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H M Young

Publications and source records attributed to H M Young.

At least 55 records · Page 3Linked to original sources

Inhibitory transmission to the longitudinal muscle of the mouse caecum is mediated largely by nitric oxide acting via soluble guanylyl cyclase.

In this work we describe a region of mouse intestine, the caecum, in which inhibitory transmission to the longitudinal muscle is predominantly due to nitric oxide. In the presence of muscarinic receptor blockade, electrical stimulation of intramural nerves in the longitudinal muscle of the mouse caecum evoked a relaxation. The relaxation was reduced to about 25% of the control amplitude by the nitric oxide synthase inhibitor L-NMMA (NG-methyl-L-arginine), but was unaffected by D-NMMA. In the presence of the nitric oxide scavenger oxyhaemoglobin, the relaxation was reduced to less than 10% of the control amplitude. In the circular muscle of the caecum and the longitudinal muscle of the ileum, colon and rectum, electrical field stimulation either evoked only small relaxations, or relaxations that were unaffected by L-NMMA. Nitric oxide synthase-containing neurons in the caecum were localized immunohistochemically using an antibody to neuronal nitric oxide synthase or with NADPH diaphorase histochemistry. Reactive nerve cell bodies were observed in the myenteric plexus, and varicose nerve fibres were present in the longitudinal and circular muscle layers of the caecum. The transduction mechanism of the nitric oxide-mediated relaxation in the longitudinal muscle of the caecum was examined using ODQ (1 H-[1,2,4]oxadiazolo[4,3,-alpha-]quinoxalin-1-one), a selective inhibitor of soluble guanylyl cyclase. ODQ abolished the relaxations induced by applied sodium nitroprusside (0.01-1 mM) and reduced the relaxation induced by electrical stimulation to about 40% of control values. However, ODQ reduced the relaxations induced by electrical stimulation to a lesser extent than L-NMMA. Hence, although the relaxation in this tissue mediated by NO (or an NO-related substance) is largely via soluble guanylyl cyclase, an action of NO on other targets cannot be ruled out.

Animals↗

Localisation of NK1 receptor immunoreactivity to neurons and interstitial cells of the guinea-pig gastrointestinal tract.

Tachykinins, including substance P, neurokinin A, and neuropeptides K and gama, are expressed widely in the peripheral nervous system where they affect smooth muscle contraction, exocrine gland secretion, vascular permeability, and neurotransmission. Substance P, the preferred ligand for the NK1 receptor, is found in high concentrations in the enteric nervous system. In the present study, the localisation and distribution of the NK1 receptor was studied throughout the gastrointestinal tract of the guinea-pig by using a polyclonal antiserum raised against the C-terminal 15 amino acids of the NK1 receptor. Co-localisation with other neuronal markers was examined in the ileum. Nerve cell bodies reactive for the NK1 receptor were found in the myenteric plexus of all regions and the submucous plexus of the small and large intestines. In the small intestine, the interstitial cells of Cajal were also immunoreactive. Immunoreactivity was largely confined to cell surfaces. Almost all immunoreactive myenteric nerve cells had Dogiel type I morphology, and most of these were immunoreactive for nitric oxide synthase, a transmitter of inhibitory neurons to the muscle and of descending interneurons. Neuropeptide Y-containing secretomotor neurons in the submucous and myenteric plexuses also exhibited NK1 receptor immunoreactivity. NK1 receptors were present on a minority of tachykinin immunoreactive neurons of submucous ganglia. The results suggest that receptors on the longitudinal muscle might not be conventional NK1 receptors, that excitation of the circular muscle of the ileum is indirect, perhaps via the interstitial cells of Cajal, and that enteric inhibitory neurons may be excited via NK1 receptors.

Amino Acid Sequence↗

Chemical coding of neurons in the myenteric plexus and external muscle of the small and large intestine of the mouse.

Immunohistochemical techniques were used to examine the presence and co-localisation of a range of putative neurotransmitters and other neuronal markers in the myenteric plexus of the small and large intestine of the mouse. Distinct sub-populations of myenteric neurons were identified, based on the combinations of substances they contained and the distribution of their fibres. In the small intestine, there were two major classes of circular muscle motor neurons; one class was characterised by the presence of nitric oxide synthase, vasoactive intestinal peptide plus neuropeptide Y (NOS/VIP/NPY), and the second class contained calretinin plus substance P (CalR/SP). There were seven classes of neurons that innervated myenteric ganglia; these contained nos, vip, nos/vip, npy, calr/calbindin (calb), sp or 5-ht. In the large intestine, there were five major classes of motor neurons that contained nos, nos/vip, gaba, sp, or calr/sp, and seven major classes of neurons that innervated myenteric ganglia and contained nos, vip, calr/calb, calr, sp, gaba or 5-ht. Although some aspects of the patterns of co-localisation are similar to those in other species, this study re-inforces recent analyses that indicate significant species differences in neurochemical patterns in the enteric neurons of different species.

Animals↗

Ultrastructural examination of the targets of serotonin-immunoreactive descending interneurons in the guinea pig small intestine.

Serotonin neurons are descending interneurons in the myenteric plexus of the guinea pig small intestine. Preembedding single- and double-label immunocytochemistries at the ultrastructural level were used to identify the targets of these serotonin interneurons. Serial ultrathin sections were taken through a myenteric ganglion that had been processed for serotonin immunocytochemistry. The ganglion contained the cell bodies of 69 neurons, including 2 serotonin neurons and 6 neurons with the ultrastructural features of Dogiel type II cells. For each cell body in the ganglion, the number of serotonin inputs (synapses and close contacts) was determined. About 59% of the cell bodies did not receive any serotonin inputs. The most abundant serotonin terminals were related to two targets: other serotonin descending interneurons and a population of neurons with Dogiel type I morphology, but whose neurochemistry and function is unknown. The serotonin inputs to the serotonin cell bodies were located predominantly on the lamellar dendrites. Each of the Dogiel type II neurons received 3 or fewer serotonin inputs, and none of the serotonin inputs to Dogiel type II neurons formed a synapse. Overall, about 40% of the serotonin inputs formed synapses. The serotonin inputs to neurons that received many serotonin inputs were more likely to show synaptic specializations than serotonin inputs to neurons that received few serotonin inputs. Inhibitory motor neurons contain nitric oxide synthase (NOS). At the light microscope level, serotonin nerve fibers do not form dense pericellular baskets around NOS cell bodies. To determine whether there are serotonin inputs to NOS neurons, serial ultrathin sections were taken through a myenteric ganglion that had been processed for preembedding double-label immunocytochemistry, in which the NOS neurons were labeled with peroxidase-diaminobenzidine and the serotonin neurons with silver-intensified 1 nm gold. Only 1 out of 9 NOS cells examined in serial section received more than 5 serotonin inputs. The results suggest that, in the guinea pig small intestine, the serotonin descending interneurons are not an essential element of the descending inhibitory reflex.

Animals↗

Distribution of pituitary adenylyl cyclase activating peptide (PACAP) immunoreactivity in neurons of the guinea-pig digestive tract and their projections in the ileum and colon.

Pituitary adenylyl cyclase activating peptide (PACAP) is a novel hypothalamic peptide that is widely distributed in neurons, including those of the gastrointestinal tract. In this study, a polyclonal antiserum directed against PACAP-27 was used to investigate the localisation of PACAP throughout the gut and to determine the projections of PACAP-immunoreactive (IR) neurons in the guinea-pig small and large intestines. PACAP-IR fibres were seen in the myenteric and submucous plexuses, in the longitudinal and circular muscle layers and around blood vessels of the submucosa throughout the gut. In both the small and large intestine, PACAP-IR cell bodies, most with Dogiel type-I morphology, were seen in the myenteric ganglia following colchicine treatment. Lesion studies (myotomy and myectomy operations) revealed that PACAP-IR interneurons projected anally in the ileum and colon. Myectomy operations resulted in a loss of PACAP-IR fibres in the circular muscle under the operation, whereas PACAP-IR fibres remained in the submucosa and around blood vessels. Following extrinsic denervation of the ileum, the number of PACAP-IR fibres in the submucosal ganglia and around blood vessels decreased. This suggests that a portion of PACAP-IR fibres supplying the submucosal ganglia and blood vessels have an extrinsic source. To investigate this, immunohistochemical studies were performed on sympathetic and dorsal root ganglia. Numerous reactive cells were seen in the dorsal root ganglia, but none was seen in sympathetic pre- or paravertebral ganglia.

Animals↗

Do vasoactive intestinal peptide (VIP)- and nitric oxide synthase-immunoreactive terminals synapse exclusively with VIP cell bodies in the submucous plexus of the guinea-pig ileum?

In the submucous plexus of the guinea-pig ileum, previous light-microscopic studies have revealed that vasoactive intestinal peptide (VIP)-immunoreactive and nitric oxide synthase (NOS)-immunoreactive terminals are found predominantly in association with VIP-immunoreactive nerve cell bodies. In this study, double-label immunohistochemistry at the light-microscopic level demonstrated co-localization of NOS-immunoreactivity and VIP-immunoreactivity in axon terminals in submucous ganglia. About 90% of nerve fibres with NOS-immunoreactivity or VIP-immunoreactivity were immunoreactive for both antigens; only about 10% of labelled varicosities contained only NOS-immunoreactivity or VIP-immunoreactivity. The VIP/NOS varicosities were more often seen in the central parts of the ganglia, close to the VIP-immunoreactive cell bodies. Ultrastructural immunocytochemistry with antibodies to VIP was used to determine if NOS/VIP terminals synapse exclusively with VIP-immunoreactive nerve cell bodies. We examined the targets of VIP-immunoreactive boutons in two submucous ganglia from different animals. Serial ultrathin sections were taken through the ganglia after they had been processed for VIP immunocytochemistry. For each cell body, the number of VIP inputs (synapses and close contacts) was determined. The number of VIP-immunoreactive synapses received by the cell bodies of submucous neurons varied from 0-4 and the number of VIP-immunoreactive close contacts varied from 3-10. There was no significant difference between VIP-immunoreactive nerve cell bodies and non-VIP nerve cell bodies in the number of VIP-immunoreactive synapses and close contacts they received. Thus, the implication from light microscopy that NOS/VIP terminals end predominantly on VIP nerve cells was not vindicated by electron microscopy.

Animals↗

Analysis of connections between nitric oxide synthase neurons in the myenteric plexus of the guinea-pig small intestine.

In the myenteric plexus of the guinea-pig ileum, a sub-population of descending interneurons contains nitric oxide synthase. Final neurons in descending motility pathways, inhibitory circular muscle motor neurons, also contain nitric oxide synthase. In this study we used ultrastructural immunocytochemistry to determine whether nitric oxide synthase descending interneurons provide inputs to all nitric oxide synthase neurons. The presence of nitric oxide synthase inputs to 35 nitric oxide synthase nerve cells from three animals was examined. Nine nerve cells from one ganglion were studied in serial section. Every nerve cell received inputs (close contacts and synapses) from nitric oxide synthase terminals. The number of inputs to the nine serially sectioned neurons ranged from 13 to 45. The inputs were found in about equal numbers on the cell bodies and the dendrites. There was no significant correlation between the size of nitric oxide synthase neurons and the number of nitric oxide synthase inputs they received. There was also no correlation between the number of nitric oxide synthase inputs and the number of 5-hydroxytryptamine inputs (determined in a previous study) received by nitric oxide synthase neurons. Random sections through an additional 26 nitric oxide synthase neurons (seven in the same ganglion and 19 from another two myenteric ganglia from different animals) were examined and nitric oxide synthase synapses and close contacts were observed on each neuron. Nitric oxide synthase interneurons and motor neurons are morphologically indistinguishable.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

Nitric oxide synthase is localized predominantly in the Golgi apparatus and cytoplasmic vesicles of vascular endothelial cells.

The localization of nitric oxide synthase (NOS) in vascular endothelial cells of submucosal blood vessels from the guinea-pig ileum was examined using NADPH diaphorase histochemistry at the light microscopic level, and endothelial NOS immunohistochemistry at the light and electron microscopic level. The pattern of staining observed following NADPH diaphorase histochemistry and endothelial NOS immunohistochemistry was identical. Endothelial cells of the arterioles, capillaries and venules showed small patches of intense, perinuclear staining. Under the electron microscope, endothelial NOS immunoreactivity was found predominantly in association with the Golgi apparatus and with the membranes of some vesicles. Small regions of the plasma membrane and the rough endoplasmic reticulum also showed some immunoreactivity. The presence of NOS in the Golgi apparatus and in vesicles raises the possibility that NOS may be exteriorized by endothelial cells, and hence that nitric oxide is synthesized extracellularly.

Animals↗

Plurichemical transmission and chemical coding of neurons in the digestive tract.

The enteric nervous system contains neurons with well-defined functions. However, when neurons of the same function are examined in different regions or species, they are found to show subtle differences in their pharmacologies of transmission and different chemical coding. Individual enteric neurons use more than one transmitter, i.e., transmission is plurichemical. For example, enteric inhibitory neurons have three or more primary transmitters, including nitric oxide, vasoactive intestinal peptide, and possibly adenosine triphosphate and pituitary adenylyl cyclase activating peptide. Primary transmitters are highly conserved, although their relative roles vary considerably between gut regions. Multiple substances, including transmitters and their synthesizing enzymes and nontransmitters (such as neurofilament proteins), provide neurons with a chemical coding through which their functions and projections can be identified. Although equivalent neurons in different regions have the same primary transmitters, other chemical markers differ substantially. Caution must be taken in extrapolating pharmacological and neurochemical observations between species or even between regions in the one species. On the other hand, careful interregion and interspecies comparisons lead to an understanding of the features of enteric neurons that are highly conserved and can be used in valid extrapolation.

Animals↗

Nitric oxide synthase in the enteric nervous system of the guinea-pig: a quantitative description.

The distribution and abundance of nitric oxide synthase (NOS)-containing neurons and their terminals in the gastrointestinal tract of the guinea-pig were examined in detail using NADPH diaphorase histochemistry and NOS immunohistochemistry. NOS-containing cell bodies were found in the myenteric plexus throughout the gastrointestinal tract and in the submucous plexus of the stomach, colon and rectum. NOS-containing neurons comprised between 12% (in the duodenum) and 54% (in the esophagus) of total myenteric neurons. In the ileum, NOS neurons represented 19% of total myenteric neurons. Most of the NOS neurons throughout the gastrointestinal tract possessed lamellar dendrites and a single axon. NOS-containing terminals were abundant in the circular muscle, including that of the sphincters, but were rare in the longitudinal muscle, except for the taeniae of the caecum. The muscularis mucosae of the esophagus, stomach, colon and rectum received a medium to dense innervation by NOS terminals. Within myenteric ganglia, NOS-containing terminals were extremely sparse in the esophagus, stomach and duodenum, common in the ileum and distal colon and extremely dense in the proximal colon and rectum. The submucous plexus in the ileum and large intestine contained a sparse plexus of NOS-containing terminals. NOS terminals were not observed in the mucosa of any region. We conclude that throughout the gastrointestinal tract of the guinea-pig, NOS neurons are inhibitory motor neurons to the circular muscle; in the ileum and large intestine, NOS neurons may also function as interneurons.

Amino Acid Oxidoreductases↗

Co-localization of GABA- and tyrosine hydroxylase-like immunoreactivities in amacrine cells of the rabbit retina.

Previous studies have shown that many of the tyrosine hydroxylase-immunoreactive (TH-IR) amacrine cells in the retina of mammals also show GABA-like immunoreactivity (GABA-IR). However such co-localization has yet to be demonstrated in the rabbit retina. In this study the proportion of TH-IR amacrine cells that show GABA-IR has been determined in the retina of the cat, rat and rabbit following fixation with 4% paraformaldehyde plus varying concentrations of glutaraldehyde. In the retina of the cat and rat, most of the TH-IR amacrine cells showed GABA-IR following fixation using low concentrations (0.01 or 0.1%) of glutaraldehyde. However in the rabbit retina very few of the TH-IR amacrine cells showed GABA-IR unless the glutaraldehyde concentration in the fixative was 0.5% or greater. The results suggest that the dopaminergic amacrine cells in the rabbit retina contain only very low levels of GABA, which are close to the detection limit of the antibody.

Animals↗

Combined intracellular injection of Neurobiotin and pre-embedding immunocytochemistry using silver-intensified gold probes in myenteric neurons.

We have developed methods to examine the neurochemistry of synaptic inputs to individual myenteric neurons labeled by dye injection through intracellular recording electrodes. Myenteric neurons of the guinea-pig ileum were filled with Neurobiotin, fixed, washed in 50% ethanol, exposed to sodium cyanoborohydride, incubated in avidin-biotin-horseradish peroxidase and incubated in antisera to calretinin or calbindin. The Neurobiotin-filled cells were revealed using the diaminobenzidine (DAB) reaction. The tissue was examined at the light microscope level to determine the morphology and projections of the Neurobiotin-filled neurons, and then incubated in 1 nm gold-labeled secondary antibodies. Following osmication, the gold probes were silver-intensified and the tissue embedded flat in resin. The tissue was re-examined at the light microscope level. Neurons containing a DAB reaction product could be distinguished from neurons containing a silver-intensified gold reaction product using oblique or epipolarized illumination. Ultrathin sections were taken through the injected neurons and examined. At the ultrastructural level, Neurobiotin-filled cell bodies and their processes (labeled with DAB) were easily distinguished from the structures labeled by silver-intensified gold. Gold-labeled terminals of enteric interneurons made synapses and close contacts with Neurobiotin-filled nerve cell bodies and their processes. This technique is valuable for the neurochemical identification of synaptic inputs to morphologically and/or functionally characterized myenteric neurons and could be easily applied to other preparations, such as brain slices.

Animals↗

Nitric oxide synthase in neurons of the gastrointestinal tract of an avian species, Coturnix coturnix.

The distribution of reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase staining and its colocalisation with nitric oxide synthase immunoreactivity was examined in neurons of the quail gastrointestinal tract. Immunoreactivity and enzyme activity were found in identical populations of neurons. Nitric oxide synthase activity was present in 30-40% of myenteric nerve cells in each region. Numerous reactive cells were also in the submucous plexus and many positive nerve fibres innervated the muscle. In the small intestine, some of the fibres innervating the circular muscle formed a deep muscular plexus and in the large intestine there was a submuscular plexus. Nerve fibres formed baskets around nerve cells of myenteric and submucous ganglia. Intramural arterioles were innervated, most prominently in the oesophagus and stomach. Very few fibres innervated the mucosa, except for some oesophageal glands and the core of villi in the cloaca. It is concluded that nitric oxide is probably involved in transmission to muscle of the avian intestine, as it is in mammals, and that it is probably also produced at neuroneuronal and neurovascular junctions.

Amino Acid Oxidoreductases↗

Using social support to promote breast self-examination performance.

PURPOSE/OBJECTIVES: To describe support strategies used by selected partners and peer partners in a study examining the effects of support on adherence to breast self-examination (BSE). DESIGN: Experimental. SETTING: Large health maintenance organization in the Pacific Northwest. SAMPLE: 175 women (mean age of 61 years) and 53 partners selected by one of the study groups. METHODS: Subjects were assigned to one of three groups: selected-partner support, peer-partner support, and no support. All groups attended a BSE group instructional session consisting of group discussion, a BSE slide presentation, and one-on-one practice of BSE. Members of the selected-partner and peer-partner support groups wrote contracts to provide supportive activities over the subsequent six months to ensure BSE performance. At 6 and 12 months, all participants completed a questionnaire to determine BSE adherence and perceptions of the support experience. MAIN RESEARCH VARIABLES: Performance of BSE, supportive activities provided, and perceptions of support. FINDINGS: Selected partner/subject dyads identified nearly three times the total number of support strategies (147 versus 55) and had greater variability in the types of support categories developed. These subjects had significantly more contact from their support partners, were more comfortable with their partners, and indicated greater likelihood of continuing the supportive contact after the study period. CONCLUSIONS: Selected partners demonstrated more involvement and commitment in fulfilling their supportive role than did peer partners. Further research is needed that will allow more reciprocity between selected partner and subject. IMPLICATIONS FOR NURSING PRACTICE: Nurses can encourage women to recruit supportive partners who help them incorporate BSE into a health maintenance regimen in a consistent fashion. Partners can benefit from some structured orientation to the support process.

Adult↗

Total numbers of neurons in myenteric ganglia of the guinea-pig small intestine.

Two techniques that are thought to stain all of the neurons in the myenteric ganglia of the intestine are NADH diaphorase histochemistry and immunohistochemistry using a "nerve cell body" antiserum. However, this assumption has never been directly verified. In the present study myenteric ganglia of the guinea-pig ileum were prepared as whole-mounts and stained with either of these techniques. All nerve cells that could be identified in the whole-mounts were counted. The whole-mounts were then embedded flat in resin and serially sectioned at 1 micron. Nerve cells were identified and counted from the serial sections, and the data compared to those obtained from the whole-mounts. NADH diaphorase histochemistry did not reveal all the neurons at incubation times that gave selective staining. In contrast, "nerve cell body" antiserum stained the entire neuronal population. To determine the total number of nerve cell bodies/ganglion and the proportion of nerve cell bodies with calbindin immunoreactivity, whole-mounts that had been processed for calbindin immunohistochemistry were serially sectioned and reconstructed. The total number of neurons per myenteric ganglion was 105 +/- 10 (SE). Calbindin-immunoreactive neurons comprised about 20% of the myenteric neurons, which is considerably less than previous estimates, because previously the total population has been underestimated. The spatial density of myenteric neurons in the undistended ileum of the guinea-pig is 17,300 nerve cells/cm2.

Animals↗

Nitric oxide targets in the guinea-pig intestine identified by induction of cyclic GMP immunoreactivity.

The immunohistochemical localization of cyclic GMP was used to determine potential physiological sites of action of nitric oxide in the guinea-pig small intestine and colon. In control tissue, cyclic GMP-immunoreactivity was observed only in macrophages, whose identity was confirmed by double-label experiments using either F4/80, a macrophage-specific antibody, or fluorescein isothiocyanate-labelled dextran injected intravenously. Following exposure to the nitric oxide donor, sodium nitroprusside, cyclic GMP-immunoreactivity was induced in subpopulations of neurons in the myenteric and submucosal plexuses of the ileum and colon. In the colon, cyclic GMP-immunoreactivity was induced in 5-10% of myenteric neurons. The cyclic GMP-immunoreactive neurons did not contain nitric oxide synthase. In the ileum, cyclic GMP-immunoreactive neurons comprised about 2% of myenteric neurons and 40% of submucosal neurons; these cyclic GMP-immunoreactive neurons were also immunoreactive for vasoactive intestinal peptide, but they did not contain nitric oxide synthase. Interstitial cells between the mesothelium and the longitudinal muscle layer, vascular smooth muscle and vascular pericytes also showed sodium nitroprusside-induced cyclic GMP-immunoreactivity. The interstitial cells of Cajal at the inner surface of the circular muscle layer and the smooth muscle cells of the circular and longitudinal muscle layers showed increases in cyclic GMP-immunoreactivity that varied in extent from animal to animal. The results suggest that nitric oxide could act at several sites in the intestine through the stimulation of guanylyl cyclase.

1-Methyl-3-isobutylxanthine↗

Does expressed emotion in spouses predict subsequent problems among care recipients with Alzheimer's disease?

Researchers have observed that Expressed Emotion (i.e., criticism; EE) in caregivers is predictive of poorer functioning in psychiatric care recipients over time. Few studies have examined, however, whether EE has predictive validity for the decline of care recipients with a clearly defined organic illness such as Alzheimer's disease. This study evaluated whether Alzheimer's disease care recipient problems [in cognition, activities of daily living (ADLs), and negative behaviors] were predicted longitudinally by caregiver EE. As hypothesized, caregiver EE was not predictive of care recipient cognitive or ADL decline; however, data suggested that EE was predictive of increased negative behaviors over time. The specific predictions of negative care recipient behaviors, and not care recipient cognitive/ADL decline, suggest that the former outcomes may be determined by environmental factors as well as the organicity of the disease. These data may be important because researchers have reported that caregivers are more distressed by negative care recipient behaviors than by care recipient cognitive/ADL decline.

Activities of Daily Living↗

Development and psychometric evaluation of the Resilience Scale.

This study describes the development and initial psychometric evaluation of the 25-item Resilience Scale (RS) in a sample of 810 community-dwelling older adults. Principal components factor analysis of the RS was conducted followed by oblimin rotation indicating that the factor structure represented two factors (Personal Competence and Acceptance of Self and Life). Positive correlations with adaptational outcomes (physical health, morale, and life satisfaction) and a negative correlation with depression supported concurrent validity of the RS. The results of this study support the internal consistency reliability and concurrent validity of the RS as an instrument to measure resilience.

Adaptation, Psychological↗