The social buffering of the hypothalamic–pituitary–adrenocortical axis in humans: Developmental and experiential determinants

Social buffering, a subset of social support, is the process through which the availability of a conspecific reduces the activity of stress-mediating neurobiological systems. While its role in coping and resilience is significant, we know little about its developmental history in humans. This brief review presents an integrative developmental account of the social buffering of hypothalamic–pituitary–adrenocortical (HPA) stress reactivity in humans, from infancy to adulthood. During infancy, parents are powerful stress-regulators for children, but child temperament also plays a role and interacts with parenting quality to predict the magnitude of stress responses to fear or pain stimuli. Recent work indicates that parental support remains a potent stress buffer into late childhood, but that it loses its effectiveness as a buffer of the HPA axis by adolescence. Puberty may be the switch that alters the potency of parental buffering. Beginning in middle childhood, friends may serve as stress buffers, particularly when other peers are the source of stress. By adulthood, romantic partners assume this protective role, though studies often reveal sex differences that are currently not well understood. Translational research across species will be critical for developing a mechanistic understanding of social buffering and the processes involved in developmental changes noted in this review.     

What's to lose and what's to learn: development under auditory deprivation, cochlear implants and limits of cortical plasticity

Sensory and environmental manipulations affect the development of sensory systems. Higher-order auditory representations (auditory categories or “objects”) evolve with experience and via top–down influences modify representations in early auditory areas. During development of a functional auditory system, the capacity for bottom–up reorganizations is successively less well expressed due to a molecular change in synaptic properties. It is, however, complemented by top–down influences that direct and modulate the residual (adult) capacity for circuit reorganization. In a deprived condition, this developmental step is substantially affected. As higher-order representations cannot be established in absence of auditory experience, the developmental decrease in capacity for “bottom–up regulated” reorganizations (as repeatedly demonstrated in also in deprived sensory systems) cannot be complemented by an increasing influence of top–down modulations. In consequence, the ability to learn is compromised in sensory deprivation, resulting in a sensitive period for recovery.     

Mechanisms and functional implications of social buffering in infants: Lessons from animal models

Social buffering, which is the attenuation of stress hormone release by a social partner, occurs in many species throughout the lifespan. Social buffering of the infant by the caregiver is particularly robust, and animal models using infant rodents are uncovering the mechanisms and neural circuitry supporting social buffering. At birth, the hypothalamic-pituitary-adrenal (HPA) stress system is functional but is suppressed via extended social buffering by the mother: the profound social buffering effects of the mother can last for 1–2 hours when pups are removed from the mother. At 10 days of age, pups begin to mount a stress response immediately when separated from the mother. The stimuli from the mother supporting social buffering are broad, for tactile stimulation, milk, and an anesthetized mother (no maternal behavior) all sufficiently support social buffering. The mother appears to produce social buffering by blocking norepinephrine (NE) release into the hypothalamic paraventricular nucleus (PVN), which blocks HPA activation. Since the infant amygdala relies on the presence of corticosterone (CORT), this suggests that social buffering of pups by the mother attenuates the neurobehavioral stress response in infancy and prevents pups from learning about threat within mother-infant interactions.     

Neonatal lipopolysaccharide and adult stress exposure predisposes rats to anxiety-like behaviour and blunted corticosterone responses: Implications for the double-hit hypothesis

The double-hit hypothesis posits that an early life genetic or environmental insult sets up a neural predisposition to psychopathology, which may emerge in the presence of a subsequent insult, or ‘second hit’ in later life. The current study assessed the effect of neonatal lipopolysaccharide (LPS) exposure on anxiety-like behaviours in the adult Wistar rat. Rats were administered either LPS (Salmonella enterica, serotype enteritidis, 0.05 mg/kg, ip) or saline (equivolume) on days 3 and 5 of life (birth = day 1). In adulthood (85 days), subjects were allocated to either “stress” or “no stress” treatment groups. For the “stress” group, subjects were exposed to a three-day stress protocol consisting of a 30 min period of restraint and isolation. The “no stress” group was left unperturbed but were handled during this period to control for handling effects between adult “stress” and “no stress” conditions. All animals then underwent behavioural testing using standardised tests of anxiety-like behaviour, including either the Hide Box/Open Field, Elevated Plus Maze (EPM) or Acoustic Startle Response (ASR). Time and event measures for restraint and isolation, the Hide Box/Open Field and EPM were recorded using automated tracking software. Startle amplitude and habituation across time was measured in the ASR test. Prior to and following behavioural test sessions, peripheral blood was collected to assess serum corticosterone and ACTH levels. Data analysis indicated that LPS-treated animals exposed to stress in adulthood exhibited increased anxiety-like behaviour across all behavioural tests compared to controls. Sexually dimorphic effects were observed with males exhibiting increased anxiety-related behaviours compared to females (p < .05). Neonatal LPS exposure induced a significant increase in corticosterone compared to controls (p < .05), whereas corticosterone responses to stress in adulthood were associated with a significantly blunted HPA axis response (p < .05). No differences in ACTH were observed. These results lend support to the double-hit hypothesis of anxiety-related behaviour, demonstrating that neonatal immune activation produces an enhanced propensity toward anxiety-related behaviour following stress in adulthood, and that this susceptibility is associated with alterations to HPA axis ontogeny.     

Childhood Obsessive–Compulsive Disorder in the NIMH MECA Study: Parent Versus Child Identification of Cases

Because as many as 50% of obsessive–compulsive disorder (OCD) cases have had onset by age 15, interest in its detection in childhood is strong. Clinical experience indicates that children often try to keep their OCD secret and that parental report may give marked underestimates. The authors examined the prevalence of childhood OCD in the NIMH Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) Study, a four-site community survey which allowed comparison of both parent and child report of the child's OCD and related symptoms and disorders. OCD cases, based on structured interviews (DISC-2.3 with DSM-III-R criteria) with 1,285 caretaker-child pairs, were identified separately for parent and child (aged 9 through 17) informants from the MECA database. Cases were then examined for demographic characteristics, for obsessive–compulsive symptoms and other diagnoses reported in cases “missed” by one reporter, and for comorbid disorders. Of a total of 35 (2.7%) identified cases, four (0.3%) were identified by the parent and 32 (2.5%) were identified by the child, with only one overlapping case. In general, when OCD cases were “missed” by one reporter, that reporter did not substitute another disorder. These findings support clinical data that children with OCD often hide their illness and underscore the importance of child interviews for its detection.     

Elevation of guinea pig brain preprodynorphin mRNA expression and hypothalamic-pituitary-adrenal axis activity by “binge” pattern cocaine administration

The endogenous opioid system and the hypothalamic-pituitary-adrenal (HPA) axis have been implicated in many of the neurobiological effects of cocaine. Previous studies in our laboratory showed that “binge” pattern cocaine administration increases preprodynorphin (ppDyn) mRNA levels in the caudate putamen and circulating levels of corticosterone in the rat. The present study extended these findings to guinea pigs, a species known to have a κ opioid receptor profile similar to that of humans. Male guinea pigs were treated with: (a) “binge” pattern cocaine for 7 days (subchronic) (3 × 15 mg/kg/day, hourly, intraperitoneal); (b) “binge” pattern saline for 5 days followed by “binge” pattern cocaine for 2 days (subacute); or (c) “binge” pattern saline for 7 days. Thirty minutes after the final injection, levels of ppDyn mRNA were quantitated in the nucleus accumbens, caudate putamen, frontal cortex, amygdala, hippocampus, and hypothalamus using a solution hybridization RNase protection assay. Regional distribution of ppDyn mRNA levels in the guinea pig brain was similar to that found in rat, with highest levels in the nucleus accumbens and caudate putamen. In the caudate putamen, ppDyn mRNA was significantly increased following either 2 days (38% increase) or 7 days (32% increase) of “binge” pattern cocaine administration as compared to saline-treated controls. No significant changes in ppDyn mRNA levels were found in any other brain region. Both subacute and subchronic “binge” cocaine administration significantly elevated plasma levels of adrenocorticotropin hormone (ACTH) and cortisol. However, the ACTH and cortisol increases were significantly blunted following 7 days of “binge” cocaine administration as compared to 2 days of drug treatment, reflecting the development of HPA tolerance or adaptation to repeated cocaine administration. Thus, the ppDyn mRNA and HPA responses to cocaine in guinea pigs are similar to those observed in rats.     

Lesch–Nyhan disease and the basal ganglia

The purpose of this review is to summarize emerging evidence that the neurobehavioral features of Lesch–Nyhan disease (LND), a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal ganglia. Affected individuals have severe motor disability described by prominent extrapyramidal features that are characteristic of dysfunction of the motor circuits of the basal ganglia. They also display disturbances of ocular motility, cognition, and behavioral control that may reflect disruption of other circuits of the basal ganglia. Though neuropathologic studies of autopsy specimens have revealed no obvious neuroanatomical abnormalities in LND, neurochemical studies have demonstrated 60–90% reductions in the dopamine content of the basal ganglia. In addition, recent PET studies have documented significant reductions in dopamine transporters and [¹⁸F]fluorodopa uptake in the basal ganglia. These findings support the proposal that many of the neurobehavioral features of LND might be related to dysfunction of the basal ganglia.     

Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy

Depression is frequently reported in epilepsy patients; however, mechanisms of co-morbidity between epilepsy and depression are poorly understood. An important mechanism of depression is disinhibition within the hypothalamo–pituitary–adrenocortical (HPA) axis. We examined the functional state of the HPA axis in a rat model of co-morbidity between temporal lobe epilepsy and depression. Epilepsy was accompanied by the interictal elevation of plasma corticosterone, and by the positively combined dexamethasone/corticotropin releasing hormone test. The extent of the HPA hyperactivity was independent of recurrent seizures, but positively correlated with the severity of depressive behavior. We suggest that the observed hyperactivity of the HPA axis may underlie co-morbidity between epilepsy and depression.     

Fenfluramine-Phentermine (Fen-Phen) and Seizures: Evidence for an Association

Fenfluramine–phentermine combination therapy (“fen–phen”) became a popular treatment for obesity in the 1990s. Although this treatment causes cardiac toxicity, use of these medications has not previously been associated with seizures. We report five cases with apparent association between use of fenfluramine–phentermine and occurrence of seizures. Three patients with a history of childhood-onset idiopathic generalized epilepsy in remission experienced a recrudescence of seizures following treatment with fenfluramine–phentermine. Two patients presented with new-onset seizures in midlife following use of fenfluramine–phentermine, and seizures persisted following discontinuation of this therapy. One of these patients restarted fenfluramine–phentermine months later, and experienced recurrent seizures. The nature of the association between fenfluramine–phentermine and seizures is uncertain from this preliminary report. There may be a specific association with idiopathic generalized epilepsies, which appeared to be overrepresented in this case series. An effect of fen–phen on seizure threshold appears most likely; however, an epileptogenic effect cannot be excluded.     

Deficits in Social Attribution Ability in Prader–Willi Syndrome

Prader–Willi syndrome (PWS), a genetic form of mental retardation, involves a myriad of physical and behavioral problems. Poor social adjustment has been reported, but the origin of this difficulty is unknown. The Social Attribution Task, a measure of one's ability to make appropriate social attributions from an ambiguous visual display [Klin (2000) Journal of Child Psychology and Psychiatry, 33(5) [861–876] was administered to study participants with PWS, participants with pervasive developmental disorder and an IQ matched comparison group with no known syndrome. The participants with PWS performed significantly more poorly than participants with comparable intellectual ability, and not significantly differently from the group of participants with a pervasive developmental disorder. Poor performance on this task by the PWS participants suggests an underlying difficulty interpreting social information that is presented visually, which may be a critical factor in the impairment in social functioning in this population.     

Social buffering of stress responses in nonhuman primates: Maternal regulation of the development of emotional regulatory brain circuits

Social buffering, the phenomenon by which the presence of a familiar individual reduces or even eliminates stress- and fear-induced responses, exists in different animal species and has been examined in the context of the mother–infant relationship, in addition to adults. Although it is a well-known effect, the biological mechanisms that underlie it as well as its developmental impact are not well understood. Here, we provide a review of evidence of social and maternal buffering of stress reactivity in nonhuman primates, and some data from our group suggesting that when the mother–infant relationship is disrupted, maternal buffering is impaired. This evidence underscores the critical role that maternal care plays for proper regulation and development of emotional and stress responses of primate infants. Disruptions of the parent–infant bond constitute early adverse experiences associated with increased risk for psychopathology. We will focus on infant maltreatment, a devastating experience not only for humans, but for nonhuman primates as well. Taking advantage of this naturalistic animal model of adverse maternal caregiving, we have shown that competent maternal care is critical for the development of healthy attachment, social behavior, and emotional and stress regulation, as well as of the neural circuits underlying these functions.     

Mutations in connexin 32: the molecular and biophysical bases for the X-linked form of Charcot–Marie–Tooth disease

The connexins are a family of homologous integral membrane proteins that form channels that provide a low resistance pathway for the transmission of electrical signals and the diffusion of small ions and non-electrolytes between coupled cells. Individuals carrying mutations in the gene encoding connexin 32 (Cx32), a gap junction protein expressed in the paranodal loops and Schmidt–Lantermann incisures of myelinating Schwann cells, develop a peripheral neuropathy — the X-linked form of Charcot–Marie–Tooth disease (CMTX). Over 160 different mutations in Cx32 associated with CMTX have been identified. Some mutations will lead to complete loss of function with no possibility of expression of functional channels. Some mutations in Cx32 lead to the abnormal accumulation of Cx32 proteins in the cytoplasm, particularly in the Golgi apparatus; CMTX may arise due to incorrect trafficking of Cx32 or to interference with trafficking of other proteins. On the other hand, many mutant forms of Cx32 can form functional channels. Some functional mutants have conductance voltage relationships that are disrupted to a degree which would lead to a substantial reduction in the available gap junction mediated communication pathway. Others have essentially normal steady-state g–V relations. In one of these cases (Ser26Leu), the only change introduced by the mutation is a reduction in the pore diameter from 7 Å for the wild-type channel to less than 3 Å for Ser26Leu. This reduction in pore diameter may restrict the passage of important signaling molecules. These findings suggest that in some, if not all cases of CMTX, loss of function of normal Cx32 is sufficient to cause CMTX.     

Development and evaluation of the Parkinson Psychosis Questionnaire

Objective Drug-induced psychosis is a frequent side–effect in the treatment of advanced Parkinson’s disease (PD). We sought to develop and evaluate a brief instrument for early recognition of drug–induced psychosis in PD. Methods We developed the “Parkinson Psychosis Questionnaire” (PPQ), which consists of screening questions for typical early signs and psychotic symptoms in PD and which quantifies the frequency and severity of four clinical categories—sleep disturbances, hallucinations/illusions, delusions and orientation. We performed an internal validation of the PPQ in 50 unselected patients with parkinsonism. The Brief Psychiatric Rating Scale (BPRS) and the “Structurized Clinical Interview” (SCID) for DSM IV were applied to the same patients as external references. Results Of 50 subjects, 49 suffered from idiopathic PD and one from probable MSA–P. Hoehn and Yahr stages in “on” ranged from 1.5 to 4. Sensitivity of the PPQ test for drug–induced psychosis according to SCID was 100 % (95 % CI: 73.5%, 100%); while specificity was 92.1 % (95% CI: 78.6%, 98.3 %). The PPQ severity score was highly correlated with BPRS. We derived a linear prediction formula, which transformed PPQ into BPRS scores. Conclusion The PPQ appears to be a suitable, and easily administered instrument for early diagnosis of druginduced psychosis in routine PD care. Whether the PPQ could also be a valuable tool for monitoring follow–up studies and therapeutic intervention trials remains to be tested.     

Sex,stress and steroids

The hypothalamo–pituitary–adrenal (HPA) axis plays a key role in the neuroendocrine response to stress and in maintaining physiological homoeostasis. However, stress that is chronic in nature can lead to HPA axis dysfunction and increase the risk for developing affective disorders, particularly if the stress is experienced during vulnerable periods in life. Sex differences in how the HPA axis responds to stress are well established, with females typically displaying heightened responses. The underlying cause of these sex differences is important to understand, as many neuropsychiatric disorders disproportionately affect females. Much research has provided evidence for gonadal sex steroids in underpinning sex differences in HPA axis responsivity; however, we suggest that neuroactive metabolites of these steroids also play a key role in the brain in mediating sex differences in HPA axis responses to stress. The relationship between neuroactive steroids and stress is complex. Acute stress rapidly increases neuroactive steroid production, which can in turn modulate activity of the HPA axis. However, under chronic stress conditions, stress can impact the brain's capacity to generate steroids, and this in turn has corollary effects on HPA axis function that may increase the propensity for psychopathology, given both HPA axis dysfunction and deficits in neuroactive steroids are implicated in affective disorders. Hence, here we review the evidence from animal and human studies for sex differences in the interactions between neuroactive steroids and the stress axis at various stages of life, under physiological and pathophysiological stress conditions and consider the implications for health and disease.     

Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam

Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal–medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1 mg alprazolam or placebo, respectively, 1 h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale “wakefulness” and increased ratings on the scale “good mood”, whereas ratings on scales assessing “state anxiety” or “agitation” were not affected.

In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.     

Social and lifestyle determinants of depression, anxiety, sleeping disorders and self-evaluated quality of life in Russia

Background The paper investigates social and lifestyle determinants of depression, anxiety, sleeping disorders and self-evaluated low quality of life in a population sample from the northwest of Russia.Methods Altogether 1968 men and 1737 women aged 18–90 years participated in a population-based study in Arkhangelsk, Russia, in the period 1999–2000. Depression, anxiety, and sleeping disorders were evaluated by a questionnaire with the formulations that have been previously used in population studies in Northern Norway. Alcohol dependence was diagnosed by the Alcohol Use Disorders Identification Test (AUDIT). Quality of life was evaluated by a 10-score Cantril Ladder. A score lower than five was defined as low quality of life. Relations between depression, anxiety, and sleeping disorders and socioeconomic/lifestyle factors were tested by logistic regression analyses.Results Women reported significantly higher prevalence of depression, anxiety and/or sleeping disorders than men: 68.7% and 32.3%, respectively. Depression, anxiety, sleeping disorders and low quality of life were positively associated with self-evaluation of nutrition as “poor”, low consumption of food, and with low-paid professional status. Depression and sleeping disorders were associated with smoking, hazardous level of alcohol drinking and alcohol dependence. Anxiety and low quality of life were associated with alcohol dependence. Depression, anxiety, sleeping disorders and low quality of life had a strong positive association with circulatory diseases and gastrointestinal diseases, the association remained significant after adjustment for smoking and alcohol variables.Conclusions A considerable part of the examined Russian population experienced depression, anxiety, and sleeping disorders that were strongly positively associated with poor nutrition, low socioeconomic status and adverse health behaviors (alcohol use disorders, smoking).     

Reaction of sleep–wakefulness cycle to stress is related to differences in hypothalamo–pituitary–adrenal axis reactivity in rat

Acute stress is known to modify sleep–wakefulness cycle, although with considerable interindividual differences. The origin of these individual differences remains unknown. One possibility is an involvement of the hypothalamo–pituitary–adrenal axis (HPA), as its reactivity is correlated with an individual's behavioral reactivity to stress, and it is known to influence the sleep–wakefulness cycle. The present study was designed to analyze relationships between natural differences in behavioral reactivity to stress associated with differential HPA reactivity and stress-induced changes in sleep–wakefulness. Adult rats were classified into two sub-groups according to their locomotor reactivity to a mild stress (novel environment): the `low responders (LR)' and the `high responders (HR)' animals exhibited different glucocorticoid secretion in response to stress. We show that immobilization stress induced an increase in wakefulness in LR animals and a decrease in wakefulness in HR animals. On the other hand, paradoxical sleep was increased in both LR and HR animals. Moreover, we observed that LR animals slept more than the HR animals, whereas the two groups had similar levels of paradoxical sleep. These results indicate that the response of the sleep–wakefulness cycle to stress is related to the behavioral reactivity to stress, in turn governed by the individual's reactivity of the HPA axis. The involvement of dopaminergic mechanisms is discussed.     

Functional sex differences (‘sexual diergism') of central nervous system cholinergic systems, vasopressin, and hypothalamic–pituitary–adrenal axis activity in mammals: a selective review

Sexual dimorphism of the mammalian central nervous system (CNS) has been widely documented. Morphological sex differences in brain areas underlie sex differences in function. To distinguish sex differences in physiological function from underlying sexual dimorphisms, we use the term, sexual diergism, to encompass differences in function between males and females. Whereas the influence of sex hormones on CNS morphological characteristics and function of the hypothalamic–pituitary–gonadal axis has been well-documented, little is known about sexual diergism of CNS control of the hypothalamic–pituitary–adrenal (HPA) axis. Many studies have been conducted on both men and women but have not reported comparisons between them, and many animal studies have used males or females, but not both. From a diergic standpoint, the CNS cholinergic system appears to be more responsive to stress and other stimuli in female than in male mammals; but from a dimorphic standpoint, it is anatomically larger, higher in cell density, and more stable with age in males than in females. Dimorphism often produces diergism, but age, hormones, environment and genetics contribute differentially. This review focuses on the sexual diergism of CNS cholinergic and vasopressinergic systems and their relationship to the HPA axis, with resulting implications for the study of behavior, disease, and therapeutics.     

Signs of rapidly progressive dementia in a case of intravascular lymphomatosis

Intravascular lymphomatosis (IVL), a rare type of non–Hodgkin’s lymphoma, is an uncommon cause of progressive dementia, usually followed by death within a few months of onset of clinical disease. Often this aggressive tumor is only diagnosed at autopsy, because of misleading clinical features mimicking a broad spectrum of syndromes and the absence of circulating lympoma cells in the blood, bone marrow or cerebrospinal fluid in many cases. Here we present IVL in a 78–year–old woman with findings leading to the clinical diagnosis of vascular dementia with sudden beginning and positive 14–3–3 protein in the CSF, commonly reported in Creutzfeldt–Jakob disease (CJD).     

The natural course of non–classic Pompe’s disease; a review of 225 published cases

Pompe’s disease is a neuromuscular disorder caused by deficiency of lysosomal acid α–glucosidase. Recombinant human α– glucosidase is under evaluation as therapeutic drug. In light of this development we studied the natural course of cases not fitting the definition of classic infantile Pompe’s disease. Our review of 109 reports including 225 cases shows a continuous spectrum of phenotypes. The onset of symptoms ranged from 0 to 71 years. Based on the available literature, no criteria to delineate clinical sub–types could be established.A common denominator of these cases is that first symptoms were related to or caused by muscle weakness. In general, patients with a later onset of symptoms seemed to have a better prognosis. Respiratory failure was the most frequent cause of death. CK, LDH, ASAT, ALAT and muscle glycogen levels were frequently but not always elevated. In most cases a muscle biopsy revealed lysosomal pathology, but normal muscle morphology does not exclude Pompe’s disease. In 10% of the cases in which the enzyme assay on leukocytes was used, a normal α–glucosidase activity was reported.Data on skeletal muscle strength and function, pulmonary function, disability, handicap and quality of life were insufficiently reported in the literature. Studies of non–classic Pompe’s disease should focus on these aspects, before enzyme replacement therapy becomes generally available.