Regulated necrosis and failed repair in cisplatin-induced chronic kidney disease

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Longitudinal dynamics of infection and serum antibody in A. actinomycetemcomitans periodontitis

OBJECTS: This report describes one of the first prospective studies delineating the relationship between infection, host antibody responses and disease exacerbations and remissions in a distinct subset of periodontitis patients infected with A. actinomycetemcomitans. DESIGN: The design of this longitudinal study included visits for each patient approximately every 2 months for up to 3 years. SUBJECTS AND METHODS: Subjects (n = 51) included 16 adult periodontitis (AP) and 11 early-onset periodontitis (EOP) patients with elevated serum IgG antibody to A. actinomycetemcomitans and infection with this microorganism, 12 AP patients with normal levels of anti-Aa antibody, and 12 normal subjects. MEASUREMENT OUTCOMES: Clinical parameters included a gingival index, plaque index, bleeding on probing, pocket depth, and attachment level. Disease activity was defined as loss of attachment during the monitoring intervals. Serum IgG, IgM and IgA antibody to A. actinomycetemcomitans Y4 (serotype b) was quantit-ated using an ELISA. Subgingival plaque samples were examined for A. actinomycetemcomitans using colony immunobiotting. Human serum IgG antibody specificities to outer membrane antigens (OMA) of A. actinomycetemcomitans Y4 were determined using Western immunoblotting. RESULTS: A. actinomycetemcomitans-infected AP patients had a higher frequency of teeth infected when compared to the EOP patients. However, the EOP patients exhibited a trend for higher levels of A. actinomycetemcomitans in those teeth that were infected. Active disease patients demonstrated a significantly greater frequency of infected sites, as well as significant elevations in the proportions of A. octinomycetemcomitans. Both EOP and AP groups showed significantly elevated IgG, IgM and IgA antibody to A. actinomycetemcornitans when compared to a periodontally normal group. The level of IgG antibody was significantly elevated in A. actinomycetemcomitans-positive patients with active disease, while IgA antibody was decreased in a number of the active group patients. Plaque samples derived from active sites showed a clear and significant increase in A. actinomycetemcomitans that occurred from 2–6 months prior to the identification of disease activity. Approximately 70% of the active disease patients showed an increase in IgG antibody level by 2–4 months prior to disease activity. Studies of the antigen reactivity patterns of serum IgG indicated that antibody to antigens of 65, 58, 48, 29 and 24 kDa were more frequent in patients who showed active disease, while those patients with the greatest frequency of active disease appeared to show a general decrease in the recognition of the A. actinomycetemcomitans OMA. CONCLUSIONS: It appears that A. actinomycetemcomitans infection relates to a particular type of disease with accompanying antibody responses that reflect periods of active disease. The dynamics of A. actinomycetemcomitans infection and the level and specificity of systemic antibody responses to this pathogen support an important contribution of the immune response to managing this infection.     

Salivary gland involvement in hypohidrotic ectodermal dysplasia

Ectodermal dysplasias (EDs) are a group of developmental disorders (more than 100) mainly affecting ectodermal tissues and organs. The X-linked hypohidrotic ED (HED) is the most common form of EDs, involving defects in teeth, sweat glands, and hair. In a few reports, HED has been associated with reduced salivary function. In the present case report, a dramatically reduced salivary fluid and acidic proline rich protein production was identified in a 38-year-old man with HED. Computed tomography was performed, revealing that one submandibular gland and both parotid glands were hypoplastic, whereas the right submandibular gland seemed to be absent. These findings are in line with a general developmental disturbance also involving the salivary glands. As salivary tests are inexpensive and easy to perform, it is suggested to routinely evaluate salivary secretion in persons with HED, to prevent a possible negative impact on oral health.     

Maternal choline supplementation differentially alters the basal forebrain cholinergic system of young‐adult Ts65Dn and disomic mice

Down syndrome (DS), trisomy 21, is a multifaceted condition marked by intellectual disability and early presentation of Alzheimer's disease (AD) neuropathological lesions including degeneration of the basal forebrain cholinergic neuron (BFCN) system. Although DS is diagnosable during gestation, there is no treatment option for expectant mothers or DS individuals. Using the Ts65Dn mouse model of DS that displays age‐related degeneration of the BFCN system, we investigated the effects of maternal choline supplementation on the BFCN system in adult Ts65Dn mice and disomic (2N) littermates at 4.3–7.5 months of age. Ts65Dn dams were maintained on a choline‐supplemented diet (5.1 g/kg choline chloride) or a control, unsupplemented diet with adequate amounts of choline (1 g/kg choline chloride) from conception until weaning of offspring; post weaning, offspring were fed the control diet. Mice were transcardially perfused with paraformaldehyde, and brains were sectioned and immunolabeled for choline acetyltransferase (ChAT) or p75‐neurotrophin receptor (p75^NTR). BFCN number and size, the area of the regions, and the intensity of hippocampal labeling were determined. Ts65Dn‐unsupplemented mice displayed region‐ and immunolabel‐dependent increased BFCN number, larger areas, smaller BFCNs, and overall increased hippocampal ChAT intensity compared with 2N unsupplemented mice. These effects were partially normalized by maternal choline supplementation. Taken together, the results suggest a developmental imbalance in the Ts65Dn BFCN system. Early maternal‐diet choline supplementation attenuates some of the genotype‐dependent alterations in the BFCN system, suggesting this naturally occurring nutrient as a treatment option for pregnant mothers with knowledge that their offspring is trisomy 21. J. Comp. Neurol. 522:1390–1410, 2014. © 2013 Wiley Periodicals, Inc.     

The Sequential Relation Between Changes in Catastrophizing and Changes in Posttraumatic Stress Disorder Symptom Severity

Catastrophizing has been discussed as a cognitive precursor to the emergence of posttraumatic stress disorder (PTSD) symptoms following the experience of stressful events. Implicit in cognitive models of PTSD is that treatment-related reductions in catastrophizing should yield reductions in PTSD symptoms. The tenability of this prediction has yet to be tested. The present study investigated the sequential relation between changes in a specific form of catastrophizing—symptom catastrophizing—and changes in PTSD symptom severity in a sample of 73 work-disabled individuals enrolled in a 10-week behavioral activation intervention. Measures of symptom catastrophizing and PTSD symptom severity were completed at pre-, mid-, and posttreatment assessment points. Cross-sectional analyses of pretreatment data revealed that symptom catastrophizing accounted for significant variance in PTSD symptom severity, β = .40, p < .001, sr = .28 (medium effect size), even when controlling for known correlates of symptom catastrophizing, such as pain and depression. Significant reductions in symptom catastrophizing and PTSD symptoms were observed during treatment, with large effect sizes, ds = 1.42 and 0.94, respectively, ps < .001. Cross-lagged analyses revealed that early change in symptom catastrophizing predicted later change in PTSD symptoms; early changes in PTSD symptom severity did not predict later change in symptom catastrophizing. These findings are consistent with the conceptual models that posit a causal relation between catastrophizing and PTSD symptom severity. The clinical implications of the findings are discussed.     

Short-term culture of acute myeloid leukemia blasts: analysis of acquired susceptibility to activated natural killer cells

Following a cryopreservation step, short-term cultures of circulating leukemic blasts from a patient with acute myeloid leukemia (AML) were performed. Because cultured tumor cells became susceptible to natural killer (NK) activity, in vitro alteration of the blasts was studied. Immediately after thawing, cell suspensions consisted of a relatively homogeneous population of undifferentiated blasts. In culture, tritiated thymidine uptake by the leukemic cells was low during the first 24 hours and then increased (X20) to a peak on day 7. The cell concentration started to increase on day 4. On day 8, less than 10% of the cultured cells still appeared as undifferentiated blasts, whereas up to 60% were granular and 30% to 40% had a monocytoid morphology. Prior to being cultured, the blasts were resistant to resting and IL2- activated natural killing. When the kinetics of in vitro acquired susceptibility were studied, it was found that maximum cytotoxicity against these leukemic cells was reached within 24 hours. Thus, the blasts had become NK-sensitive prior to increase in DNA synthesis, proliferation, and differentiation based on morphological and cytochemical criteria. In contrast, there was a positive correlation between acquired susceptibility and surface expression of an activation antigen, termed TNKtar. To dissect further the mechanisms of acquired susceptibility, a series of six NK clones representing four distinct phenotypes of NK active lymphocytes were tested against the leukemic cells. Immediately after thawing, blasts were essentially resistant to all clones, whereas they were strongly killed by 5 of 6 clones when cultured for 24 hours. Cold target inhibition assays indicated that resistance of fresh blasts was likely to be due to a binding defect. These results suggested that tumor cells became susceptible because they surface-expressed NK target structure(s) in the early phase of an activation process leading to their proliferation and/or differentiation. This hypothesis was substantiated for one clone, termed JT9, because the anti-TNKtar antibody blocked cytotoxicity of JT9 cells against the cultured blasts.