Biomedical subjects

M Yamakage

Publications and source records attributed to M Yamakage.

At least 37 records · Page 2Linked to original sources

PubMed2000

Low-temperature modification of the inhibitory effects of volatile anesthetics on airway smooth muscle contraction in dogs.

BACKGROUND: Because exposure to low temperature can modify the effect of volatile anesthetics on airway smooth muscle contraction, this study was conducted to investigate low-temperature modifications of the inhibitory effects of isoflurane and sevoflurane on canine tracheal smooth muscle tone by simultaneously measuring the muscle tension and intracellular concentration of Ca2+ ([Ca2+]i) and by measuring voltage-dependent Ca2+ channel activity. METHODS: [Ca2+]i was monitored by the 500-nm light emission ratio of preloaded fura-2, a Ca2+ indicator. Isometric tension was measured simultaneously. Whole cell patch clamp recording techniques were used to observe voltage-dependent Ca2+ channel activity in dispersed muscle cells. Isoflurane (0-3.0%) or sevoflurane (0-3%) was introduced to a bath solution at various temperatures (37, 34, or 31 degrees C). RESULTS: Low temperature (34 or 31 degrees C) reduced high-K+-induced (72.7 mm) muscle contraction and increased [Ca2+]i, but it enhanced carbachol-induced (1 microm) muscle contraction with a decrease in [Ca2+]i. The volatile anesthetics tested showed significant inhibition of both high-K+-induced and carbachol-induced airway smooth muscle contraction, with a concomitant decrease in [Ca2+]i. The inhibition of the carbachol-induced muscle contraction by volatile anesthetics was abolished partially by exposure to low temperature. Volatile anesthetics and low-temperature exposure significantly inhibited voltage-dependent Ca2+ channel activity of the smooth muscle. CONCLUSIONS: Exposure of airway smooth muscle to low temperature leads to an increase in agonist-induced muscle contractility, with a decrease in [Ca2+]i. The inhibition of voltage-dependent Ca2+ channel activity by exposure to low temperature and by volatile anesthetics cam be attributed, at least in part, to the decrease in [Ca2+]i.

Anesthetics, Inhalation↗

PubMed2000

[Anesthetic management of a patient with Freeman-Sheldon syndrome].

We describe a case of Freeman-Sheldon syndrome that presented some problems for anesthetic management. A 2-yr-old girl required orthopedic surgery for the bilateral lower extremities. Anesthesia was induced via a mask with oxygen (2 l.min-1), nitrous oxide (4 l.min-1) and sevoflurane (approximately 5%). Tracheal intubation by direct laryngoscopy was successfully achieved. Combined caudal epidural block was, however, avoided because spina bifida occulta was suspected. Spina bifida occulta was revealed postoperatively by X-ray. For anesthetic management of a patient with Freeman-Sheldon syndrome, the spine should be evaluated preoperatively when performing epidural/spinal anesthesia.

Abnormalities, Multiple↗

PubMed1999

Effects of adrenergic stimulus on the activities of Ca2+ and K+ channels of dorsal root ganglion neurons in a neuropathic pain model.

We hypothesized that abnormal activity and adrenergic sensitivity in injured dorsal root ganglion (DRG) neurons are due to an intrinsic alteration of the cell body membrane. We investigated the effects of adrenergic stimulus on the activities of Ca2+ and K+ channels of DRG neurons in a rat chronic constriction injury (CCI) model. At first, we demonstrated thermal hyperalgesia and sprouting sympathetic nerve fibers in the ipsilateral L4-L5 DRGs. Using whole-cell patch clamp techniques, we found that alpha2-adrenergic stimulus by 10 microM norepinephrine (NE) inhibited inward currents (IBa, Ba2+ as a charge carrier) through voltage-dependent Ca2+ channels (VDCCs) of DRGs in the CCI model by 42%, whereas it enhanced the IBa by 18% in control animals. The inhibitory effect of NE disappeared by pretreatment with the N-type VDCC antagonist omega-conotoxin GVIA (1 microM). NE shifted the inactivation curve to a more negative potential, showing that it has inhibitory effects on IBa both in activated and in inactivated states. alpha2-Adrenergic stimulus also inhibited outward K+ currents by 24% in the CCI model, while it had no effect on the currents in control animals. The inhibitory effect of NE was blocked by pretreatment with the Ca2+-activated K+ (KCa) channel antagonist charybdotoxin (40 nM). The NE-induced inhibitory effects both on N-type VDCC and on KCa channels in injured DRG neurons of the CCI model could lead to cell membrane depolarization, resulting in a spontaneous discharge of action potential and an increase in sensitivity to adrenergic stimulus.

Animals↗

PubMed1999

Changes in respiratory pattern and arterial blood gases during sedation with propofol or midazolam in spinal anesthesia.

STUDY OBJECTIVE: To investigate changes in respiratory pattern and arterial blood gases during sedation with propofol or midazolam in spinal anesthesia. DESIGN: Randomized, placebo-controlled study. SETTING: Operating room of a university-affiliated hospital. PATIENTS: 40 ASA physical status I and II patients who required spinal anesthesia. INTERVENTIONS: Spinal anesthesia with tetracaine and subsequent sedation with propofol (n = 15), midazolam (n = 15), or placebo (n = 10) was performed. MEASUREMENTS: Respiratory pattern [rib cage contribution to the tidal volume (%RC) and phase shift between rib cage and abdominal movements (PSrc-ab)] with a respiratory inductive plethysmograph (Respigraph) and arterial blood gas analysis (pH, pO2, and pCO2) were recorded. MAIN RESULTS: Spinal anesthesia per se increased %RC by 35% without changing PSrc-ab values (1.00). Sedation with propofol and midazolam decreased %RC by 60% and by 40%, respectively. PSrc-ab increased in both groups following sedation, and the increase in this parameter was higher in the propofol group (1.12) than in the midazolam group (1.04). In the placebo group, %RC decreased by 20% without any change in PSrc-ab. The decrease in pO2 was more significant in the propofol group (65.1 mmHg) than in the midazolam (74.2 mmHg) and placebo (83.1 mmHg) groups. CONCLUSION: Significant decreases in %RC and pO2 during propofol sedation seem to depend on paradoxical respiration due, in part, to upper airway obstruction; therefore, attention should be directed to the respiratory pattern during sedation, especially with propofol.

Adult↗

PubMed1999

In vitro effects of propofol on blood coagulability and fibrinolysis by the use of thromboelastograph technique.

BACKGROUND: To investigate the in vitro effects of propofol on blood coagulability and fibrinolysis by the use of thromboelastograph (TEG) technique. METHODS: The blood samples, obtained from 14 healthy volunteers, were divided into two groups: propofol (n = 7) and intralipid (n = 7), and 360 microliters volumes of whole blood were incubated with 2 microliters of 1% propofol and with its solvent intralipid, respectively. The incubated sample was then used for TEG measurements. RESULTS: The maximum amplitude (MA), which reflects coagulability, in the intralipid group significantly increased by about 7% and 16% compared to the control and propofol groups, respectively (P < 0.05), whereas the MA in the propofol group did not change. The fibrinolytic rate (FR) in the propofol group significantly increased by about 170% and 210% compared to the control and intralipid groups, respectively (P < 0.05), whereas the FR in the intralipid group did not change. CONCLUSIONS: Propofol, per se, has at the concentration of 55.6 micrograms.ml-1 an in vitro accelerative effect on blood fibrinolysis detected by TEG.

Anesthetics, Intravenous↗

PubMed1999

The direct effects of heparin and protamine on canine tracheal smooth muscle tone.

UNLABELLED: Heparin and protamine are used for cardiopulmonary bypass in cardiac surgery; however, the direct effects and mechanisms of these drugs on airway smooth muscle tone are still not fully known. We investigated the in vitro effects of these drugs on canine tracheal smooth muscle by measuring the muscle tension and intracellular Ca2+ concentration ([Ca2+]i) and by measuring inward Ca2+ currents (I(Ca)) through voltage-dependent Ca2+ channels. [Ca2+]i was monitored by the 500-nm light emission ratio of preloaded Ca2+ indicator fura-2. Isometric tension was measured simultaneously. Whole-cell patch clamp recording techniques were used to investigate the effects of the drugs on I(Ca) in freshly dispersed smooth muscle cells. Heparin (0.12-120 U/mL), protamine (0.15-150 U/mL), or heparin-protamine complex (4:5 U/U) was introduced into a bath solution. Protamine and heparin-protamine complex dose-dependently inhibited both carbachol-induced contraction of the muscle and increase in [Ca2+]i. These drugs also decreased the I(Ca) of the muscle cells and shifted the inactivation curve to a more negative potential. Heparin itself had a slight enhancing effect on carbachol-induced muscle contraction without changing [Ca2+]i. Protamine and heparin-protamine complex can decrease the agonist-induced increase in [Ca2+]i by the inhibition of voltage-dependent Ca2+ channels both in the activated and inactivated states. IMPLICATIONS: Protamine and heparin-protamine complex inhibited carbachol-induced canine tracheal smooth muscle contraction by inhibiting the increase in intracellular concentration of free Ca2+. These drugs can decrease the agonist-induced increase in intracellular Ca2+ by the inhibition of voltage-dependent Ca2+ channels in both the activated and inactivated states.

Animals↗

PubMed1999

Inhibitory effects of diazepam and midazolam on Ca2+ and K+ channels in canine tracheal smooth muscle cells.

BACKGROUND: Benzodiazepines have a direct bronchodilator action in airway smooth muscle, but the mechanisms by which these agents produce muscle relaxation are not fully understood. The current study was performed to identify the effects of the benzodiazepines diazepam and midazolam on Ca2+ and K+ channels in canine tracheal smooth muscle cells. METHODS: Whole-cell patch-clamp recording techniques were used to evaluate the effects of the benzodiazepines diazepam (10(-8) to 10(-3) M) and midazolam (10(-8) to 10(-3) M) on inward Ca2+ and outward K+ channel currents in dispersed canine tracheal smooth muscle cells. The effects of the antagonists flumazenil (10(-5) M) and PK11195 (10(-5) M) on these channels were also studied. RESULTS: Each benzodiazepine tested significantly inhibited Ca2+ currents in a dose-dependent manner, with 10(-6) M diazepam and 10(-5) M midazolam each causing approximately 50% depression of peak voltage-dependent Ca2+ currents. Both benzodiazepines promoted the inactivated state of the channel at more-negative potentials. The Ca2+-activated and voltage-dependent K+ currents were inhibited by diazepam and midazolam (> 10(-5) M and > 10(-4) M, respectively). Flumazenil and PK11195 had no effect on these channel currents or on the inhibitory effects of the benzodiazepines. CONCLUSIONS: Diazepam and midazolam had inhibitory effects on voltage-dependent Ca2+ channels, which lead to muscle relaxation. However, high concentrations of these agents were necessary to inhibit the K+ channels. The lack of antagonized effects of their antagonists is related to the non-gamma-aminobutyric acid-mediated electrophysiologic effects of benzodiazepines on airway smooth muscle contractility.

Anesthetics, Intravenous↗

PubMed1999

[Utility of an infrared ear thermometer as an intraoperative core temperature monitor].

We investigated the utility of an infrared ear thermometer (M 10, Terumo) as an intraoperative core temperature monitor. Temperatures of the axilla and inner ear were measured before and after anesthesia. Bladder, rectal, and forehead deep temperatures were continuously measured using a core temperature monitor (CTM-205, Terumo) during anesthesia. At the same time, the temperature of the inner ear was measured 4 times every 15 minutes (twice from cephalad and twice from caudal directions). There were no significant differences in the measured inner ear temperatures, either between directions of measurement or between the 1st and 2nd measurements. The inner ear temperature showed a close correlation with rectal, bladder, forehead deep, and axillary temperatures (r = 0.72-0.79, P < 0.01). The smallest temperature difference in this study was found to be that between the inner ear and forehead deep temperatures (-0.10), and the limit of agreement between these temperatures was also the smallest (0.81). In conclusion, we recommended the use of an infrared ear thermometer as an intraoperative core temperature monitor, especially in lower abdominal surgery, in which neither rectal nor bladder temperature monitoring is reliable.

Anesthesia, General↗

PubMed1998

The usefulness of celite-activated thromboelastography for evaluation of fibrinolysis.

PURPOSE: Although thromboelastography is useful for measuring both coagulability and fibrinolysis, it takes about two hours to measure all parameters including fibrinolytic rate. The present study aimed to investigate the usefulness of celite-activated thromboelastography (TEGc) to evaluate fibrinolytic status in non-cardiac surgery. METHODS: Whole blood samples were obtained from 30 patients for non-cardiac surgery, and used for measurements of both native TEG (TEGn) and TEGc. The final concentration of 1% (w/v) celite was used for TEGc. RESULTS: Time for measurement of the fibrinolytic rate (FR) of TEGc in patients (56.7 +/- 4.0 min) was less than half that of FR of TEGn (123.3 +/- 15.6 min) (P < 0.05), suggesting a more rapid assessment of fibrinolytic status. A linear relationship was observed between FR values of TEGc and those of TEGn (r = 0.93, P < 0.0001), suggesting the usefulness of the fibrinolytic parameter of TEGc. CONCLUSION: TEGc is a useful technique for a more rapid assessment of fibrinolytic status.

Adult↗

PubMed1998

Triggering delay time and work of breathing in three paediatric patient-triggered ventilators.

PURPOSE: To compare the effectiveness of three patient-triggered ventilators by evaluating triggering delay time and pressure-volume loops during initiation of inspiration. METHODS: In a two-part study, a model lung was used in part 1 and 20 children, after tracheal intubation, in part 2. Triggering delay time and work of breathing (WOB) during pressure support ventilation using three patient-triggered ventilators: Servo Ventilator 300, VIP Bird, and SLE 2000 Neonatal Ventilator. Triggering delay time was from the beginning of negative deflection in the oesophageal pressure trace, to the onset of inspiration. The WOB was estimated directly by measuring the oesophageal pressure-volume loop. RESULTS: The Servo demonstrated superior triggering delay time and reduced WOB in the model study. The VIP Bird demonstrated shorter triggering delay and reduced WOB in the clinical component of the study. In the model lung, triggering delay time in the Servo 300 [62 +/- 6 msec (mean +/- SD)] was shorter than that in the VIP Bird (76 +/- 7 msec) (P < 0.05), and WOB with the SLE 2000 (202 +/- 37 g.cm) was greater than with other ventilators, (Servo 300, 112 +/- 32 g.cm and VIP Bird 72 +/- 41 g.cm) (P < 0.05). In the clinical study, triggering delay time in the VIP Bird (52 +/- 19 msec) was shorter than in the other ventilators, Servo 300 (66 +/- 14 msec), SLE 2000 (68 +/- 65 msec) (P < 0.05). The Servo 300 (56 +/- 34 g.cm) required higher WOB than the other ventilators: VIP Bird (22 +/- 12 g.cm), SLE 2000 (14 +/- 3 g.cm) (P < 0.05). CONCLUSION: Comparative model lung performance of these ventilators does not correspond with their clinical performance. In our clinical evaluation, the VIP Bird ventilator demonstrated superior performance with shorter triggering delay time, low WOB needed to initiate inspiration, and little air leak.

Air Pressure↗

PubMed1998

Surgical/tourniquet pain accelerates blood coagulability but not fibrinolysis.

Tissue damage during surgery induces coagulation factors and activates platelets. Surgical pain may provoke release of catecholamines, leading to hypercoagulability. We have investigated the effect of surgical pain on blood coagulability and fibrinolysis in orthopaedic operations using tourniquets in 22 patients undergoing total knee replacement. Patients were allocated to one of two groups to receive extradural anaesthesia (EA; n = 11) or general anaesthesia (GA; n = 11). The EA group received lumbar extradural block with lidocaine. The GA group received only general anaesthesia, maintained with 1.5-2.5% sevoflurane and 66% nitrous oxide in oxygen. Using a thrombelastogram technique, blood coagulability and fibrinolysis were measured. Mean maximum amplitude (MA), which reflects coagulability, increased after tourniquet inflation (11%) in group GA whereas MA in group EA did not change. After tourniquet deflation, MA values in both GA and EA groups increased significantly (10% and 20%, respectively) (P < 0.05), and there was also a significant difference in MA between groups (P < 0.05). The fibrinolytic rate did not change in either group during tourniquet inflation, but increased significantly (160%) after tourniquet deflation. There was no significant difference in fibrinolytic rate between the groups. We conclude that the hypercoagulability seen in group GA could have been caused by surgical or tourniquet pain, or both, and that extradural anaesthesia is a useful technique to prevent hypercoagulability.

Aged↗

PubMed1998

Role of intracellular Ca2+ stores in the inhibitory effect of halothane on airway smooth muscle contraction.

BACKGROUND: Halothane directly inhibits contraction of airway smooth muscle, mainly by decreasing the intracellular concentration of free Ca2+ ([Ca2+]i). The role of intracellular Ca2+ stores, sarcoplasmic reticulum, is still unclear. We investigated the role of sarcoplasmic reticulum in the inhibitory effect of halothane on contraction of airway smooth muscle by measuring [Ca2+]i and intracellular concentration of inositol 1,4,5-triphosphate ([IP3]i), a second messenger for release of Ca2+ from sarcoplasmic reticulum. METHODS: [Ca2+]i was monitored by measuring the 500-nm light emission ratio (F340/F380) of a Ca2+ indicator fura-2 with isometric tension of canine tracheal smooth muscle strip. During Ca2+-free conditions, carbachol (10(-5) M) was introduced with pretreatment of halothane (0-3%). During Ca2+-free conditions, 20 mM caffeine, a Ca2+-induced Ca2+ release channel opener, was introduced with or without halothane. We measured [IP3]i during exposure to carbachol and halothane by radioimmunoassay technique. RESULTS: Pretreatment with halothane significantly diminished carbachol-induced increases in [Ca2+]i by 77% and muscle tension by 83% in a dose-dependent manner. Simultaneous administration of halothane significantly enhanced caffeine-induced transient increases in [Ca2+]i and muscle tension in a dose-dependent manner, by 97% and 69%, respectively. Pretreatment with halothane abolished these responses. Rapid increase in [IP3]i produced by carbachol was significantly inhibited by 32% by halothane in a dose-dependent manner. CONCLUSIONS: Halothane, during Ca2+-free conditions, inhibits transient contraction of airway smooth muscle induced by muscarinic receptor stimulation, mainly by attenuating the increase in [Ca2+]i. Depletion of Ca2+ from sarcoplasmic reticulum via Ca2+-induced Ca2+ release channels also may contribute to the attenuation of the increase in [Ca2+]i by halothane.

Anesthetics, Inhalation↗

PubMed1998

[Changes in circulation and end-tidal sevoflurane concentration during infusion of sevoflurane into vaporizer].

We observed the changes in circulation and endtidal sevoflurane concentration during the infusion of the anesthetic into a vaporizer, and investigated some techniques to prevent these changes during general anesthesia. The patients were randomly divided into three groups: conventional, high concentration (conc.) and low flow groups. Inspiratory concentration of sevoflurane was kept at 1.0% and the duration of the pause in sevoflurane supply was 90 sec. The high conc. group was exposed to 2.0% sevoflurane for 60 sec. just before and after the pause, and the low flow group had a low fresh gas flow (0.5 l.min-1) during the pause. An increase in blood pressure and a tendency towards tachycardia were observed in the conventional group, and the circulation was kept constant best in the low flow group. The lowest concentrations of sevoflurane during the pause were 0.46, 0.46 and 0.93% in the conventional, high conc., and low flow groups, respectively, and exposure to high concentration of the anesthetic could not prevent the decrease. These results indicate that low flow anesthesia is a useful technique to prevent undesirable changes in circulation and anesthetic concentration.

Anesthesia, Epidural↗

PubMed1998

[An analysis of the status of surgical transfusion in Sapporo Medical University Hospital].

To evaluate the present status of blood transfusion during operation in our hospital, we retrospectively analyzed the amount of preoperative preparation & intraoperative use of homologous blood and the circumstances of autologous blood transfusions. The amount of prepared blood was 4,505 units of which 1,187 units were transfused; the mean cross matched-to-transfused (C/T) ratio was 3.8. A trial of maximum surgical blood order schedule (MSBOS, C/T = 1.5) revealed that we could save over 70% of the homologous blood presently prepared. Preoperative blood donation (PBD) and intraoperative autologous blood transfusion (IAT) were performed in 74 cases (47.4%) and 55 cases (35.3%), respectively, of all 156 blood-transfused cases, and the operations were performed without homologous blood transfusion in 88.0% of PBD cases and 67.3% of IAT cases respectively. We are sure that the introduction of MSBOS will lead to a more efficient use of autologous blood, and that we should use homologous blood transfusion techniques so far as is possible to avoid autologous blood transfusion.

Blood Loss, Surgical↗

PubMed1998

[The effect of scalp infiltration with bupivacaine on blood coagulability and fibrinolysis in neurovascular surgery].

We investigated the effect of scalp infiltration with bupivacaine on blood coagulability and fibrinolysis in neurovascular surgery. Patients were randomly divided into two groups: scalp infiltration group (who received scalp infiltration with 0.5% bupivacaine prior to surgical incision, n = 7) and control group (n = 6). The blood coagulability and fibrinolysis were measured before and after surgical incision using a thromboelastogram (Thromboelastograph C-3000, Haemoscope). In the control group, the reaction and coagulation times were significantly shortened (30% and 23%, respectively, P < 0.05) and the maximum amplitude, which reflects coagulability, increased significantly (21%, P < 0.01) compared to each presurgical value. The scalp infiltration prior to the surgical incision prevented these reactions (P < 0.05). The fibrinolytic rate did not change in either group. We conclude that scalp infiltration prior to surgical incision is beneficial for attenuating an increase in blood coagulability, which could induce perioperative complications due to associated systemic diseases (i.e. hypertension, diabetes, ischemic heart disease, etc.).

Aged↗

PubMed1998

[Two cases of clipping surgery of cerebral aneurysm under profound hypothermia with closed-chest extracorporeal circulation].

A 68-year-old female and a 47-year-old male patients underwent clipping surgery for giant basilar arterial and thrombotic internal carotid arterial aneurysms respectively with closed-chest extracorporeal circulation (femoro-femoral bypass). Profound hypothermia and continuous infusion of thiamylal were used to prevent brain damage. Blood outflow via the femoral vein was sufficient to induce profound hypothermia down to 20 degrees C. Hemodynamics were controllable without catecholamines during closed-chest extracorporeal circulation. Preoperative symptoms significantly improved and no neurological complication was observed in either case postoperatively. Right femoral phlebothrombosis was, however, observed in one case. In conclusion, profound hypothermia with closed-chest extracorporeal circulation is a safe technique to reduce the complications induced by open-chest technique, but special attention should be given to postoperative phlebothrombosis.

Aged↗

PubMed1998

[Preventive effect of fluid warmer system on hypothermia induced by rapid intravenous infusion].

The changes in body temperature induced by rapid intravenous infusion of lactated Ringer solution and the effect of a fluid warmer system (HOT LINE, Level 1 Technologies, Inc., Rockland, MD) were investigated in 35 patients undergoing cardiovascular surgery. The patients were divided into 5 groups by categories of the fluid temperature (-19 or -38 degrees C), infusion route (radial or right subclavian vein), and infusion rate of lactated Ringer solution (1000 or 250 ml for 30 min). Pulmonary arterial, esophageal, bladder, and forehead deep temperatures, which reflect core temperature, were significantly decreased by the rapid infusion of unwarmed solution (0.8-1.0 degree C, P < 0.05). In contrast, these temperatures were maintained in the warmed solution groups as well as in the group of slow infusion rate. With regard to the infusion route, there was no significant difference in the temperature between the radial vein and subclavian vein groups. Plantar deep temperature showed no significant change during this study. In conclusion, infusion of warmed solution using HOT LINE could prevent hypothermia induced by rapid intravenous infusion, and this effect is not greatly influenced by route of venous infusion.

Adult↗

PubMed1998

[Evaluation of risks for postoperative pulmonary complications using a preoperative consultation system].

We retrospectively investigated the perioperative management and postoperative pulmonary complications of patients who had preoperative respiratory problems and consultations with anesthesiologists. These patients numbered eight hundred, 23.7% of all patients who had preoperative consultations, and 40.9% and 62.0% of the 800 had preoperative and postoperative respiratory management, respectively. Forty eight patients (6.0%) received postoperative artificial respiration. One hundred and twenty four patients (15.5%) had some respiratory complications post-operatively, and 5 patients (0.7%) died mainly because of the complications. In an evaluation of these patients with the modified predicted risk factors of Okutsu including the obesity factor and smoking history, there was no respiratory complication in patients under 14 points. Patients with high points of more than 20 included almost all of the patients (114 patients, 91.9%) who had postoperative respiratory complications. We conclude that our preoperative consultation system works well and that the modified predicted-risk factors for postoperative pulmonary complications is useful for the standardization and objectivity of preoperative patient evaluation.

Humans↗