Induced and constitutive heat shock protein expression in the olfactory system--a review, new findings, and some perspectives

Heat shock, or stress, proteins (HSPs) are cellular proteins induced in response to conditions that cause protein denaturation, and their induction is essential for survival of such conditions. In the olfactory system we have found intense HSP expression occurs during normal processing of environmental odorants/inhalants as well as following hyperthermia and drug exposure. The HSPs involved include ubiquitin, HSP70, HSC70, and HSP25. Responses are both cell type- and stress-specific, occurring primarily in olfactory supporting cells and to some extent in Bowman’s gland acinar cells. Responses to these stresses are not seen in olfactory sensory neurons. This article reviews those studies and the significance of their findings. It also discusses a distinct subpopulation of rat olfactory sensory neurons (OSNs), the 2A4(+)OSNs, found to be constitutively reactive with HSP70, the predominantly stress-inducible isoform of the 70 kD HSP family. Their high HSP70 expression appears to confer on the 2A4(+)OSNs an enhanced ability to survive damage-induced OSN turnover. New findings are also presented on HSP25-specific changes following olfactory bulbectomy. All data are discussed in the context of the overall olfactory and bioprotective functions of the olfactory mucosa.     

Magnitude and time course of changes in maximal oxygen uptake in response to distinct regimens of chronic interval training in sedentary women

Purpose

This study aimed to compare changes in maximal oxygen uptake (VO_2max) in response to two regimens of chronic interval training.

Methods

Twenty healthy sedentary women (mean ± SD age and VO_2max = 23.0 ± 5.7 years and 30.1 ± 4.4 mL kg^?1 min^?1, respectively) were randomized to complete 12 weeks of one of two interval training regimes, while an additional seven women served as controls. Training was performed 3 days week^?1 on a cycle ergometer and consisted of 6–10 bouts of 1 min duration at lower (60–80 % W _max = LO, n = 10) or more intense (80–90 % W _max = HI, n = 10) workloads separated by a brief recovery. Every 3 weeks, measures of VO_2max and W _max were repeated to assign new training intensities. Changes in blood pressure and body composition were also examined.

Results

Data revealed significant (p < 0.001) improvements in VO_2max in LO (22.3 ± 6.9 %) and HI (21.9 ± 11.6 %) that were similar (p > 0.05) between groups. Approximately 60 % of the increase in VO_2max in HI was observed in the initial 3 weeks, compared to only 20 % in LO. No change (p > 0.05) in body weight or body composition was revealed in response to training. Results demonstrate that a relatively prolonged regimen of moderate or more intense interval training induces similar improvements in cardiorespiratory fitness, although HI induced greater increases in VO_2max early on in training than LO. Completion of more intense interval training may be an effective means to expedite increases in VO₂max soon after initiation of exercise training.     

The relationship between lymphovascular invasion and angiogenesis,hormone receptors,cell proliferation and survival in patients with primary operable invasive ductal breast cancer

Background

Several well-established tumour prognostic factors are used to guide the clinical management of patients with breast cancer. Lymphovascular invasion and angiogenesis have also been reported to have some promise as prognostic factors. The aim of the present study was to examine the prognostic value of tumour lymphovascular invasion and microvessel density compared with that of established prognostic factors in invasive ductal breast cancer.

Methods

In addition to hormone receptor status and Ki-67 proliferative activity, lymphovascular invasion and microvessel density and their relationship with survival were examined in patients with invasive ductal breast cancer. Full sections and tissue microarrays (n?=?384 patients) were utilised to assess these factors and were scored by appropriate methods.

Results

On univariate analysis tumour size (P?<?0.05), lymph node involvement (P?<?0.01), lymphovascular invasion (P?<?0.05), microvessel density (P?<?0.05) and local- regional treatment (P?<?0.01) were associated with poorer survival in ER negative tumours. On multivariate analysis in ER negative tumours lymph node involvement (P?<?0.01) and local- regional treatment (P?<?0.05) were independently associated with poorer cancer-specific survival. On univariate analysis tumour grade (P?<?0.05), lymph node involvement (P?<?0.001), HER-2 (P?<?0.05), Ki-67 (P?<?0.01) and lymphovascular invasion (P?<?0.001) were associated with poorer survival in ER positive tumours. On multivariate analysis lymph node involvement (P?<?0.001), Ki-67 (P?<?0.001) and lymphovascular invasion (P?<?0.05) were independently associated with poorer cancer-specific survival in ER positive tumours.

Conclusion

Lymphovascular invasion but not microvessel density was independently associated with poorer survival in patients with ER positive but not ER negative invasive ductal breast cancer.

     

Autoantibodies against the platelet glycoprotein IIb/IIIa complex in patients with chronic ITP

Chronic idiopathic thrombocytopenic purpura (ITP) is caused by an antibody reactive with platelet-associated antigens. The present studies provide direct evidence that some patients with chronic ITP have autoantibodies against the platelet glycoprotein (GP) IIb/IIIa complex. Microtiter wells, coated with a monoclonal antibody (2G12) specific for GPIIb/GPIIIa were reacted with GPIIb/GPIIIa contained in a platelet extract. Control wells containing the same antibody were reacted with a cell extract containing no GPIIb/GPIIIa. After washing, the wells were reacted with patient or control plasma, and IgG binding was detected using 125I-Fab2-anti-human IgG. Assay values were expressed as binding ratios (cpm GPIIb/GPIIIa wells/cpm control wells). Plasma from 5 of 56 patients with chronic ITP had ratios (1.36-3.14) greater than 3 standard deviations above the mean (+/- SD) of control plasmas--0.93 +/- 0.12. Elevated values were also noted in two patients with anti-P1A1 antibody (ratios greater than 30) and in one patient with Hodgkin's disease and an ITP-like syndrome (ratio 1.53). Normal values were noted in 34 patients with a variety of immune and nonimmune diseases. Plasma from two of the positive ITP patients was reacted with 125I-surface-labeled platelets and, after solubilization, the IgG and bound antigen were precipitated with Staph-A. Autoradiographs from SDS- PAGE electrophoresis of the Staph-A-bound proteins shows two radioactive bands consistent in size with GPIIb and GPIIIa.     

Functional differences between human cutaneous mast cells and basophils: a comparison of morphine-induced histamine release

Intravenous administration of morphine sulfate often produces urticarial and hypotensive reactions associated with elevations in plasma histamine. The source of this histamine and mechanisms controlling its release are poorly understood. Previous studies of morphine-induced histamine release compared human leukocytes to rat peritoneal mast cells. The effects of morphine on human cutaneous mast cells has not been examined. We studiedin vitro histamine release from human basophils and human skin preparations containing cutaneous mast cells to evaluate their relative, contribution to the pharmacologic effects of morphine.Human skin mast cell preparations showed dosedependent histamine release over a morphine concentration range of 1.5×10^–5 to 4.5×10^–3 M, with peak release occurring at 5×10^–4 M, with peak release occurring at 5×10^–4 M. Clinically, morphine sulfate is usually injected as a 1.5×10^–2 M solution. Histamine release was calcium dependent and equivalent to that obtained with 3 and 10 mM strontium. Morphologic examination revealed degranulation and exocytosis occurring in morphine-stimulated tissue but not in specimens exposed to buffer alone. Lactate dehydrogenase levels did not increase following morphine incubation, thus supporting a noncytolytic mechanism of histamine release.Basophils, in contrast, showed no significant histamine release from exposure to morphine up to 10^–2 M. Concanavalin A, as a positive control in these same preparations, produced a mean histamine release of 21.0%.Our studies indicate distinct functional differences between human skin mast cell and human blood basophil responses to morphine sulfate. We conclude that the cutaneous and systemic reactions to morphine sulfate probably result from the release of histamine from mast cells rather than from basophils.This study was supported by: National Institutes of Health Grants 2-T32 AMO7153, 5-RO1 AI18615, AI 15557, HL 25831, American Society of Anesthesiologists Starter Grant 1283, and a grant from the Bramble Foundation.     

What is the association between traumatic life events and alcohol abuse/dependence in people with and without PTSD? Findings from a nationally representative sample

Background: Approximately 60–90% of the general population will experience a traumatic event during their lifetime. However, relatively few will develop a trauma‐related psychological disorder. Possible psychological sequelae of trauma include posttraumatic stress disorder (PTSD) and alcohol‐use disorders (AUDs). While AUDs often occur in the context of PTSD, little is known about the degree to which AUDs are attributable to specific traumatic events. The purpose of the present investigation was to assess the degree to which specific traumatic events are predictive of AUDs in people with and without PTSD. Methods: The current sample was selected from the National Epidemiological Survey of Alcohol and Related Conditions (NESARC; N = 34,160), a nationally representative sample of American adults. Multiple logistic regressions were performed to examine odds ratios of 27 traumatic events among individuals with and without PTSD in the prediction of AUD diagnoses. Results: Results indicated significant positive odds ratios among individuals meeting criteria for PTSD and having experienced a childhood trauma (OR = 1.40 [95% CI: 1.08–1.83], P<.01) or assaultive violence (OR = 1.41 [95% CI: 1.13–1.77], P<.01) for predicting AUDs. Also, among individuals without PTSD, childhood trauma (OR = 1.32 [95% CI: 1.23–1.41], P<.001), assaultive violence (OR = 1.42 [95% CI: 1.13–1.78], P<.001), unexpected death (OR = 1.19 [95% CI: 1.12–1.28], P<.001), and learning of trauma (OR = 1.22 [95% CI: 1.13–1.30], P<.001) positively predicted the presence of AUDs. Conclusions: Results indicate significant positive relationships between traumatic events and AUDs, particularly among individuals without PTSD. Specific associations and theoretical implications will be discussed. Depression and Anxiety, 2011. © 2011 Wiley‐Liss, Inc.     

Effects of ketamine and midazolam on resting state connectivity and comparison with ENIGMA connectivity deficit patterns in schizophrenia

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting‐state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19–37 years) underwent a randomized, three‐way, cross‐over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long‐distance (seed‐based and dual‐regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10^?3), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia‐related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = ?.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug.     

A sinister subject: Quantifying handedness‐based recruitment biases in current neuroimaging research

Approximately ten per cent of humans are left‐handed or ambidextrous (adextral). It has been suggested that, despite their sizable representation at the whole‐population level, this demographic is largely avoided by researchers within the neuroimaging community. To date, however, no formal effort has been made to quantify the extent to which adextrals are excluded from neuroimaging‐based research. Here, we aimed to address this question in a review of over 1,000 recent articles published in high‐impact, peer‐reviewed, neuroimaging‐focused journals. Specifically, we sought to ascertain whether, and the extent to which adextrals are underrepresented in neuroimaging study samples, and to delineate potential trends in this bias. Handedness data were available for over 30,000 research subjects; only around 3%–4% of these individuals were adextral—considerably less than the 10% benchmark one would expect if neuroimaging samples were truly representative of the general population. This observation was generally consistent across different areas of research, but was modulated by the demographic characteristics of neuroimaging participants. The epistemological and ethical implications of these findings are discussed.     

Selection Criteria for Postmastectomy Radiotherapy in T1–T2 Tumors with 1 to 3 Positive Lymph Nodes

Background

Postmastectomy radiotherapy (PMRT) is well established in patients with ≥4 positive axillary lymph nodes (ALN); indications in 1 to 3 positive ALN remains controversial. We examined clinicopathologic criteria used for PMRT selection and compared locoregional recurrence (LRR), recurrence-free survival (RFS), and overall survival (OS) among patients with and without PMRT.

Methods

Between 1995 and 2006, a total of 1,331 patients with T1–T2 tumors and 1 to 3 positive ALN underwent mastectomy. We excluded T3/T4 tumors and neoadjuvant chemotherapy; we analyzed 1,087 patients (924 without PMRT, 163 with PMRT). Chi square testing compared clinicopathologic features between groups. The Kaplan–Meier method and Cox regression analysis examined the association between PMRT and LRR, RFS, and OS.

Results

PMRT patients were more likely to be ≤50 years old (p = 0.001) and to have larger tumors (p = 0.01), disease of a higher histologic grade (p = 0.03), lymphovascular invasion (LVI) (p < 0.0001), a greater number of positive ALN (p < 0.0001), extranodal invasion (p < 0.0001), and macroscopic ALN metastases (p < 0.0001). With a median follow-up of 7 years, PMRT and no-PMRT groups were similar in LRR (p = 0.57), RFS (p = 0.70), and OS (p = 0.28). On multivariate analysis of the no-PMRT group, age ≤50 years (p = 0.002) and presence of LVI (p < 0.0001) were associated with LRR. Stratified by age and LVI, patients ≤50 years old and with LVI had the highest 5-year LRR, 10.1 versus 1.1 %, than in patients >50 years old without LVI (p < 0.001).

Conclusions

By using clinicopathologic features, clinicians delivered PMRT to a select group of patients with T1–T2 tumors and 1 to 3 positive ALN, resulting in similarly low rates of 5-year LRR. Among patients not receiving PMRT, age ≤50 years and LVI were associated with increased LRR rates and warrant PMRT consideration.