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Biomedical subjects

Arnold G Coran

Publications and source records attributed to Arnold G Coran.

At least 19 recordsLinked to original sources
PubMed2007

Effect of testicular ischemia-reperfusion on recruitment of neutrophils, E-selectin expression and germ cell apoptosis in the contralateral testis in a rat.

Recent evidence suggests that neutrophil recruitment may initiate germ cell apoptosis in the ischemic testis. The purpose of the present study was to examine the relationship between germ cell apoptosis and neutrophil recruitment in the contralateral testis following testicular ischemia-reperfusion (IR) injury in a rat. Adult male Sprague-Dawley rats were divided randomly into two experimental groups: Group A: Sham operated animals; Group B: IR rats underwent 90 min of unilateral testicular ischemia following by 96 h of reperfusion. The rats were sacrificed and testes were harvested. Johnsen's criteria and the number of germinal cell layers were measured to categorize the spermatogenesis. TUNEL assay was used to determine germ cell apoptosis in both the ischemic and contralateral testis. The recruitment of neutrophils was calculated per 100 venules. Expression of E-selectin was determined using immunohistochemical analysis. Statistical analysis was performed using Student's t test, with P less than 0.05 considered statistically significant. Germ cell apoptosis in both the ischemic and the contralateral testis increased significantly after IR. E-selectin expression was significantly greater in ischemic testis from IR rats compared to sham animals. The small increase in E-selectin expression and the concomitant increase in neutrophil recruitment in the contralateral testis of the IR rats (vs. sham animals) were not statistically significant. In conclusion, testicular ischemia causes an increase in germ cell apoptosis in the contralateral testis. Mechanisms other than neutrophil recruitment apparently initiate this process.

Animals↗
PubMed2007

The effect of leptin on intestinal recovery following ischemia-reperfusion injury in a rat.

Recent evidence suggests that the adipose tissue derived cytokine leptin (LEP) is involved in the modulation of growth and differentiation of normal small intestine. The purpose of the present study was to examine the effect of leptin on enterocyte turnover and intestinal recovery after ischemia-reperfusion (IR) injury in a rat. Male Sprague-Dawley rats were divided into three experimental groups: (1) sham rats underwent laparotomy, (2) IR-rats underwent occlusion of both superior mesenteric artery and portal vein for 30 min followed by 24 h of reperfusion, and (3) IR-LEP rats underwent IR and were treated with leptin given subcutaneously at a dose of 50 microg/kg once a day for 48 h before and 24 h following IR. Intestinal structural changes, enterocyte proliferation and enterocyte apoptosis were determined 24 h following IR. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with P < 0.05 considered statistically significant. Treatment with leptin resulted in a significant increase in bowel weight in ileum, mucosal weight in jejunum and ileum, mucosal DNA content in ileum, mucosal protein content in jejunum and ileum, villus height in jejunum and ileum, and crypt depth in jejunum compared to IR-animals. IR-LEP rats also had a significantly lower intestinal injury score as well as lower apoptotic index and higher cell proliferation index in jejunum and ileum compared to the IR-animals. In conclusion, pre-treatment with leptin prevents gut mucosal damage and improves intestinal rehabilitation following intestinal IR in a rat.

Analysis of Variance↗
PubMed2007

Are the long-term results of the transanal pull-through equal to those of the transabdominal pull-through? A comparison of the 2 approaches for Hirschsprung disease.

PURPOSE: The transanal endorectal pull-through (TERPT) is becoming the most popular procedure in the treatment of Hirschsprung disease (HD), but overstretching of the anal sphincters remains a critical issue that may impact the continence. This study examined the long-term outcome of TERPT versus conventional transabdominal (ABD) pull-through for HD. METHODS: Records of 41 patients more than 3 years old who underwent a pull-through for HD (TERPT, n = 20; ABD, n = 21) were reviewed, and their families were thoroughly interviewed and scored via a 15-item post-pull-through long-term outcome questionnaire. Patients were operated on between the years 1995 and 2003. During this time, our group transitioned from the ABD to the TERPT technique. Total scoring ranged from 0 to 40: 0 to 10, excellent; 11 to 20 good; 21 to 30 fair; 31 to 40 poor. A 2-tailed Student t test, analysis of covariance, as well as logistic and linear regression were used to analyze the collected data with confidence interval higher than 95%. RESULTS: Overall scores were similar. However, continence score was significantly better in the ABD group, and the stool pattern score was better in the TERPT group. A significant difference in age at interview between the 2 groups was noted; we therefore reanalyzed the data controlling for age, and this showed that age did not significantly affect the long-term scoring outcome between groups. CONCLUSION: Our long-term study showed significantly better (2-fold) results regarding the continence score for the abdominal approach compared with the transanal pull-through. The stool pattern and enterocolitis scores were somewhat better for the TERPT group. These findings raise an important issue about the current surgical management of HD; however, more cases will need to be studied before a definitive conclusion can be drawn.

Child↗
PubMed2006

Effect of leptin on intestinal re-growth following massive small bowel resection in rat.

Recent evidence suggests that the adipose tissue-derived cytokine leptin (LEP) is involved in modulation of growth and differentiation of normal small intestine. The purpose of the present study was to evaluate the effects of parenteral LEP on structural intestinal adaptation, cell proliferation and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: Sham rats underwent bowel transection and re-anastomosis, SBS-rats underwent a 75% small bowel resection, and SBS-LEP-rats underwent bowel resection and were treated with LEP given subcutaneously at a dose of 20 mug/kg, once daily, from day 3 through 14. Parameters of intestinal adaptation (bowel and mucosal weights, mucosal DNA and protein, villus height and crypt depth in jejunum and ileum), enterocyte proliferation and enterocyte apoptosis were determined on day 15 following operation. Ileal tissue samples were taken for detection of bax and bcl-2 gene expression using RT-PCR technique. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with P<0.05 considered statistically significant. Treatment with subcutaneous LEP resulted in a significant increase in jejunal (17%, P<0.05) and ileal (13%, P<0.05) bowel weight, jejunal (10%, P<0.05) and ileal (25%, P<0.05) mucosal weight, jejunal (26%, P<0.05) and ileal (38%, P<0.05) mucosal DNA, ileal (25%, P<0.05) mucosal protein, jejunal (41%, P<0.05) and ileal (21%, P<0.05) villus height, jejunal (37%, P<0.05) crypt depth, and jejunal (24%, P<0.05) and ileal (21%, P<0.05) enterocyte proliferation compared to SBS-animals. Enterocyte apoptosis increased significantly after bowel resection in jejunum and ileum compared to sham animals and was accompanied by an increased bax gene expression and a decreased bcl-2 gene expression in ileal samples. SBS-LEP rats showed a trend toward a decrease in enterocyte apoptosis in ileum and a mild decrease in bax gene expression compared to SBS-untreated animals. In conclusion, in a rat model of SBS parenteral LEP stimulates structural intestinal adaptation. Increased cell proliferation and decreased cell death via apoptosis may be responsible for this increased cell mass.

Adaptation, Physiological↗
PubMed2006

Effect of diclofenac on germ cell apoptosis following testicular ischemia-reperfusion injury in a rat.

Recent evidence suggests that enhanced cell apoptosis is responsible for germ cell loss following testicular ischemia-reperfusion (IR) injury. A nonsteroidal anti-inflammatory drug diclofenac sodium (Voltaren) is a prostaglandin-synthesis inhibitor, which is widely used in many testicular disorders. The purpose of the present study was to examine the effect of diclofenac (DIC) on germ cell apoptosis in the ischemic and contralateral testes following testicular IR in a rat. Forty rats were divided randomly into four experimental groups of ten rats each: group A (Sham)-Sham operated animals; group B (Sham-DIC)-Sham operated rats that were treated with DIC given subcutaneously at a dose of 10 mg/kg, once daily, 24, 48 and 72 h following operation; group C (IR) underwent 90 min of unilateral testicular IR; group D (IR-DIC)-rats underwent 90 min of unilateral testicular IR and were treated with DIC similarly to group B. Ninety-six hours following operation, the rats were sacrificed and testes were harvested. Johnsen's criteria and the number of germinal cell layers were used to categorize the spermatogenesis. TUNEL assay was used to determine germ cell apoptosis in both the ischemic and contralateral testes. Statistical analysis was performed using the non-parametric Kruskal-Wallis ANOVA test, with P less than 0.05 considered statistically significant. Testicular ischemia in rats led to histological damage in the ipsilateral testis. In the contralateral testis, minimal damage was observed. Germ cell apoptosis in both the ischemic and the contralateral testes increased significantly after IR. Treatment with DIC did not change histologic parameters of spermatogenesis in both the ischemic and contralateral testes, but decreased germ cell apoptosis in both testes following testicular IR. We conclude that testicular ischemia causes an increase in germ cell apoptosis in the contralateral testis. Diclofenac may be beneficial for spermatogenesis following testicular IR by decreasing germ cell apoptosis.

Analysis of Variance↗
PubMed2006

Effect of dexamethasone on germ cell apoptosis in the contralateral testis after testicular ischemia-reperfusion injury in the rat.

OBJECTIVE: To evaluate the effect of dexamethasone on spermatogenesis and germ cell apoptosis in the ipsilateral and contralateral testis after testicular ischemia-reperfusion (IR) in rats. DESIGN: Laboratory study. SETTING: Medical research laboratory in a university setting. ANIMAL(S): Forty adult Sprague-Dawley rats weighing 250-280 g. INTERVENTION(S): Testicular IR, treatment with dexamethasone (10 mg per kilogram of body weight). MAIN OUTCOME MEASURE(S): Testicular germ cell apoptosis was assessed by deoxyuridine nick-end labeling immunohistochemical assay. RESULT(S): Testicular ischemia in rats led to histological damage in the ipsilateral testis. In the contralateral testis, minimal damage was observed. Germ cell apoptosis in both the ischemic and the contralateral testis increased significantly after IR. Treatment with dexamethasone did not change germ cell apoptosis in ischemic testis but decreased germ cell apoptosis in the contralateral testis. CONCLUSION(S): Glucocorticoids may be beneficial for spermatogenesis after testicular IR by decreasing germ cell apoptosis in the contralateral testis.

Animals↗
PubMed2005

Advances in short bowel syndrome: an updated review.

Short bowel syndrome (SBS) continues to be an important clinical problem due to its high mortality and morbidity as well as its devastating socioeconomic effects. The past 3 years have witnessed many advances in the investigation of this condition, with the aim of elucidating the cellular and molecular mechanisms of intestinal adaptation. Such information may provide opportunities to exploit various factors that act as growth agents for the remaining bowel mucosa and may suggest new therapeutic strategies to maintain gut integrity, eliminate dependence on total parenteral nutrition, and avoid the need for intestinal transplantation. This review summarizes current research on SBS over the last few years.

Adaptation, Biological↗
PubMed2005

The time relationship between ipsilateral testicular ischemia and germ cell apoptosis in the contralateral testis in rat.

Unilateral testicular ischemia-reperfusion (IR) in the rat is followed by histologic damage in the contralateral testis, which has been previously explained on immunologic grounds. There is evidence to suggest that apoptosis in the contralateral testis is involved in germ cell loss following IR injury to the testis. We examined the time-dependent effect of testicular ischemia on germ cell apoptosis in the contralateral testis in a rat. Adult Sprague-Dawley rats weighing 250-280 g, were subjected to testicular ischemia for 1, 2, 3 or 24 h. Twenty-four hours following onset of the ischemic insult, testes were harvested for immunohistochemical studies. Apoptosis was detected using TUNEL immunohistochemical assay. Testicular ischemia in rats led to histological damage, which was related to the duration of the ischemia. In the contralateral testis, the minimal damage included a decrease in number of germ cell layers, mild disorganization, and single cell apoptosis. Apoptosis in the contralateral testes increased significantly after 2, 3, and 24 h of ischemia and showed direct, time-related correlation with the duration of ischemia. We conclude that testicular ischemia causes an increase in germ cell apoptosis in the contralateral testis. The extent of apoptosis increases with the duration of the ischemia.

Animals↗
PubMed2005

Identical twins concordant for pulmonary sequestration communicating with the esophagus and discordant for the VACTERL association.

Communicating bronchopulmonary foregut malformations (CBPFMs) are unusual congenital structures composed of a segment of lung tissue connected to the foregut. We present what we believe is the first reported case of identical twins concordant for CBPFM who are discordant for the VACTERL association. Their nonfunctional lung tissue was successfully removed and the fistulae were corrected, and they are expected to live normal life spans. We review the literature concerning these malformations and the proposed theories of their etiology. This case report of concordance in identical twins suggests that a possible genetic component to CBPFMs cannot be ruled out. The discordance for the VACTERL association implies that the etiology is most likely multifactorial.

Abnormalities, Multiple↗
PubMed2005

Parenteral arginine impairs intestinal adaptation following massive small bowel resection in a rat model.

The nitric oxide precursor L-arginine (ARG) has been shown to influence intestinal structure and absorptive function. It is also well known that the route of administration modulates the effects of ARG. The present study evaluated the effects of parenteral ARG on structural intestinal adaptation, cell proliferation, and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: Sham rats underwent bowel transection and reanastomosis, SBS rats underwent a 75% small bowel resection, and SBS-ARG rats underwent a 75% small bowel resection and were treated with ARG given subcutaneously at a dose of 300 mug/kg, once daily, from days 3 to 14. Parameters of intestinal adaptation, enterocyte proliferation, and enterocyte apoptosis were determined on day 15 following operation. The SBS rats demonstrated a significant increase in jejunal and ileal bowel and mucosal weight, villus height and crypt depth, and cell proliferation index compared with the sham group. The SBS-ARG animals demonstrated lower ileal bowel and mucosal weights, jejunal mucosal DNA and ileal mucosal protein, and jejunal and ileal villus height and crypt depth compared with SBS animals. The SBS-ARG rats also had a lower cell proliferation index in both jejunum and ileum and a greater enterocyte apoptotic index in ileum compared with the SBS-untreated group. In conclusion, in a rat model of SBS, parenteral arginine inhibits structural intestinal adaptation. Decreased cell proliferation and increased apoptosis are the main mechanisms responsible for decreased cell mass.

Adaptation, Physiological↗
PubMed2005

Laparoscopic vs open surgical approach for intussusception requiring operative intervention.

PURPOSE: Laparoscopy has recently been used to treat intussusception that cannot be reduced radiologically. The effectiveness and practical nature of this approach has been questioned. METHODS: This study retrospectively analyzed the authors' experience with this laparoscopic approach and compared this to the conventional open laparotomy procedure. RESULTS: Sixteen patients were treated via laparoscopy, with 2 of these requiring conversions to an open procedure (12.5%). Twenty-five patients underwent an open reduction. Operative time was not significantly different (P = .698) between the laparoscopic (49.56 +/- 26.40 minutes) and open groups (45.00 +/- 24.74). Length of stay, however, was significantly reduced (P = .005) in the laparoscopic group (3.00 +/- 1.31 days) compared to the open group (4.52 +/- 1.98). Total hospital charges were lower in the laparoscopic group ($8171 +/- 2595) compared to the open group ($11,672 +/- 5466); this difference was not significant (P = .088). There were no significant differences in intra- or postoperative complication rates (P = .637) between the 2 approaches. CONCLUSIONS: Although there remains a group who will require a conversion to an open procedure, the laparoscopic approach should be considered a safe and effective option for all children who do not respond to a radiological reduction.

Child↗
PubMed2005

Total colonic Hirschsprung's disease: a 28-year experience.

PURPOSE: The aim of this study was to review outcomes after surgical treatment of total colonic Hirschsprung's disease (TCH). METHODS: Twenty-five records of patients with TCH treated between 1974 and 2002 were reviewed. Follow-up data were collected using a standardized questionnaire. Objective functional outcome was assessed using a scoring system. RESULTS: Twenty patients had aganglionosis of the colon and distal ileum, 5 of whom had a more extensive condition. One of these 5 patients underwent an endorectal pull-through (ERPT), 1 underwent intestinal transplantation, and 3 died. Four of the remaining 20 patients underwent a primary ERPT, 16 received a stoma as neonates followed by ERPT in 12, and a Martin-Duhamel procedure or Swenson's operation in 3 (median age, 10.5 months); 1 remains with an ostomy. Postoperative complications included enterocolitis (55%), anal stricture (25%), and perineal excoriation (20%). Mean follow-up were 17.5 years (+/-11.1 years). Eighty-nine percent were free of recurrent enterocolitis. Frequency of bowel movements is 1 to 5 per day in 82% of the patients, 18% have 6 or more bowel movements per day. Occasional soiling is noted in 40% (one third of those requiring nighttime diapers). Overall functional outcome was good in 83%. Those patients with the longest follow-up periods had the best stooling scores (P = .04). CONCLUSIONS: Surgical treatment of TCH is associated with a number of complications including recurrent enterocolitis and anal strictures. Long-term outcome is quite favorable.

Anastomosis, Surgical↗
PubMed2005

The effect of phenol on ingrown toenail excision in children.

PURPOSE: Ingrown toenails in children are a common problem with a high recurrence rate. The objective of this retrospective data review was to compare simple excision of the nail matrix with excision plus phenol (EPP) application in the treatment of ingrown toenails. METHODS: The charts of 69 children who underwent surgical treatment of one or more ingrown toenails from 1994 to 2000 were reviewed. The primary procedure was noted (excision alone [EA] vs EPP) and dates of recurrences and reoperations were recorded. Parents were then surveyed by phone regarding complications, cosmetic outcome, and overall satisfaction with the procedure. Five scale categories, ranging from "strongly agree" to "strongly disagree", were used, with responses of "strongly agree" and "agree" considered as a good outcome. Either Student's t test or the chi2 test (P < .05 considered significant) was used for analysis. RESULTS: Thirty-one patients (45%) were in the EPP group whereas the remaining 38 had EA. Mean length of follow-up was 4.3 years for the EA group and 2.1 years for the EPP group. There was no difference in age at operation or length of follow-up between the 2 groups. Boys were predominant in both groups. The survey response rate was 50/69 (73%). The recurrence rate of ingrown toenails in the EA group was 42% vs 4% in the EPP group (P = .003). There were no significant differences in parental response with regard to operative experience (P = .31) and the cosmetic result (P = .13), with most of the respondents (78%) indicating a good outcome for both questions. CONCLUSIONS: The addition of phenol to the surgical excision of ingrown toenail significantly reduced the incidence of recurrence, with similar patient satisfaction and an equivalent cosmetic result.

Adolescent↗
PubMed2005

Effect of sex and sex hormones on structural intestinal adaptation after massive small bowel resection in rats.

PURPOSE: The gonadal steroids play a major role in the regulation of many functions. The purpose of the current study was to evaluate the effect of sex and sex hormones on intestinal adaptation in a rat model of short bowel syndrome (SBS). METHODS: In the first experiment, male and female Sprague-Dawley rats underwent bowel transection and re-anastomosis (sham group) or 75% small bowel resection and anastomosis (SBS group). Relative changes in parameters of intestinal adaptation (overall bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth) were measured on day 15 and were compared with respect to sex. In the second experiment, male rats were divided into 4 experimental groups: SBS rats, SBS castrated rats, SBS castrated rats treated with testosterone, and SBS castrated rats treated with estradiol. Parameters of intestinal adaptation were compared with respect to hormonal treatment. Statistical significance was determined by Student's t test and analysis of variance with P < .05 considered significant. RESULTS: Sex had minimal effects on intestinal adaptation. Both male and female rats showed a comparable increase in all parameters of intestinal adaptation. In the second experiment, castration led to significant decrease in bowel and mucosal weight, mucosal DNA and protein in both jejunum and ileum compared with SBS animals. Castrated rats also had lower jejunal villus height and crypt depth compared with SBS animals. Testosterone attenuated this negative effect of castration on bowel regrowth. Rats treated with testosterone showed a significant increase in bowel and mucosal weight, mucosal protein in both jejunum and ileum, mucosal DNA, villus height, and crypt depth in jejunum compared with castrated nontreated animals. Treatment with estradiol after resection and castration had minimal effect on bowel regrowth. CONCLUSIONS: Bowel regrowth after massive small bowel resection is not sex-related. Depletion of androgens by castration inhibited intestinal adaptation. Testosterone has shown a strong stimulating effect on bowel regrowth.

Adaptation, Physiological↗
PubMed2004

Oral arginine improves intestinal recovery following ischemia-reperfusion injury in rat.

Arginine and nitric oxide are critical to the normal physiology of the gastrointestinal tract and maintain the mucosal integrity of the intestine in various intestinal disorders. In the present study, we evaluate the effects of oral arginine (ARG) supplementation on intestinal structural changes, enterocyte proliferation, and apoptosis following intestinal ischemia-reperfusion (IR) in the rat. Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent laparotomy and superior mesenteric artery mobilization, IR rats underwent superior mesenteric artery occlusion for 30 min following by 24 h of reperfusion, and IR-ARG rats were treated with enteral arginine given in drinking water (2%) 48 h before and following IR. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 24 h following IR. A nonparametric Kruskal-Wallis ANOVA test was used for statistical analysis with p <0.05 considered statistically significant. IR rats demonstrated a significant decrease in bowel weight in duodenum and jejunum, mucosal weight in jejunum and ileum, and villus height in jejunum and ileum compared with control animals. IR rats also had a significantly lower cell proliferation index in jejunum and ileum and a higher apoptotic index in ileum compared with control rats. IR-ARG animals demonstrated greater duodenal and jejunal bowel weight; duodenal, jejunal, and ileal mucosal weight; and jejunal and ileal cell proliferation index compared with IR animals. In conclusion, oral ARG administration improves mucosal recovery following IR injury in the rat.

Administration, Oral↗
PubMed2004

Effect of subcutaneous insulin on intestinal adaptation in a rat model of short bowel syndrome.

Insulin has been shown to influence intestinal structure and absorptive function. The purpose of the present study was to evaluate the effects of parenteral insulin on structural intestinal adaptation, cell proliferation, and apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection and reanastomosis, SBS rats underwent a 75% small bowel resection, and SBS-INS rats underwent a 75% small bowel resection and were treated with insulin given subcutaneously at a dose of 1 U/kg, twice daily, from day 3 through day 14. Parameters of intestinal adaptation, enterocyte proliferation, and enterocyte apoptosis were determined on day 15 following operation. SBS rats demonstrated a significant increase in jejunal and ileal bowel and mucosal weight, villus height and crypt depth, and cell proliferation index compared with the sham group. SBS-INS animals demonstrated higher jejunal and ileal bowel and mucosal weights, jejunal and ileal mucosal DNA and protein, and jejunal and ileal crypt depth compared with SBS animals. SBS-INS rats also had a greater cell proliferation index in both jejunum and ileum and a trend toward a decrease in enterocyte apoptotic index in jejunum and ileum compared with the SBS untreated group. In conclusion, parenteral insulin stimulates structural intestinal adaptation in a rat model of SBS. Increased cell proliferation is the main mechanism responsible for increased cell mass.

Adaptation, Physiological↗
PubMed2004

Effect of dietary fat on early morphological intestinal adaptation in a rat with short bowel syndrome.

Among factors promoting mucosal hyperplasia after bowel resection, long-chain fatty acids may have a special role. The purpose of the present study was to evaluate the effects of high-fat diet (HFD) on early intestinal adaptation in rats with short bowel syndrome (SBS). Male Sprague-Dawley rats underwent either a bowel transection with re-anastomosis (Sham rats) or 75% small bowel resection (SBS rats). Animals were randomly assigned to one of three groups: Sham rats fed normal chow (Sham-NC); SBS rats fed NC (SBS-NC); and SBS rats fed HFD (SBS-HFD). Rats were killed on days 3 or 14. Body weight and parameters of intestinal adaptation (overall bowel and mucosal weight, mucosal DNA and protein, villus height, and crypt depth) were determined at time of killing. By day 3, SBS-HFD rats demonstrated higher duodenal and jejunal bowel and mucosal weights and ileal villus height and jejunal crypt depth vs SBS-NC rats. By day 14 SBS-HFD rats continued to demonstrate increased duodenal and jejunal bowel weight and duodenal mucosal weight vs SBS-NC animals. We conclude that early exposure to HFD both augmented and accelerated structural bowel adaptation in a rat model of SBS.

Adaptation, Physiological↗