First ladies in laying the foundation of neuroendocrinology.

Although women were welcomed into medical practice in increasing numbers by the close of the nineteenth century, it was not until the second quarter of the twentieth century that they were recognised as valuable collaborators and contributors in the nascent field of neuroendocrinology, wherein they soon made advances that have stood the test of time. Mary Pickford at Edinburgh measured the action of acetyl choline in the supraoptic nucleus of the hypothalamus and helped to establish that vasopressin and oxytocin are formed in separate and distinct neurons. Berta Scharrer, like her future husband Ernest Scharrer, was born in Munich. Their great contribution was the proof that the posterior pituitary is not a gland, but the location of the release into the circulation of vasopressin and oxytocin from fibres in the hypothalamico-hypophysial tract. Their work succeeded in establishing against high-powered, vehement opposition the value of histological evidence in elucidating synthesis, storage and release of secretion from neuro-endocrine cells. A Rockefeller travelling fellowship allowed Marthe Vogt to move from Berlin in 1932 to London and then to Cambridge. The relations between the cortex and medulla of the suprarenal gland and the control of adrenocorticotropin were her main concerns. Dora Jacobsohn emigrated to Sweden after graduating in Berlin in 1934. She investigated control of the anterior pituitary gland by the hypothalamus, and co-operated with Geoffrey Harris in establishing the role of the hypothalamico-hypophysial portal venous system that conveys the releasing factors that preside over anterior pituitary cells. Laboratory discoveries do not constitute the whole of science, for the interpretation of evidence and recognition of general principles deserve attention. Dorothy Price, from Aurora, Illinois, received her BS in 1922 at the University of Chicago, and was glad to find employment as a histology technician in the zoology laboratory, where she was quietly appropriated by Carl Moore (1892-1955), an investigator seeking the key to hormonal control of gonadal function. The burning question was the part played by what was (then) called hormone antagonism in the biology of the testis. Price recognised that the common factor in explaining the deleterious effects of oestrin and testosterone on the testes could be traced to the anterior pituitary: the pituitary controlled testicular secretion, and the male hormone in turn controlled gonadotropin release in the pituitary. This seesaw balance explained the problem, and was the first of many regulatory systems to be recognised as ensuring stability--and later became known as negative feedback. The contributions of these five women helped place neuro-endocrinology on a firm foundation for its later expansion.

William Wilde and the early records of consumption in Ireland.

Absence of documentary or bony evidence before the seventeenth century in Ireland is not conclusive evidence of freedom from tuberculosis. Clear records begin with Bills of Mortality kept in Dublin, the city at the centre of English administration of Ireland, and they show that the basis for an epidemic was firmly established therein before 1700. In the middle of the nineteenth century the cataclysmic Famine opened the floodgates of poverty and urban overcrowding that resulted in an alarming death rate that continued to increase until the early years of the twentieth century. It is to William Wilde (1815-1876) we owe the nuanced investigation of the earliest numerical records of consumption and related disorders in Ireland.

Psychoneuroimmunology: the example of psoriasis.

The relationship between the central nervous system (CNS) and the endocrine system have been known for many years. Indeed some of the hormone secreting glands are actually located in the brain. The notion that the CNS and hormones are also involved in the bi-directional cross-talk with the Immune System has been the target of intense research in the recent decades. In this manner, for example, psychological states can be closely related to changes in immune mediators, and not only they may influence the evolution of human diseases, but may in the future lead to novel therapeutic interventions. This is the subject of this review, with particular emphasis on the role of psychoneuroimmunology (PNI) in psoriasis.

Chemical sympathectomy increases numbers of inflammatory cells in the peritoneum early in murine listeriosis.

Here, we investigated the effects of sympathectomy on systemic bacterial loads following infection with Listeria monocytogenes, and on innate and specific immune responses in the peritoneum. Sympathectomy decreased systemic bacterial loads, and increased the number of peritoneal leukocytes and the percentage of peritoneal macrophages three days postinfection. This suggests that sympathectomy-induced decreases systemic bacterial loads are associated with increased recruitment of inflammatory cells into tissues during the innate immune response.

Chemical sympathectomy alters numbers of splenic and peritoneal leukocytes.

Sympathectomy of BALB/c mice that were injected with either Listeria monocytogenes or saline did not affect the total number of splenic leukocytes measured 1-3 days after injection, but sympathectomy did increase the percentages of neutrophils in the spleens of both infected and uninfected mice. By contrast, sympathectomy was associated with increased numbers of peritoneal exudate cells (PEC) and peritoneal macrophages in both groups of mice. Sympathectomy did not affect tumor necrosis factor-alpha, interleukin-12, or interferon-gamma production in cultured splenocytes or PEC in either infected or uninfected mice.

Respiratory and cognitive subtypes of panic. Preliminary validation of Ley's model.

A review of the panic disorder literature strongly suggests subtypes of panic attacks, including a respiratory subtype. This study empirically tested several aspects of Ley's panic subtype theory, measuring end-tidal carbon dioxide (ETCO2) levels at baseline, during psychologic and respiratory stressors, and at recovery. As predicted, Type 1 (classic or respiratory) panickers had significantly lower resting ETCO2 compared to Type 3 (cognitive) and to controls. Type 3 panickers did not differ from controls. Physiologic findings support the existence of respiratory and other subtypes of panic attacks in panic disorder. More complex measures of respiration and other physiology are likely required to elicit full subtype profiles. Distinguishing between chronic (compensated) hyperventilators and acute hyperventilators will likely be useful in clarifying the subtypes. Recognizing the need for differential diagnosis of panic attacks can facilitate developing more specific treatment plans and interventions (e.g., restoration of normal ETCO2 in Type 1), improving treatment success rates.

Evading detection on the MMPI-2: does caution produce more realistic patterns of responding?

Studies on MMPI and MMPI-2 malingering indexes often sacrifice generalizability in an attempt to control internal validity. This study improves external validity while still maintaining internal validity by providing graduate student participants with a realistic context for malingering on the MMPI-2 (n=94) and MMPI (n=30). Contextual parameters include a realistic life predicament, psychological knowledge, an incentive, the presence versus absence of a specific diagnosis, and a caution to be realistic. This study found that cautioning participants not to overexaggerate their responses significantly improves their ability to evade detection on the MMPI-2 and MMPI. Standard malingering indexes (Infrequency, F; Back Side, F, Fb; F-Correction, F-K; and Infrequency-Psychopathology, F(p)) were insufficiently sensitive in identifying simulators using common cutoff scores for these cautious simulators.

Glucocorticoid treatment reduces exhaled nitric oxide in cystic fibrosis patients.

In cystic fibrosis (CF), low concentrations of exhaled nitric oxide (NO) and reduced expression of inducible nitric oxide synthase (iNOS) in airway epithelium have been reported. However, abundant iNOS expression has been found in the subepithelial tissues and elevated concentrations of NO metabolites in breath condensate and sputum. These conflicting results may be explained by increased scavenging of NO by superoxide radicals, resulting in rapid conversion to peroxynitrite, so that only a small proportion of the NO produced in the lung tissue reaches the airway lumen. If iNOS were active in the CF lung, exhaled NO would be further reduced by glucocorticoid treatment. CF patients (n = 13) were recruited to a double-blind, placebo-controlled study with crossover. Treatment comprised prednisolone or placebo for 5 days with a 9 day washout. After each treatment, exhaled NO was measured, spirometry performed and blood collected for measurement of serum nitrogen dioxide/nitrous oxide (NO2/NO3). Ten patients (8 male) completed the study. Following prednisolone treatment (mean +/- SD) exhaled NO concentration (3.1 +/- 1.6 parts per billion (ppb)) was significantly reduced versus placebo treatment (4.9 +/- 4.2 ppb; p<0.05, Wilcoxon signed-rank test). Spirometric indices and serum NO2/NO3 concentration were unchanged. These findings support the hypothesis that glucocorticoids suppress nitric oxide production in cystic fibrosis airways by reducing inducible nitric oxide synthase expression or by inhibiting recruitment of neutrophils, cells which express inducible nitric oxide synthase.

Recent advances in the development of peptide vaccines for hepatitis B.

The control of hepatitis B by vaccination is arguably one of medicine's greatest achievements in terms of protecting infants and adults at high risk of infection. Paradoxically, however, the existence of a large reservoir of chronically infected individuals will not diminish the risk of infection by those coming into close contact with such persons until universal infant immunisation is practised globally and vaccines are in place to ensure maximum efficacy in those with impaired immune responses, immunity is achieved with fewer doses, and immunisation as an adjunct to the antiviral treatment of chronic carriers is adopted. These imperatives have continued to stimulate research into vaccines based on chemically synthesised short peptides, and those systems best suited for their delivery. This review discusses the potential of synthetic peptide formulations as efficient inducers of both humoral and cellular immune responses against hepatitis B, and reviews recent advances in peptide delivery. Synthetic peptide and delivery systems technologies will, amongst others, be of paramount importance in the global fight for the eradication of hepatitis B in the 21st century.

Moderate exercise is associated with enhanced antigen-specific cytokine, but not IgM antibody production in aged mice.

It has been suggested that moderate exercise may modulate the immune response in the elderly. We investigated whether moderate exercise had an effect on the immune response to viral infection in both young (2-4 months) and older (16-18 months) male BALB/cJ mice. Exercised (EX) mice ran on a treadmill for 8 weeks at a gradually increasing speed and duration whereas control (CON) mice were only handled briefly during each exercise session and then returned to their cages. Mice were infected with herpes simplex virus type 1 (HSV-1) 24 h post-exercise. Serum IgM anti-HSV antibody, HSV-1 specific Th1/Th2 cytokine production by spleen cells, and cytokine production by alveolar cells were measured 7 days post-infection. In the aged mice, exercise was associated with an enhanced production of the HSV-1 specific Th1-associated cytokines, interleukin (IL)-2 and interferon (IFN)-gamma, but had no effect on the Th2-associated cytokine IL-10 or IgM antibody. No effect of exercise was observed in young mice. IL-12 production was not altered by exercise, but aging was associated with altered IL-12 production in a tissue-specific manner. In conclusion, moderate exercise was associated with increased antigen-specific IL-2 and IFN-gamma production in response to viral challenge in older mice.

Heart rate, neuroendocrine, and immunological reactivity in response to an acute laboratory stressor.

OBJECTIVE: The primary objective of the present study was to identify neuroendocrine and immunological correlates of cardiovascular reactivity to an acute laboratory stressor. METHODS: Subjects were 56 healthy volunteers. Heart rate and blood pressure were assessed at regular intervals during a 30-minute adaptation period and a 6-minute videotaped speech task. Blood was drawn before and after the task and was assayed for natural killer cell activity (NKCA), cortisol production, in vitro interferon gamma (IFN-gamma) and interleukin 10 production by peripheral blood mononuclear cells (PBMC), and antibody titers to the Epstein-Barr virus. Psychological measures were also administered. RESULTS: NKCA increased significantly in response to the task, and this increase was significantly and positively correlated with heart rate reactivity. IFN-gamma production by PBMC also increased in response to the task, but these increases were unrelated to heart rate reactivity. In addition, baseline cortisol levels were found to be predictive of heart rate reactivity. Finally, questionnaire data were modestly related to various aspects of stress-induced reactivity. CONCLUSIONS: Consistent with the task-related increases in NKCA and IFN-gamma, acute stress may signal an increase in at least some aspects of the cell-mediated, or TH1-driven, immune response. Furthermore, the finding that heart rate reactivity was related in part to baseline individual differences in cortisol production suggests that short-term cardiovascular responses to stress may be directly related to longer-term neuroendocrine modulation. Finally, the present results also help to highlight the influence of both sympathetic and nonsympathetic pathways in the response to acute stressors and suggest tentative links between certain psychological traits and various aspects of stress-induced reactivity.

Expression of Fas (CD95) and Fas ligand on peripheral blood mononuclear cells in critical illness and association with multiorgan dysfunction severity and survival.

OBJECTIVE: This was an exploratory study with three goals: a) to quantify the expression of the apoptotic receptor Fas and its ligand (FasL) on peripheral blood mononuclear cells (PBMCs) in patients with, or at risk for, multiple organ dysfunction syndrome (MODS); b) to compare this expression with the respective expression in matched controls; and c) to explore the association with MODS severity and survival. DESIGN: Repeated-measures correlational and cross-sectional design. SETTING: The surgical, medical, and the trauma/burn intensive care unit of an academic institution. PATIENTS: Thirty-five adult, critically ill patients meeting the diagnostic criteria for systemic inflammatory response syndrome (SIRS) with MODS, or at risk for MODS, were followed for 14 days. Thirty-five non-SIRS controls matched with patients for age, gender, and race comprised the control group. INTERVENTIONS: Peripheral blood sampling every 48 hrs. MEASUREMENTS/MAIN RESULTS: T cells were considerably depleted in SIRS/MODS patients (p <.001), and Fas and FasL expression on PBMCs (flow cytometric analysis) was elevated significantly compared with controls (p <.001). In contrast to controls, non-T cells were the major sources of Fas and FasL in SIRS/MODS patients (p <.01). Expression of Fas and FasL exhibited a bimodal correlation with severity (p <.03). High severity patients demonstrated increasing Fas and FasL expression with increasing severity in contrast to declining expression in moderately severe patients. Fas and FasL measurements were significantly and positively associated with the likelihood of survival (p <.05). CONCLUSIONS: Dysregulation in the expression of apoptotic receptors Fas and FasL, at least in PBMCs, may be involved in the pathophysiology of SIRS, the related lymphocytopenia, and the onset of MODS and the related morbidity and mortality rates.

A novel microencapsulated peptide vaccine against hepatitis B.

A 48 amino acid synthetic peptide (S121/48) representing residues 121-167 of the major envelope protein of hepatitis B virus (HBsAg) was successfully encapsulated into polylactide co-glycolide microspheres. A single immunization of the microspheres in BALB/c (H-2d) mice resulted in the production of high-titre anti-HBs antibodies (IgG1-type). The response was long lasting and was superior to that obtained using the same peptide adjuvanted with Freund's complete adjuvant. A T-cell memory response was detected 10 weeks after a booster immunization (approximately 35 weeks after initial immunization) as measured by in-vitro re-stimulation of splenocytes. This study illustrates the feasibility of a single dose vaccine for hepatitis B and is, to our knowledge, the first demonstration of a synthetic peptide immunogen inducing anti-native protein antibodies of comparable titre to those obtained with conventional vaccines for hepatitis B. The suitability of a synthetic peptide vaccine for hepatitis B is discussed.

Chemical sympathectomy increases the innate immune response and decreases the specific immune response in the spleen to infection with Listeria monocytogenes.

Many investigators have shown that ablation of the sympathetic nervous system (SNS) with 6-hydroxydopamine (6-OHDA) can alter cell-mediated and humoral immune responses to antigenic challenge. Fewer studies have examined 6-OHDA-induced changes in natural immunity. In this study, we have examined the effect of chemical sympathectomy on the nonspecific and specific phases of the response to infection with Listeria monocytogenes. Sympathectomy decreased splenic bacterial loads 3 and 5 days post-infection and increased splenic neutrophils 3 days post-infection. Sympathectomy decreased splenocyte numbers and antigen-stimulated cytokine secretion from splenocytes. These results suggest that the SNS influences specific responses by modulating innate responses.