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Nrsn1-Smarcc1 Coupling Regulates Neural Stem Cell Differentiation and Chronic-phase Recovery After Ischemic Stroke.

Stroke remains a leading cause of long-term neurological disability worldwide, largely due to irreversible neuronal loss and the limited regenerative capacity of the adult mammalian brain. Neural stem cells (NSCs) in the adult brain possess the potential to generate new neurons after injury, yet the molecular mechanisms regulating their neuronal differentiation following ischemic insult remain incompletely understood. Here, integrating single-cell multi-omics analyses with spatial transcriptomics, we systematically delineated cell type-specific spatiotemporal dynamics in the striatum of a mouse model of ischemia-reperfusion injury. We identified Neurensin 1 (Nrsn1) as a gene markedly upregulated during NSC-derived neuronal differentiation in the recovery phase. Mechanistically, Foxa2 directly activates Nrsn1 transcription, whereas Nrsn1 promotes neuronal differentiation by facilitating the nuclear translocation of the chromatin-remodeling factor Smarcc1 in vitro. In vivo, both endogenous NSCs and transplanted NSCs overexpressing Nrsn1 significantly enhanced neuronal regeneration and improved functional recovery in mice subjected to middle cerebral artery occlusion and reperfusion (MCAO/R). Collectively, these findings identify Nrsn1 as a key regulator of NSC neuronal differentiation and uncover a Nrsn1-Smarcc1 coupling mechanism that promotes neural regeneration after ischemic brain injury, highlighting a potential molecular target for strategies aimed at enhancing post-stroke recovery.

Foxa2

Epidermal Langerhans cells undergo mitosis during the early recovery phase after ultraviolet-B irradiation.

We studied the recovery phase of immune response-associated (Ia)-positive or ATPase-positive epidermal Langerhans cells (ELCs) after ultraviolet B (UVB)-induced depletion by using mouse ear epidermal sheets. An area 3 mm in diameter was irradiated with 300 nm UVB light (40 mJ/cm2). A time sequence study was carried out to 56 days. During this period the Ia-positive ELC population increased stepwise, i.e., first a rapid increase between day 7 and day 14, which we called the early recovery phase, and next a gradual increase between day 42 and day 56, which we called the late recovery phase. During the early recovery phase, we found polymorphous ELCs in the irradiated area which were giant or normal in size, dendritic or round in shape, and single or paired in distribution. Electron microscopy revealed some of round and some of paired ATPase-positive ELCs to be in metaphase or telophase of mitotic division. Within the entire observation period of our study, there was no evidence suggesting migration of ELCs from hair follicles or from the nonirradiated epidermis. These findings indicated that mitosis of ELCs contribute to their repopulation during the early recovery phase.

Animals

Micropuncture studies of the recovery phase of myohemoglobinuric acute renal failure in the rat.

Micropuncture studies of the recovery phase of glycerol-induced myohemoglobinuric acute renal failure were performed in rats whose blood urea nitrogen (BUN) had fallen at least 20% below its peak value. The glomerular filtration rate (GFR) of individual nephrons in a single kidney in the recovery period generally either was in the normal range or minimal. Each animal's BUN concentration at the time of the study was inversely related to the proportion of functioning surface nephrons, but did not correlate with individual nephron GFR values. Proximal tubule fractional water absorption was significantly depressed as manifested by both depressed inulin (TF/P) values and supernormal volumes of collections, a finding which, in the absence of a urea-induced osmotic diuresis, suggests impaired sodium transport by the damaged nephron. The mean proximal tubule hydrostatic pressure in recovery was normal and there was little variation in pressure among functioning nephrons. It is concluded that recovery from this model of acute renal failure reflects the progressive recruitment of increasing numbers of functioning nephrons. The recovery of individual nephron glomerular filtration, once begun, was rapid and complete. No evidence could be adduced that the gradual return of renal function towards normal reflects a slow release of tubular obstruction or repair of disrupted tubular epithelium. Rather, recovery appeared to be directly attributable to the return of an adequate effective glomerular filtration pressure. Significant limitation in proximal tubule water absorption persisted after individual nephron GFR had returned to normal or supernormal values in this model of experimental acute renal failure in the rat, a finding which readily accounts for the diuresis associated with the recovery phase of this syndrome.

Acute Kidney Injury

Transcriptomic analysis reveals key molecular signatures across recovery phases of hemorrhagic fever with renal syndrome.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS), a life-threatening zoonosis caused by hantavirus, poses significant mortality risks and lacks specific treatments. This study aimed to delineate the transcriptomic alterations during the recovery phases of HFRS. METHODS: RNA sequencing was employed to analyze the transcriptomic alterations in peripheral blood mononuclear cells from HFRS patients across the oliguric phase (OP), diuretic phase (DP), and convalescent phase (CP). Twelve differentially expressed genes (DEGs) were validated using quantitative real-time PCR in larger sample sets. RESULTS: Our analysis revealed pronounced transcriptomic differences between DP and OP, with 38 DEGs showing consistent expression changes across all three phases. Notably, immune checkpoint genes like CD83 and NR4A1 demonstrated a monotonic increase, in contrast to a monotonic decrease observed in antiviral and immunomodulatory genes, including IFI27 and RNASE2. Furthermore, this research elucidates a sustained attenuation of immune responses across three phases, alongside an upregulation of pathways related to tissue repair and regeneration. CONCLUSION: Our research reveals the transcriptomic shifts during the recovery phases of HFRS, illuminating key genes and pathways that may serve as biomarkers for disease progression and recovery.

Hemorrhagic Fever with Renal Syndrome

Convulsive thresholds in mice during the recovery phase from anaesthesia induced by propofol, thiopentone, methohexitone and etomidate.

1. Convulsive thresholds were measured with intravenous pentylenetetrazol in mice during the recovery phase after intravenous anaesthetic doses of propofol (10 and 20 mg kg-1), thiopentone (30 mg kg-1), methohexitone (10 mg kg-1), and etomidate 3 mg kg-1). 2. The convulsive threshold rose after each agent, indicating an anticonvulsant action for all the drugs tested; this declined to control values with initial half times of: 1.56 min (propofol 10 mg kg-1); 1.03 min (propofol 20 mg kg-1): 1.02 min (methohexitone); 3.35 min (etomidate); 13.7 min (thiopentone). 3. At no time during the recovery phase of any agent did the convulsive threshold fall below control values, which might indicate an epileptogenic effect of the drug. 4. The threshold was depressed below control values by intravenous administration of Ro 15-4513, a partial inverse agonist at the benzodiazepine receptor, thus indicating the ability of this pentylenetetrazol test to demonstrate a proconvulsant effect. 5. We conclude that the abnormal movements or convulsions associated with recovery from anaesthesia with short-acting intravenous anaesthetics may not be the result of an intrinsic proconvulsant action of the drugs.

Anesthesia, Intravenous

Permissive role of thyrotropin on thyroid radioiodine uptake during the recovery phase of subacute thyroiditis.

Serial measurements of serum triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), and 4-hr thyroidal 131I uptake were carried out in nine patients with subacute thyroiditis. In the acute phase, suppressed TSH and 131I uptake were observed simultaneously with the elevations of T3 and T4. Thyrotropin-releasing hormone (TRH) failed to increase TSH in all patients studied. The mean value of an increment in serum TSH was only 1.8 muU/ml during the recovery phase when 131I uptake was normal or hypernormal. In addition, an elevated 131I uptake was not necessarily associated with an immediate increase in the serum T3 and T4. These observations suggest that the resumption of the iodide pump may be more important than an increment in TSH in producing normal or hypernormal 131I uptake during the recovery phase. There appears to be a dissociation between the reestablishment of 131I uptake and the resumption of the mechanism of hormonal synthesis and secretion in the thyroid.

Adult

Recovery-phase patterns of ST segment depression in the heart rate domain. Identification of coronary artery disease by the rate-recovery loop.

Although the time course of ST segment depression after exercise has been related to the presence and severity of coronary artery disease, recovery-phase patterns of ST segment depression with reference to changing heart rate have not been quantified. We have found distinct recovery loop patterns of ST segment depression that distinguish subjects without coronary disease from patients with coronary artery disease when ST segment depression is examined in the heart rate domain. Continuous plots of ST segment depression and heart rate were constructed throughout treadmill exercise and recovery in 100 clinically normal subjects, in 124 patients with coronary artery disease proven by catheterization, and in 17 patients with no significant coronary disease at catheterization. Among clinically normal subjects, 95% (95 of 100) had normal (clockwise) rate-recovery loops, and 5% (five of 100) had abnormal (counterclockwise) rate-recovery loops. In these normal subjects, the resulting 95% specificity of a normal rate-recovery loop was similar to the 93% (93 of 100) specificity of standard end-exercise ST segment depression criteria. Among patients with coronary disease proven by angiography, 93% (115 of 124) had abnormal (counterclockwise) rate-recovery loops, and 7% (nine of 124) had normal rate-recovery loops. In contrast was the significantly lower 74% (92 of 124) sensitivity of standard ST segment criteria (p less than 0.001 vs. the rate-recovery loop). Specificity of a normal rate-recovery loop (71%, 12 of 17) and standard ST segment depression criteria (71%, 12 of 17) were similar in the patients with normal coronary arteries at angiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult

Persistent normal anion gap acidosis in the recovery phase of diabetic ketoacidosis.

Diabetic ketoacidosis is associated with an increased anion gap but its recovery phase may be complicated by hyperchloraemic acidosis with a normal anion gap. We report a case where this complication developed. There was a delayed return to normal acid-balance, possibly aggravated by administration of hyperchloraemic fluids, and the true diagnosis was overlooked. Measurement of the anion gap remains an important part of the assessment of diabetic acid-base disturbances.

Acid-Base Equilibrium

Comparison of haematological recovery times and supportive care requirements of autologous recovery phase peripheral blood stem cell transplants, autologous bone marrow transplants and allogeneic bone marrow transplants.

The haematological recovery time, infection rate and supportive care requirements of patients receiving recovery phase autologous peripheral blood stem cell transplants (APBSCT) (n = 38), autologous bone marrow transplants (autoBMT) (n = 13) and allogeneic bone marrow transplants (alloBMT) (n = 14) were compared with respect to the time post-transplant to reach 0.1, 0.5 and 2.0 x 10(9) neutrophils/l and 50 and 150 x 10(9) platelets/l, the length of hospitalization, fever and antibiotic use, the incidence of documented infection and the number of red cell and platelet transfusions. The APBSCT group had a significantly more rapid recovery of neutrophils and platelets and their supportive care requirements were significantly less than the autoBMT and the alloBMT groups. There was no difference between the latter two groups. The most significant variables contributing to the differences in haematological recovery times were the granulocyte-macrophage progenitor (CFU-GM) dose infused and, to a lesser extent, patient age. The APBSCT group received a higher CFU-GM dose of 87 +/- 12 x 10(4)/kg BW compared with 12 +/- 5 and 17 +/- 3 x 10(4)/kg BW in the autoBMT and the alloBMT groups, respectively (p = 0.0001). Patient age showed a negative correlation with the rate of recovery because the APBSCT group, which recovered faster was also older (48 +/- 2 years, compared with 33 +/- 3 and 31 +/- 2, respectively, p = 0.0001). On multivariate analysis, CFU-GM dose was the only variable to show a significant correlation with all the haematological recovery endpoints studied in these 65 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent

Hyperchloremic acidosis during the recovery phase of diabetic ketosis.

We have studied 35 patients to find the occurrence of hyperchloremic acidosis during the recovery phase of diabetic ketoacidosis. At admission the patients had typical normochloremic acidosis, with increased anion gap exactly balancing decreased serum bicarbonate. In contrast, in 18 patients with phenformin-induced lactic acidosis, the increase in anion gap at admission was much greater than the decrease in bicarbonate. The difference between lactic acidosis and ketoacidosis may be explained by a slower rate of excretion of lactate than of ketone anions. After the patients with ketoacidosis were treated, the acidosis became predominantly hyperchloremic with normal anion gap. Failure to normalize serum bicarbonate is attributed to excretion of ketone anions in the urine.

Adolescent

Study of the pharmacokinetics and pharmacodynamic activity of almitrine bismesylate in infants during the recovery phase following bronchopulmonary dysplasia.

The efficacy and pharmacokinetics of almitrine bismesylate were studied in 6 infants (age 2.5-9.5/months) during the recovery phase following bronchopulmonary dysplasia. The infants did not require assisted ventilation, but needed oxygen therapy with an FiO2 of 25-30% in stable condition. One to three hours after a single oral dose of almitrine (1.5 mg/kg), there was a marked increase in transcutaneous PO2 (TcPO2) (mean 2kPa) followed by a regular decrease to the baseline level. Nine to fourteen days after repeated administration of almitrine (1.5 mg/kg/12 h) in 4 children, the mean gain in TcPO2 was only 0.85 kPa. There was a very early flagging in efficacy of almitrine, since none of the children could be weaned from oxygen therapy. The absorption peak occurred 1-3 h after the administration of the compound. The maximum almitrine concentration was 173 +/- 44 ng/ml; plasma clearance was 21.9 +/- 6.6 ml/min and the volume of distribution was 18.7 +/- 2.1 liters/kg. The drug was eliminated biphasically. In the 4 studies with repeated drug administration, the pharmacokinetic results suggested that a steady state was still not achieved after 9-14 days of treatment. These results and the absence of any sustained effect of repeated doses of the drug raise the problem of a particular type of almitrine metabolization in the infant.

Administration, Oral

[The electrocardiographic anomalies and 2D-echocardiographic findings during the recovery phase of the stress test in the postinfarct patient].

BACKGROUND: The appearance or the increase of repolarization abnormalities in the EKG during post exercise (ET) recovery phase (R) is considered a marker of ischemia. METHODS: In order to evaluate the real meaning of these changes we compared the EKG data with eventual modifications of left ventricular kinesis analyzed by 2D-ECHO. 10 male patients with previous myocardial infarction, mean age 50 +/- 4.8 y, underwent exercise testing on a treadmill (Bruce's protocol) and continuous 2D-ECHO observation from the end of exercise along the whole R. Patients were divided in two groups: Group A (6 patients) and Group B (4 patients), all free of symptoms. RESULTS: Group A showed ischemic EKG markers during exercise which increased during R; Group B showed ischemic EKG markers only during R. The 2D-ECHO showed in Group A an impairment of left ventricular kinesis at peak exercise without increase or extension during R (WMSI at rest 1.32; peak ET 1.60; R 1.60); in Group B the kinetic alterations appeared only in R (WMSI at rest 1.33, peak ET 1.42; R 1.80), strictly related to EKG markers. CONCLUSIONS: The data suggest : 1) that the increase of EKG abnormalities already present during exercise do not seem to imply more severe ischemia; 2) that EKG changes appearing during R are markers of ischemia which occur in the R.

Echocardiography

Serum levels of insulin-like growth factor (IGF) and IGF binding protein in insulin-dependent diabetics during an episode of severe metabolic decompensation and the recovery phase.

Serum insulin-like growth factor (IGF) and IGF-binding protein (IGF BP) levels were determined in 13 insulin-dependent diabetic patients (30-60 yr of age) during an episode of severe metabolic decompensation and the recovery phase. After separation by acidic gel filtration, the samples were assayed for IGF using a protein-binding assay (which measures mainly IGF I-related peptides) and for IGF BP by measuring the binding activity, in both assays using IGF I as tracer. The reference standard was a pool of normal adult serum with an assigned potency of 1 U IGF and 1 U IGF BP per ml. The mean IGF level in the uncontrolled state, 0.55 +/- 0.05 (SEM) U/ml, was about half that of normal subjects (1.03 +/- 0.03 U/ml, P less than 0.001). With treatment, IGF levels reached the normal range within 3 days. The pattern of changes in IGF BP levels was roughly similar, although the values in the uncontrolled state were less depressed (0.78 +/- 0.04 U/ml vs. 0.98 +/- 0.04 in normal subjects, P less than 0.01). Highly significant correlations (P less than 0.001) were found between IGF levels and the biological parameters reflecting control of the diabetes: glycosuria (r = -0.60), glycemia (r = -0.52), ketonemia (r = -0.65), and HCO3- (r = 0.58). Similar but less significant correlations were found for IGF BP. The mean GH level during the period of metabolic decompensation (9.0 +/- 1.5 ng/ml) was elevated compared to that after recovery (2.9 +/- 0.8 ng/ml) (P less than 0.025). There was a negative correlation between GH values and IGF levels (r = -0.67, P less than 0.001). The correlation with IGF BP was much less significant (r = -0.38, P less than 0.05). The results clearly reflect the role of insulin and nutritional factors in the control of IGF levels. They also support the notion that the biosynthesis of IGF and IGF BP is not regulated in the same way.

Adult

[Multiparameter analysis of the ergometric test. Significance of the failure of systolic blood pressure to decrease during recovery phase as an index of coronary disease].

Ergometric tests were performed in 27 patients who had previously undergone coronarography following instrumental findings and/or symptoms which seemed highly indicative of ischemic cardiopathy. The aim of the study was to assess the diagnostic importance of the failure of systolic blood pressure to decrease during the third minute of the recovery phase of the test as an index of coronary disease. In particular, as reported by other studies, the ratio between systolic blood pressure at the third minute of recovery and maximum systolic blood pressure during the test was also assessed values above 0.7 were considered pathological. Sixteen out the 27 patients examined showed lesions which were hemodynamically significant, whereas 11 patients were free of lesions and 9 had previous myocardial necrosis. The level of the above ratio in subjects without significant coronary lesions was 0.66 +/- 0.05, whereas it was 0.85 +/- 0.04 (p less than 0.01) in patients with coronary disease. Sensitivity, specificity, and positive and negative prognostic values were respectively 91.6%, 62%, 64.7% and 90.9%. In patients with lesions to the three main arteries both the sensitivity and the specificity were 100%. In the same patients, the ST criteria were 85.7%, 50%, 81.8% and 74.3%.

Blood Pressure

The use of pulse oximetry in the immediate recovery phase following dental extractions under general anesthesia in children.

Over the past decade, an array of monitoring devices have been developed to continuously assess patient oxygenation. While actual tissue oxygenation is the most desirable measurement, the pulse oximeter offers a non-invasive method of measuring oxygenation of arterial blood. In this study, the arterial oxygen saturation (SaO2) of children presenting for oral surgical procedures under general anesthesia was continuously monitored. We were particularly interested in the saturation during the period from termination of anesthesia until arrival in the recovery room, a potentially critical 2-3 minutes. This study showed that 22.5 per cent of children significantly desaturated (SaO2 less than 90 per cent) during this period - a figure which is in complete agreement with several similar studies done recently. This desaturation preceded not only hemodynamic changes, but frequently changes in tissue and blood colour as well. The authors conclude that children should receive supplemental oxygen in the immediate recovery phase following general anesthesia.

Adolescent

Renal ammoniagenesis during the recovery phase of postischemic acute renal failure in the dog.

Renal ammoniagenesis has been studied in 6 dogs before and 48 h after a 60-min period of renal ischemia induced by clamping the renal artery and in 6 sham-operated animals. Two days after temporary renal ischemia, the dogs showed a 25% decrease in glomerular filtration rate and renal plasma flow and a similar decrease in sodium reabsorption. Renal production of ammonium was not significantly different under basal conditions or 2 days after ischemia, but more ammonia was released by the urine in the postischemic dogs. Renal uptake of glutamine was similar in control and in postischemic kidneys. It is concluded that during the recovery phase of the ischemia, renal ammoniagenesis is conserved.

Acute Kidney Injury