oral bacteria and organic materials, were observed in the definite section on the surface of fracture. 2) The line of the root fracture ran parallel with the canaliculus dentalis. 3) The cracks were observed to run through the face of crosscutting of canaliculus dentalis. 4) Ca and P on the surface of the fracture is 32.75 and 27.70 (atomic %), respectively (Ca/P 1.18). These values are lower than these of control group. In the same surface of the root fractures, the values of Ca and P in the middle parts were less than those of the outside. Reversely, the more deep parts have a little higher values than those of the middle parts. 5) The values of Zn increased on the surface of the fracture than those of the control. 6) The values of S was not detected on the control surface. On the other hand, S was detected in the relatively higher density (15.04) on the surfaces of the root fractures.