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Biomedical subjects

O Zinder

Publications and source records attributed to O Zinder.

At least 19 recordsLinked to original sources
PubMed2006

Does adding intravenous fentanyl to caudal block in children enhance the efficacy of multimodal analgesia as reflected in the plasma level of catecholamines?

BACKGROUND AND OBJECTIVE: Several studies showed that single analgesic modality management can attenuate perioperative stress, but little is known about the effect of multimodal analgesia on catecholamine responses to surgical trauma in children. METHODS: Fifty children (American Society of Anesthesiologists Grade I or II) were randomly allocated to one of two groups: one received general anaesthesia and a caudal block (control group), and one group was given general anaesthesia, caudal block and intravenous (i.v.) fentanyl 2 microg kg(-1) (fentanyl group). Plasma epinephrine and norepinephrine concentrations were measured three times during the perioperative period: at induction time (T(0)), at the end of surgery (T(1)) and when the children were fully awake in the postanaesthesia care unit (T(2)). RESULTS: There was a significant reduction in the catecholamine levels in the two groups when (T(1)) and (T(2)) were compared with T(0). When plasma epinephrine levels (at T(0), T(1) and T(2)) between the two groups were compared, a statistically significant reduction at T(2) was obtained in the fentanyl group, when compared with the control group. However, plasma norepinephrine levels showed no statistically significant difference between the two groups (at T(0), T(1) and T(2)). CONCLUSION: These findings suggest that the multimodal analgesic approach of adding i.v. low-dose fentanyl to a caudal block may decrease the plasma epinephrine release in children undergoing inguinal herniotomy.

Analgesia↗
PubMed2004

Obesity is the major determinant of elevated C-reactive protein in subjects with the metabolic syndrome.

OBJECTIVE: To investigate the relationship between C-reactive protein (CRP) and various characteristics of the metabolic syndrome. DESIGN: Population-based cross-sectional study. SUBJECTS: A total of 1929 subjects undergoing a medical examination in a preventive medicine clinic (age, 50+/-10 y; 63% males). RESULTS: The proportion of subjects with CRP levels above the cut point generally used to indicate an obvious source of infection or inflammation (>10 mg/l) was 3, 7, and 15% in subjects who were normal weight, overweight, and obese, respectively. Subjects with obesity had markedly higher CRP level compared to patients without obesity regardless of whether they had the metabolic syndrome. However, there was no significant difference in CRP levels between nonobese subjects without the metabolic syndrome and subjects in whom the diagnosis of the metabolic syndrome was based on criteria other than obesity (adjusted geometric mean CRP 1.75 vs 2.08 mg/l, P=0.79). Similarly, CRP levels did not differ among obese subjects with and without the metabolic syndrome (adjusted geometric mean CRP 3.22 vs 3.49 mg/l, P=0.99). There was a linear increase in CRP levels with an increase in the number of metabolic disorders (P(trend) <0.0001), which was substantially diminished after controlling for body mass index (BMI) (P(trend)=0.1). Stepwise multivariate linear regression analysis identified BMI, triglyceride levels, HDL cholesterol levels (inversely), and fasting glucose as independently related to CRP levels. However, BMI accounted for 15% of the variability in CRP levels, whereas triglycerides, HDL cholesterol and fasting glucose levels accounted for only approximately 1% of the variability in CRP levels. CONCLUSION: Obesity is the major factor associated with elevated CRP in individuals with the metabolic syndrome. CRP levels in the range suggesting a source of infection or inflammation (>10 mg/l) are more common among obese subjects than in nonobese subjects.

Adult↗
PubMed2004

Association between fasting glucose and C-reactive protein in middle-aged subjects.

AIMS: C-reactive protein (CRP), a marker of subclinical inflammation, predicts the occurrence of coronary heart disease in healthy subjects. Hyperglycaemia is known to stimulate the release of inflammatory cytokines from various cell types and can lead to the induction and secretion of acute-phase reactants by adipocytes. The aim of the present study was to determine the relation between glycaemic status and CRP in healthy subjects. METHODS: We studied the relation of high-sensitivity CRP to fasting glucose and other components of the metabolic syndrome in a population-based cross-sectional study (n = 1000; age 50 +/- 9 years). RESULTS: Plasma CRP levels increased continuously from the lowest quartile of normal fasting glucose level to impaired fasting glucose and to diabetes (ln CRP 0.47 +/- 0.09, 0.95 +/- 0.12, and 1.11 +/- 0.13, respectively; Ptrend < 0.0001). Increasing CRP with higher fasting glucose levels was apparent even among subjects with fasting glucose in the normal range (Ptrend = 0.039), and subjects with fasting glucose level in the upper quartile of normal fasting glucose had higher CRP levels compared with subjects in the lower quartile (P = 0.035). There was a positive crude correlation between CRP and smoking, post-menopausal hormone use, body mass index, fasting glucose, triglycerides, hypertension, and uric acid (r = 0.11-0.36, P = 0.002-0.0001). A negative correlation was found between CRP and HDL-cholesterol (r = 0.12, P < 0.0001) and physical activity (r = 0.11, P = 0.002). After adjustment for potential confounders in a stepwise multivariate linear regression model, fasting glucose remained significantly and independently related to CRP levels (correlation coefficient 0.06; 95% confidence interval 0.014-0.11, P = 0.011). CONCLUSIONS: Fasting glucose is significantly and positively associated with plasma CRP in middle-aged subjects. CRP levels increase continuously across the spectrum of fasting glucose, beginning in the lowest quartile of normal fasting glucose. This finding suggests that a proinflammatory effect may contribute to the adverse cardiovascular outcome associated with diabetes, impaired fasting glucose, and increasing glucose levels within the normal range.

Blood Glucose↗
PubMed2004

Increased C-reactive protein levels in the polycystic ovary syndrome: a marker of cardiovascular disease.

The polycystic ovary syndrome (PCOS), one of the most common reproductive abnormalities, shares some components of the metabolic cardiovascular syndrome. Therefore, PCOS patients may represent the largest group of women at high risk for the development of early-onset cardiovascular disease (CVD) and/or diabetes. C-reactive protein (CRP) is a strong independent predictor of future CVD and/or stroke. Only one small published study has looked for such an association (17 PCOS patients vs. 15 controls). The objective of this study was to compare the levels of CRP and other risk factors of CVD in a large group of PCOS patients and controls. CRP measurements were undertaken in 116 PCOS patients and 94 body mass index-matched controls with regular menstrual cycles. Whereas 36.8% of the PCOS patients had CRP levels above 5 mg/liter, only 9.6% of the controls exhibited high CRP levels (P < 0.001). The mean +/- SD was 5.46 +/- 7.0 in the PCOS group vs. 2.04 +/- 1.9 mg/liter in the control (P < 0.001). The body mass index, white blood cell count, TSH, glucose, cholesterol, and homocysteine levels were not significantly different between the two groups. CRP levels are elevated in patients with PCOS and may be a marker of early cardiovascular risk in these patients. High CRP levels may explain why some PCOS women may possibly be at an increased risk for the development of early-onset CVD. Consequently, whether treatment regimens directed toward lowering CVD risk factors should be more aggressive for those PCOS women with increased CRP levels, awaits further clinical experience.

Adult↗
PubMed2001

Acute exercise effect on postabsorptive serum leptin.

We postulated that high circulating cortisol levels during intense exercise would lead to increased serum leptin concentrations. Young, lean men ate a small meal and then exercised on a cycle ergometer for 41 min or rested on a control day. Serum leptin concentration was 10% greater during exercise than in the control condition (P < 0.05). Directly after exercise, serum leptin dropped to approximately 10% less than the control level (P < 0.05) but had recovered to the nonexercised level after approximately 2 h of recovery. Rapid exercise effects on circulating leptin were related to changes in hemoconcentration rather than changes in leptin mass. When serum leptin was normalized to serum protein, leptin increased by 10% in the exercise condition compared with control by the end of recovery (P < 0.05). Although exercise increased serum cortisol concentration threefold, there was no relation between differences in cortisol and exercise vs. control differences in normalized leptin. The increased leptin mass after exercise may have been related to greater plasma glucose concentration during recovery after exercise compared with the control condition.

Adult↗
PubMed2000

The physiological state of captive and migrating Great White Pelicans (Pelecanus onocrotalus) revealed by their blood chemistry.

The Great White Pelican Pelecanus onocrotalus is an endangered migratory bird, threatened by diminishing natural feeding sites and by persecution by fishermen. The majority of the migrating White Pelican (71000) stop-over in Israel during their autumn migration to Africa. As part of a larger study, aimed to assess the necessity of feeding during the stop-over in Israel, we examined the blood chemistry of captive and migrating White Pelicans. Blood was sampled from captive birds maintained on a fish diet, after food deprivation for 48 h and from wild birds brought from the field during migration. Food deprivation resulted in increased plasma levels of triglycerides and in lower levels of urea, potassium and calcium. In migrating birds, increased plasma levels of urea and CPK and lower levels of creatinine were revealed. In general, the coefficient of variation in the blood chemistry of migrating pelicans was higher than in the captive birds, that is to say, that these birds were in a variable physiological condition. The blood profile of migrating and wintering pelicans did not indicate a state of dehydration but did indicate energy deficiency. The less extreme changes in blood chemistry of the 48 h food-deprived compared to migrating pelicans suggest that the former did not reach a state of starvation. We conclude that for White Pelicans the stop-over in Israel is a must in order to rest and replenish their fuel reserves for completion of their autumn migration to Africa.

Animals↗
PubMed2000

Quantification of p53 expression in the nervous system.

The transcription factor p53 is a short lived protein that is thought to be associated with cellular proliferation and apoptosis. In the current study, we present a protocol to measure p53 expression across both the central and peripheral nervous systems of transgenic and parental mice using the enzyme linked immuno-substrate assay (ELISA), chloramphenicol acetyl transferase reporter assay (CAT) and immunohistochemistry approaches. The profiles of the ELISA tissue data of CD1 mice were compared to the CAT assay data of the p53-promoter-driven CAT gene transgenic mice. Subsequently, high resolution immunohistochemical analysis of positive tissues in both mouse strains were evaluated. As the p53 protein is apparently subject to high turnover, the comparison of the more stable CAT data to the pan p53 ELISA assay should effectively complement each other in identifying which nervous system structures express p53. ELISA analysis alone could give ambiguous data. Immunohistochemical studies confirmed and further defined p53 expression in several regions of the nervous system. Significantly, p53 promoter-driven CAT expression was visualized in the Purkinje cells of the cerebellum and in the cornea as well as in the retina of the eye. This approach for the analysis of very short half-life proteins in the nervous system should be transferable to the study of other proteins.

Animals↗
PubMed2000

Does the addition of fentanyl to bupivacaine in caudal epidural block have an effect on the plasma level of catecholamines in children?

We evaluated the effect of adding fentanyl to bupivacaine, compared with bupivacaine alone, on the stress response. The effect was evaluated by determining blood levels of epinephrine (E) and norepinephrine (NE) in pediatric patients receiving caudal epidural blocks. Sixty children, 1-8 yr of age, scheduled for elective herniorrhaphy, were randomly allocated to two groups of 30 patients each. Group A received inhaled anesthesia and caudal epidural block with bupivacaine 0.25% alone, 1.0 mL/kg. Group B received identical anesthesia; however, fentanyl 1 microg/kg was added to the bupivacaine in the caudal block. Blood samples for E and NE plasma levels were drawn at induction time (H(0)), at the end of surgery (H(1)), and in the postanesthesia care unit (H(2)). In both groups, there was a significant decrease in the E and NE plasma levels, when comparing H(1) and H(2) with H(0) within the same group (P < 0.001). There were no significant differences in the E and NE plasma levels between the two groups at H(0), H(1), and H(2) (P = 0.5, P = 0.12, P = 0.5, respectively). Pain scores (modified Children's Hospital of Eastern Ontario Pain Score) were also similar in both groups (P = 0. 19). This study suggests that adding fentanyl 1 microg/kg to bupivacaine in the caudal epidural block in children does not influence plasma levels of E and NE, nor does it improve the analgesic intensity of the caudal block.

Adjuvants, Anesthesia↗
PubMed2000

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors.

Different types of lymphocytes have different roles in tumor suppression. Thus, their expression of apoptosis-related proteins (ARP - Fas and Fas ligand, bcl-2, p53) in lymphocytes and their apoptosis were analyzed immunohistochemically in ovarian tumors of different grades. Ovaries without oncologic disorders had few lymphocytes, mainly T cells, and no ARP. Benign cysts presented features of weak immune reaction: small lymphoid infiltration and few lymphocytes. The ARP were present in 13.7% to 23.5% of the lymphocytes, and apoptosis was rare. In borderline tumors, expansion of lymphoid infiltrates and increased density of lymphocytes resulted in a tenfold rise in total lymphocytes, reflecting intensification of the immune response. Most lymphocytes were T cells (92%) predominated by CD8+ cells that were in direct contact with tumor epithelial cells. ARP species were found in 47% to 65% of the lymphocytes, and apoptosis in 2.2%. In carcinomas with ligh lymphoid infiltration, lymphocytes were 2.5 times more abundant, and the apoptotic index as well as the number of CD20+ and CD25+ lymphocytes rose sharply, whereas bcl-2 positive lymphocytes decreased to 8% of their number in borderline tumors. In carcinomas with low lymphoid infiltration, the total lymphocyte count decreased eightfold compared to carcinomas with high lymphoid infiltration, reflecting the deep subcompensation of the lymphoid system. Few p53-positive lymphocytes were found in the carcinomas. In conclusion, we found a positive correlation between apoptosis and the numbers of CD4+ or CD8+ lymphocytes in epithelial ovarian tumors. This correlation could reflect the antitumor activity of T cells. However, the high expression of ARP studied by immune cells at the vicinity of the tumor ARP reveals the lymphoid vulnerability to apoptosis, resulting in devastation of the lymphoid tissue, and consequently in tumor progression.

Adenocarcinoma↗
PubMed1999

Tissue-specific p53 expression in the nervous system.

P53 is a transcription factor that has been found to be expressed in association with cell proliferation and apoptosis. Previously, bacterial chloramphenicol acetyl transferase (CAT) enzymatic expression was predominantly found in the testes of p53 promoter driven-CAT transgenic mice. In the current study, we extended this study to survey p53 expression across both the central and peripheral nervous systems of the same strain of transgenic mice as well as their parental strain. High levels of p53 promoter driven-CAT activity was observed in the cerebellum, hippocampus, hypothalamus, pons, thalamus and upper cerebral spine. Furthermore, we consistently found unexpectedly high levels of p53 promoter-driven CAT expression in the eyes. These observations were reinforced by p53 protein analysis using a p53 pan ELISA assay. Immunohistochemical studies confirmed and further defined p53 expression in several regions of the nervous system. Significantly, p53 promoter-driven CAT expression was visualized in the Ammon horn of the hippocampus, in the Purkinje cells of the cerebellum and in the cornea as well as in the retina of the eye. Furthermore, strong p53 protein expression was found in the cornea of the parental mouse strain. p53 ELISA demonstrated a profile of p53 protein concentration, which correlate well with the high p53 promoter-driven CAT activities observed in the cerebellum, hindbrain, hypothalamus, thalamus, hippocampus, whole eyes as well as with the low CAT activities observed in the cortex and spinal cord. In both of these assays considerable p53 promoter activity and p53 protein levels were found in post-mitotic non-dividing cells.

Animals↗
PubMed1999

Transcription of actin, cyclophilin and glyceraldehyde phosphate dehydrogenase genes: tissue- and treatment-specificity.

Studies involving RNA transcription, in varying biological systems, usually necessitate a term of transcriptional reference. Traditionally, the transcription of the gene of interest was compared to a constitutively expressed 'control' gene. Run-on transcription analysis was undertaken to evaluate and compare the transcription of three frequently used 'control genes' (beta-actin, cyclophilin and glyceraldehyde-3-phosphate dehydrogenase), in nine rat tissues. Similarities, but also clear and highly significant differences, were found in the transcription profiles of these three genes. There was significantly greater transcription for uterine glyceraldehyde-phosphate dehydrogenase compared to all other tissues tested, while both cyclophilin and glyceraldehyde-phosphate dehydrogenase were significantly elevated in the adrenal cortex. Upon cholinergic agonist treatment, both beta-actin and glyceraldehyde-phosphate dehydrogenase RNA expression were greatly induced in the adrenal medulla (41- and 94-fold, respectively), while cyclophilin transcription was not altered. In another treatment paradigm, surgical ovariectomy, only uterine glyceraldehyde-phosphate dehydrogenase transcription was significantly reduced. While, all three of these genes are assumed to be constitutively expressed throughout the body and hence used as normalization controls, the current study questions these accepted terms of reference. As cyclophilin transcription was not affected in both treatment paradigms, it should be considered more seriously as a RNA normalization control.

Actins↗
PubMed1999

Diurnal and seasonal changes in blood composition of the free-living Egyptian fruit bat (Rousettus aegyptiacus).

We studied the blood profile of the free-living fruit bat (Rousettus aegyptiacus) during the beginning of the activity period (around various feeding trees) and upon return to the day roost during 1994-1995. Results of the present study suggest that during winter and early spring bats are characterized by a poor physical and physiological state as reflected in the blood profile, revealing elevated urea and uric acid concentrations. It was found that at the end of the resting phase, R. aegyptiacus was in a mild state of dehydration (increased hematocrit and hemoglobin levels). At the end of activity, upon return to the day roost, both hematocrit and hemoglobin levels decreased but bats still maintained a high plasma osmolality. Several components in the blood are effected by the feeding time and show a cyclic change in concentration. The reverse relationship between glucose and triglyceride levels may indicate that glucose is the energy source during the active phase and that fat is the energy source during the resting period. The low cholesterol level in the blood reflects its absence in the fruit diet.

Animals↗
PubMed1999

Neuroactive steroids: their mechanism of action and their function in the stress response.

Steroids are usually identified as genomic regulators, yet recently a body of evidence has accumulated demonstrating specific plasma membrane effects, as well as coordinative effects, of some steroids on both membrane and intracellular receptors. The resulting rapid (<1 min) modulation of cellular activity has strongly suggested a non-genomic, and possibly modulatory, role for certain steroid compounds, and dramatic effects on membranes of excitable as well as other tissues have been demonstrated. Steroid synthesis and metabolism have been shown to exist in the CNS, and the effects have been seen in both the central and peripheral nervous systems. The major groups of neuroactive steroids, and their metabolites, have been progesterone, deoxycorticosterone, and some androgens, notably dihydroxyepiandrosterone (DHEA). These compounds show increased concentrations both in blood and in the brain following stress and they have also been associated with anxiolytic effects and antiepileptic activity. In the periphery, some of these compounds show remarkable inhibitory effects on the secretion of catecholamines and other neurotransmitters. The mechanism for the majority of the effects of these steroids is via their effect on receptor-mediated binding to ligand-gated ion channels. Activation of the GABAA receptor complex, resulting in the opening of its central chloride channel, is the major target of the neuroactive steroids, resulting in re-polarization of the plasma membrane and inhibition of further neuronal firing. The anxiolytic, anti-convulsant and sedative-hypnotic actions of these neuroactive steroids have resulted in their being used as therapeutic agents for the treatment of anxiety, epilepsy, insomnia, and possibly for the alteration of pain thresholds.

Cell Membrane↗
PubMed1999

Effect of caudal block on the plasma adrenaline and noradrenaline concentrations in paediatric patients undergoing ilioinguinal herniorrhaphy.

This study compared the effect of two anaesthetic techniques on the catecholamine levels in children undergoing ilioinguinal herniorrhaphy. Forty male paediatric patients ASA class I were allocated randomly to one of two groups: the control group (n = 20) received general anaesthesia including intravenous fentanyl; and the caudal group (n = 20) received caudal anaesthesia with bupivacaine 0.25% 1 mL kg-1 combined with general anaesthesia but without opioids. Plasma adrenaline and noradrenaline concentrations were measured at induction, at the end of surgery and in the post-anaesthesia care unit (PACU). In the caudal group, there were significant decreases in the adrenaline and noradrenaline concentrations at the end of surgery and in the PACU compared with baseline concentrations. In the control group, there was a significant increase in PACU concentrations of adrenaline and noradrenaline compared with baseline concentrations. These findings suggest that the addition of a caudal block to general anaesthesia in children undergoing ilioinguinal herniorrhaphy decreases significantly the neurohormonal responses to surgery.

Anesthesia, Caudal↗
PubMed1999

Effects of low doses of carcinogen and different antibodies on the splenic lymphoid system of p53 transgenic mice: morphometric and immunohistochemical studies.

The role of the splenic immune system in the development of high sensitivity of p53 transgenic mice to low doses of carcinogen and vaccination was investigated immunohistochemically and morphometrically. Spleens were obtained from human p53 promoter-chloramphenicol acetyl transferase transgenic mice, grouped as follows: 1, untreated controls; 2, exposed to dimethylhydrazine (DMH); 3, and 4, vaccinated with polyclonal antibodies to soluble-53 kDa protein (s53); 5, vaccinated with monoclonal PAb DO1; 6, vaccinated with monoclonal PAb 421; 7, vaccinated with polyclonal alphaH-p53 antibody. Mice in groups 4-7 were treated with DMH after the course of vaccination. Six months later all the mice were tumor-free, but effects of the low dose carcinogen were distinct in the splenic immune system. They were mainly manifested in blast transformation: the total number of lymphocytes and lymphoblasts decreased to 56.5% of the controls. The total of lymphoid cells in the follicles (B zone) and periarterial lymph sheath (T zone) declined, reflecting moderate insufficiency of the spleen's lymphoid system. Vaccination of transgenic mice with antibodies to soluble-p53 elicited mainly a B system response, with lesser T system involvement. Only few signs of B system insufficiency were found in these mice. Vaccination of mice with different antibodies, with subsequent carcinogen treatment, caused changes in the spleen that were similar to those described for DMH alone, but varied with different anti-p53 antibodies. Vaccination with polyclonal antibodies to soluble-p53, or with monoclonal antibodies PAb DO1 or PAb 421, stimulated the splenic activity of T system, and therefore can decrease the tumorigenic effect of carcinogens.

1,2-Dimethylhydrazine↗
PubMed1999

Apoptosis and apoptosis-related proteins in the epithelium of human ovarian tumors: immunohistochemical and morphometric studies.

BACKGROUND: The origin of malignant ovarian tumors is the subject of considerable controversy, which may be resolved by elucidation of molecular mechanisms of tumorigenesis. Therefore we have undertaken the study of apoptosis in these tumors. METHODS: Apoptosis and the expression of its related proteins, Fas, Fas ligand (FasL), bcl-2 and p53, in epithelial cells of human ovarian tumors of different histological grades, were determined immunohistochemically and morphometrically. RESULTS: Apoptosis-related proteins were absent from ovarian epithelia of patients afflicted with non-cancerous diseases. In ovarian tumors, the distribution of individual proteins varied, and depended on the grade and type of tumor. Fas and FasL were highly expressed in all tumors, while epithelial cells expressing bcl-2 were abundant in benign tumors, but their numbers significantly dwindled with the progression of malignancy. Cells expressing p53 were found in borderline tumors, and their numbers increased with malignancy, inverse of bcl-2 expression. Apoptotic tumor cells were scarce in borderline tumors and abundant in carcinomas. Grouping apoptosis was found in approximately 60% of the carcinomas. CONCLUSIONS: The initial development of ovarian tumors is accompanied by high epithelial expression of Fas, FasL and bcl-2 proteins, while apoptosis and p53 proteins are detected only at later stages of tumorigenesis.

Apoptosis↗
PubMed1998

Novel transcriptional mechanisms are involved in regulating preproenkephalin gene expression in vivo.

For the dissection of the temporal and spatial patterns of cell- and tissue-specific gene expression an understanding of the contributing regulating mechanisms is required. We now confirm that there are novel mechanisms regulating preproenkephalin gene expression in basal as well as cholinergic agonist treated rats. Moreover, we demonstrate that these novel transcriptional mechanisms are consistent with RNA intragenic elongation pausing, alternate promoter usage, and small sense and antisense RNA transcription from the preproenkephalin gene locus. We report that while basal striatal and olfactory bulb proenkephalin RNA transcripts are initiated from the "normal" proximal promoter, in cerebellum de novo RNA transcription appears to be initiated from the distal so-called "germ-cell" promoter. Furthermore, "normally" initiated olfactory bulb proenkephalin RNA transcripts appear to be down-regulated by the time the RNA polymerase II complex reaches the first preproenkephalin intron, in a way that is consistent with RNA elongation pausing. As the pattern of small sense and antisense transcripts found associated with this gene's expression is tissue-specific, we suggest that they may also play a role in regulating gene expression. The understanding of this gene's regulation should have widespread importance, not only to those interested in opioid gene expression, but also to those interested in gene regulation, in general.

Adrenal Medulla↗