Hyperventilation in panic disorder patients and healthy first-degree relatives

Our aim was to observe the induction of panic attacks by a hyperventilation challenge test in panic disorder patients (DSM-IV) and their healthy first-degree relatives. We randomly selected 25 panic disorder patients, 31 healthy first-degree relatives of probands with panic disorder and 26 normal volunteers with no family history of panic disorder. All patients had no psychotropic drugs for at least one week. They were induced to hyperventilate (30 breaths/min) for 4 min and anxiety scales were applied before and after the test. A total of 44.0% (N = 11) panic disorder patients, 16.1% (N = 5) of first-degree relatives and 11.5% (N = 3) of control subjects had a panic attack after hyperventilating (chi² = 8.93, d.f. = 2, P = 0.011). In this challenge test the panic disorder patients were more sensitive to hyperventilation than first-degree relatives and normal volunteers. Although the hyperventilation test has a low sensitivity, our data suggest that there is no association between a family history of panic disorder and hyperreactivity to an acute hyperventilation challenge test. Perhaps cognitive variables should be considered to play a specific role in this association since symptoms of a panic attack and acute hyperventilation overlap.

Respiratory panic disorder subtype and sensitivity to the carbon dioxide challenge test

The aim of the present study was to verify the sensitivity to the carbon dioxide (CO2) challenge test of panic disorder (PD) patients with respiratory and nonrespiratory subtypes of the disorder. Our hypothesis is that the respiratory subtype is more sensitive to 35% CO2. Twenty-seven PD subjects with or without agoraphobia were classified into respiratory and nonrespiratory subtypes on the basis of the presence of respiratory symptoms during their panic attacks. The tests were carried out in a double-blind manner using two mixtures: 1) 35% CO2 and 65% O2, and 2) 100% atmospheric compressed air, 20 min apart. The tests were repeated after 2 weeks during which the participants in the study did not receive any psychotropic drugs. At least 15 of 16 (93.7%) respiratory PD subtype patients and 5 of 11 (43.4%) nonrespiratory PD patients had a panic attack during one of two CO2 challenges (P = 0.009, Fisher exact test). Respiratory PD subtype patients were more sensitive to the CO2 challenge test. There was agreement between the severity of PD measured by the Clinical Global Impression (CGI) Scale and the subtype of PD. Higher CGI scores in the respiratory PD subtype could reflect a greater sensitivity to the CO2 challenge due to a greater severity of PD. Carbon dioxide challenges in PD may define PD subtypes and their underlying mechanisms.

Melatonin and N-acetyl-serotonin cross the red blood cell membrane and evoke calcium mobilization in malarial parasites

The duration of the intraerythrocytic cycle of Plasmodium is a key factor in the pathogenicity of this parasite. The simultaneous attack of the host red blood cells by the parasites depends on the synchronicity of their development. Unraveling the signals at the basis of this synchronicity represents a challenging biological question and may be very important to develop alternative strategies for therapeutic approaches. Recently, we reported that the synchrony of Plasmodium is modulated by melatonin, a host hormone that is synthesized only during the dark phases. Here we report that N-acetyl-serotonin, a melatonin precursor, also releases Ca2+ from isolated P. chabaudi parasites at micro- and nanomolar concentrations and that the release is blocked by 250 mM luzindole, an antagonist of melatonin receptors, and 20 mM U73122, a phospholipase C inhibitor. On the basis of confocal microscopy, we also report the ability of 0.1 µM melatonin and 0.1 µM N-acetyl-serotonin to cross the red blood cell membrane and to mobilize intracellular calcium in parasites previously loaded with the fluorescent calcium indicator Fluo-3 AM. The present data represent a step forward into the understanding of the signal transduction process in the host-parasite relationship by supporting the idea that the host hormone melatonin and N-acetyl-serotonin generate IP3 and therefore mobilize intracellular Ca2+ in Plasmodium inside red blood cells.

Eye color as an indicator of social rank in the fish Nile tilapia

We investigated the association of eye color with the dominant-subordinate relationship in the fish Nile tilapia, Oreochromis niloticus. Eye color pattern was also examined in relation to the intensity of attacks. We paired 20 size-matched fish (intruder: 73.69 ± 11.49 g; resident: 75.42 ± 8.83 g) and evaluated eye color and fights. These fish were isolated in individual aquaria for 10 days and then their eye color was measured 5 min before pairing (basal values). Twenty minutes after pairing, eye color and fights were quantified for 10 min. Clear establishment of social hierarchy was observed in 7 of 10 pairs of fish. Number of attacks ranged from 1 to 168 among pairs. The quartile was calculated for these data and the pairs were then divided into two classes: low-attack (1 to 111 attacks - 2 lower quartiles) or high-attack (112 to 168 attacks - 2 higher quartiles). Dominance decreased the eye-darkening patterns of the fish after pairing, while subordinance increased darkening compared to dominance. Subordinate fish in low-attack confrontations presented a darker eye compared to dominant fish and to the basal condition. We also observed a paler eye pattern in dominants that shared low-attack interactions after pairing compared to the subordinates and within the group. However, we found no differences in the darkening pattern between dominants and subordinates from the high-attack groups. We conclude that eye color is associated with social rank in this species. Moreover, the association between eye color and social rank in the low-attack pairs may function to reduce aggression.

Effect of the establishment of dominance relationships on cortisol and other metabolic parameters in Nile tilapia (Oreochromis niloticus)

The objective of the present study was to investigate the influence of the establishment of dominance relationships and social stress on plasma cortisol and metabolite levels in Nile tilapia (Oreochromis niloticus). During the 30-day experiment, the fish weighing 236 ± 29 g were kept in individual aquaria, except for two pairings lasting 6 h each. Blood samples were taken from the animals before and after pairing. Display, approach, attack, rebuff, chase flight, and coloration were carried out on days 16 and 30. Activities and behaviors characteristic of the establishment of dominance relationships were described. It was possible to classify all experimental fish (N = 30) as dominant or subordinate. No differences were detected between dominant (N = 15) and subordinate (N = 15) fish during isolation or after pairing in cortisol (isolated: 5.76 ± 0.98 vs 5.42 ± 0.63; paired: 10.94 ± 1.62 vs 11.21 ± 2.45 µg/dl), glucose (isolated: 60.02 ± 4.9 vs 67.85 ± 16.16; paired: 110.44 ± 15.72 vs 136.26 ± 22.46 mg/dl), triglyceride (isolated: 167.87 ± 5.06 vs 185.68 ± 7.24; paired: 210.85 ± 13.40 vs 221.82 ± 12.70 mg/dl) or total protein levels (isolated: 7.01 ± 0.42 vs 6.69 ± 0.59; paired: 9.21 ± 0.62 vs 9.51 ± 0.66 g/dl). However, when isolated (N = 30) and paired (N = 30) tilapia were compared, there were significant differences in cortisol and metabolite levels. The similar response presented by dominant and subordinate tilapia indicates that establishment of dominance relationships was a stressor for both groups.

Clinical features of panic patients sensitive to hyperventilation or breath-holding methods for inducing panic attacks

Our aim was to compare the clinical features of panic disorder (PD) patients sensitive to hyperventilation or breath-holding methods of inducing panic attacks. Eighty-five PD patients were submitted to both a hyperventilation challenge test and a breath-holding test. They were asked to hyperventilate (30 breaths/min) for 4 min and a week later to hold their breath for as long as possible, four times with a 2-min interval. Anxiety scales were applied before and after the tests. We selected the patients who responded with a panic attack to just one of the tests, i.e., those who had a panic attack after hyperventilating (HPA, N = 24, 16 females, 8 males, mean age ± SD = 38.5 ± 12.7 years) and those who had a panic attack after breath holding (BHPA, N = 20, 11 females, 9 males, mean age ± SD = 42.1 ± 10.6 years). Both groups had similar (chi² = 1.28, d.f. = 1, P = 0.672) respiratory symptoms (fear of dying, chest/pain disconfort, shortness of breath, paresthesias, and feelings of choking) during a panic attack. The criteria of Briggs et al. [British Journal of Psychiatry, 1993; 163: 201-209] for respiratory PD subtype were fulfilled by 18 (75.0%) HPA patients and by 14 (70.0%) BHPA patients. The HPA group had a later onset of the disease compared to BHPA patients (37.9 ± 11.0 vs 21.3 ± 12.9 years old, Mann-Whitney, P < 0.001), and had a higher family prevalence of PD (70.8 vs 25.0%, chi² = 19.65, d.f. = 1, P = 0.041). Our data suggest that these two groups - HPA and BHPA patients - may be specific subtypes of PD.

Patient and physician evaluation of the severity of acute asthma exacerbations

We studied the ability of patients not experienced in the use of peak expiratory flow meters to assess the severity of their asthma exacerbations and compared it to the assessment of experienced clinicians. We also evaluated which data of physical examination and medical history are used by physicians to subjectively evaluate the severity of asthma attacks. Fifty-seven adult patients (15 men and 42 women, with a mean (± SD) age of 37.3 ± 14.5 years and 24.0 ± 17.9 years of asthma symptoms) with asthma exacerbations were evaluated in a University Hospital Emergency Department. Patients and physicians independently evaluated the severity of the asthma attack using a linear scale. Patient score, physician score and forced expiratory volume at the first second (FEV1) were correlated with history and physical examination variables, and were also considered as dependent variables in multiple linear regression models. FEV1 correlated significantly with the physician score (rho = 0.42, P = 0.001), but not with patient score (rho = 0.03; P = 0.77). Use of neck accessory muscles, expiratory time and wheezing intensity were the explanatory variables in the FEV1 regression model and were also present in the physician score model. We conclude that physicians evaluate asthma exacerbation severity better than patients and that physician's scoring of asthma severity correlated significantly with objective measures of airway obstruction (FEV1). Some variables (the use of neck accessory muscles, expiratory time and wheezing intensity) persisted as explanatory variables in physician score and FEV1 regression models, and should be emphasized in medical schools and emergency settings.

Factors associated with emergency department visits due to acute asthma

It is important to identify characteristics related to poor disease control and frequent visits to the emergency department (ED). The objective of the present study was to compare the characteristics of patients attending the adult ED for treatment of asthma exacerbation with those attending an asthma specialist clinic (AC) in the same hospital, and to determine the factors associated with frequent visits to the ED. We conducted a cross-sectional survey of consecutive patients (12 years and older) attending the ED (N = 86) and the AC (N = 86). Significantly more ED patients than AC patients reported ED visits in the past year (95.3 vs 48.8%; P < 0.001) and had difficulty performing work (81.4 vs 49.4%; P < 0.001. Significantly more AC than ED patents had been treated with inhaled corticosteroids (75.6 vs 18.6%; P < 0.001) used to increase or start steroid therapy when an attack was perceived (46.5 vs 20.9%; P < 0.001) and correctly used a metered-dose inhaler (50.0 vs 11.6%; P < 0.001). The history of hospital admissions (odds ratio, OR, 4.00) and use of inhaled corticosteroids (OR, 0.27) were associated with frequent visits to the ED. In conclusion, ED patients were more likely than AC patients to be dependent on the acute use of the ED, were significantly less knowledgeable about asthma management and were more likely to suffer more severe disease. ED patients should be considered an important target for asthma education. Facilitating the access to ambulatory care facilities might serve to reduce asthma morbidity.

An acid-sensing ion channel that detects ischemic pain

Ischemic pain occurs when there is insufficient blood flow for the metabolic needs of an organ. The pain of a heart attack is the prototypical example. Multiple compounds released from ischemic muscle likely contribute to this pain by acting on sensory neurons that innervate muscle. One such compound is lactic acid. Here, we show that ASIC3 (acid-sensing ion channel #3) has the appropriate expression pattern and physical properties to be the detector of this lactic acid. In rats, it is expressed only in sensory neurons and then only on a minority (~40%) of these. Nevertheless, it is expressed at extremely high levels on virtually all dorsal root ganglion sensory neurons that innervate the heart. It is extraordinarily sensitive to protons (Hill slope 4, half-activating pH 6.7), allowing it to readily respond to the small changes in extracellular pH (from 7.4 to 7.0) that occur during muscle ischemia. Moreover, both extracellular lactate and extracellular ATP increase the sensitivity of ASIC3 to protons. This final property makes ASIC3 a "coincidence detector" of three molecules that appear during ischemia, thereby allowing it to better detect acidosis caused by ischemia than other forms of systemic acidosis such as hypercapnia.

Contested dominance modifies the anovulatory consequences of social subordination in female marmosets

Dominance status among female marmosets is reflected in agonistic behavior and ovarian function. Socially dominant females receive submissive behavior from subordinates, while exhibiting normal ovulatory function. Subordinate females, however, receive agonistic behavior from dominants, while exhibiting reduced or absent ovulatory function. Such disparity in female fertility is not absolute, and groups with two breeding females have been described. The data reported here were obtained from 8 female-female pairs of captive female marmosets, each housed with a single unrelated male. Pairs were classified into two groups: "uncontested" dominance (UD) and "contested" dominance (CD), with 4 pairs each. Dominant females in UD pairs showed significantly higher frequencies (4.1) of agonism (piloerection, attack and chasing) than their subordinates (0.36), and agonistic behaviors were overall more frequently displayed by CD than by UD pairs. Subordinates in CD pairs exhibited more agonistic behavior (2.9) than subordinates in UD pairs (0.36), which displayed significantly more submissive (6.97) behaviors than their dominants (0.35). The data suggest that there is more than one kind of dominance relationship between female common marmosets. Assessment of progesterone levels showed that while subordinates in UD pairs appeared to be anovulatory, the degree of ovulatory disruption in subordinates of CD pairs was more varied and less complete. We suggest that such variation in female-female social dominance relationships and the associated variation in the degree and reliability of fertility suppression may explain variations of the reproductive condition of free-living groups of common marmosets.

Secondary prevention of type 1 diabetes mellitus: stopping immune destruction and promoting ß-cell regeneration

Type 1 diabetes mellitus results from a cell-mediated autoimmune attack against pancreatic ß-cells. Traditional treatments involve numerous daily insulin dosages/injections and rigorous glucose control. Many efforts toward the identification of ß-cell precursors have been made not only with the aim of understanding the physiology of islet regeneration, but also as an alternative way to produce ß-cells to be used in protocols of islet transplantation. In this review, we summarize the most recent studies related to precursor cells implicated in the regeneration process. These include embryonic stem cells, pancreas-derived multipotent precursors, pancreatic ductal cells, hematopoietic stem cells, mesenchymal stem cells, hepatic oval cells, and mature ß-cells. There is controversial evidence of the potential of these cell sources to regenerate ß-cell mass in diabetic patients. However, clinical trials using embryonic stem cells, umbilical cord blood or adult bone marrow stem cells are under way. The results of various immunosuppressive regimens aiming at blocking autoimmunity against pancreatic ß-cells and promoting ß-cell preservation are also analyzed. Most of these regimens provide transient and partial effect on insulin requirements, but new regimens are beginning to be tested. Our own clinical trial combines a high dose immunosuppression with mobilized peripheral blood hematopoietic stem cell transplantation in early-onset type 1 diabetes mellitus.

Defensive responses to threat scenarios in Brazilians reproduce the pattern of Hawaiian Americans and non-human mammals

A former study with scenarios conducted in Hawaii has suggested that humans share with non-human mammals the same basic defensive strategies - risk assessment, freezing, defensive threat, defensive attack, and flight. The selection of the most adaptive strategy is strongly influenced by features of the threat stimulus - magnitude, escapability, distance, ambiguity, and availability of a hiding place. Aiming at verifying if these strategies would be consistent in a different culture, 12 defensive scenarios were translated into Portuguese and adapted to the Brazilian culture. The sample consisted of male and female undergraduate students divided into two groups: 76 students, who evaluated the five dimensions of each scenario and 248 medical students, who chose the most likely response for each scenario. In agreement with the findings from studies of non-human mammal species, the scenarios were able to elicit different defensive behavioral responses, depending on features of the threat. "Flight" was chosen as the most likely response in scenarios evaluated as an unambiguous and intense threat, but with an available route of escape, whereas "attack" was chosen in an unambiguous, intense and close dangerous situation without an escape route. Less urgent behaviors, such as "check out", were chosen in scenarios evaluated as less intense, more distant and more ambiguous. Moreover, the results from the Brazilian sample were similar to the results obtained in the original study with Hawaiian students. These data suggest that a basic repertoire of defensive strategies is conserved along the mammalian evolution because they share similar functional benefits in maintaining fitness.

Panic-like defensive behavior but not fear-induced antinociception is differently organized by dorsomedial and posterior hypothalamic nuclei of Rattus norvegicus (Rodentia, Muridae)

The hypothalamus is a forebrain structure critically involved in the organization of defensive responses to aversive stimuli. Gamma-aminobutyric acid (GABA)ergic dysfunction in dorsomedial and posterior hypothalamic nuclei is implicated in the origin of panic-like defensive behavior, as well as in pain modulation. The present study was conducted to test the difference between these two hypothalamic nuclei regarding defensive and antinociceptive mechanisms. Thus, the GABA A antagonist bicuculline (40 ng/0.2 µL) or saline (0.9% NaCl) was microinjected into the dorsomedial or posterior hypothalamus in independent groups. Innate fear-induced responses characterized by defensive attention, defensive immobility and elaborate escape behavior were evoked by hypothalamic blockade of GABA A receptors. Fear-induced defensive behavior organized by the posterior hypothalamus was more intense than that organized by dorsomedial hypothalamic nuclei. Escape behavior elicited by GABA A receptor blockade in both the dorsomedial and posterior hypothalamus was followed by an increase in nociceptive threshold. Interestingly, there was no difference in the intensity or in the duration of fear-induced antinociception shown by each hypothalamic division presently investigated. The present study showed that GABAergic dysfunction in nuclei of both the dorsomedial and posterior hypothalamus elicit panic attack-like defensive responses followed by fear-induced antinociception, although the innate fear-induced behavior originates differently in the posterior hypothalamus in comparison to the activity of medial hypothalamic subdivisions.

New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray

Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction.

Chronic kidney disease in disadvantaged populations

The increased burden of chronic kidney disease (CKD) in disadvantaged populations is due to both global factors and population-specific issues. Low socioeconomic status and poor access to care contribute to health care disparities and exacerbate the negative effects of genetic or biological predisposition. Provision of appropriate renal care to these populations requires a two-pronged approach: expanding the reach of dialysis through development of low-cost alternatives that can be practiced in remote locations, and implementation and evaluation of cost-effective prevention strategies. Kidney transplantation should be promoted by expansion of deceased donor transplant programs and use of inexpensive, generic immunosuppressive drugs. The message of World Kidney Day 2015 is that a concerted attack against the diseases that lead to end-stage renal disease, by increasing community outreach, better education, improved economic opportunity, and access to preventive medicine for those at highest risk, could end the unacceptable relationship between CKD and disadvantage in these communities.