Impact of Age 70 years or Older on Donors for Living-Donor Kidney Transplantation.

Introduction: Kidney transplantation (KT) involving elderly living kidney donors (LKDs) is becoming more frequent because of a profound organ shortage. The efficacy of KT involving grafts obtained from LKDs aged 70 years or older has been reported. However, the safety of donor nephrectomy in LKDs aged 70 years or older, including that associated with changes in the estimated glomerular filtration rate (eGFR), has not been investigated. This study investigated the outcomes of LKDs aged 70 years or older after donor nephrectomy. Methods: This single-center, retrospective cohort study included 1226 LKDs who underwent donor nephrectomy between January 2008 and December 2020. LKDs were stratified into the following age groups: 30 to 49 years (244 LKDs), 50 to 69 years (803 LKDs), and 70 to 89 years (179 LKDs). Surgical outcomes, postoperative eGFR changes, end-stage renal disease (ESRD) rates, and mortality rates were compared among these groups. Results: No significant difference in surgical outcomes was identified among the groups. LKDs aged 70 to 89 years experienced the lowest eGFR changes at all time points and the lowest eGFR improvement; however, ESRD was not identified in any group during the observation period. Mortality was the highest among LKDs aged 70 to 89 years compared to the other age groups. Conclusion: Surgical outcomes, eGFR changes, and ESRD incidences can support the safety of donor nephrectomy in LKDs aged 70 years or older. Considering the advanced age, the high mortality rates in LKDs aged 70 years or older could be considered acceptable.

Pre-Transplant Calcimimetic Use and Dose Information Improves the Accuracy of Prediction of Tertiary Hyperparathyroidism after Kidney Transplantation: A Retrospective Cohort Study.

Tertiary hyperparathyroidism (THPT) is characterized by elevated parathyroid hormone and serum calcium levels after kidney transplantation (KTx). To ascertain whether pre-transplant calcimimetic use and dose information would improve THPT prediction accuracy, this retrospective cohort study evaluated patients who underwent KTx between 2010 and 2022. The primary outcome was the development of clinically relevant THPT. Logistic regression analysis was used to evaluate pre-transplant calcimimetic use as a determinant of THPT development. Participants were categorized into four groups according to calcimimetic dose, developing two THPT prediction models (with or without calcimimetic information). Continuous net reclassification improvement (CNRI) and integrated discrimination improvement (IDI) were calculated to assess ability to reclassify the degree of THPT risk by adding pre-transplant calcimimetic information. Of the 554 patients, 87 (15.7%) developed THPT, whereas 139 (25.1%) received pre-transplant calcimimetic treatment. Multivariate logistic regression analysis revealed that pre-transplant calcimimetic use was significantly associated with THPT development. Pre-transplant calcimimetic information significantly improved the predicted probability accuracy of THPT (CNRI and IDI were 0.91 [p < 0.001], and 0.09 [p < 0.001], respectively). The THPT prediction model including pre-transplant calcimimetic information as a predictive factor can contribute to the prevention and early treatment of THPT in the era of calcimimetics.

Asymptomatic 3-methylglutaconic aciduria type 1 detected by high C5-OH on newborn screening.

3-Methylglutaconic aciduria type 1 (MGCA1) is an inborn error of leucine catabolism caused by pathogenic variants of the AUH gene. MGCA1 can be identified by newborn screening (NBS) with elevated C5-OH levels. We herein report a girl with MGCA1 detected by NBS. On day 5 after birth, NBS detected high C5-OH levels of 1.17 µmol/L (1.56 µmol/L [retest]). A urinary organic acid analysis revealed the abnormal excretion of 3-methylglutaconic, 3-methylglutaric, and 3-hydroxyisovaleric acids. Two novel heterozygous loss-of-function variants in the AUH gene were identified by genetic testing. We observed the patient without any treatment, such as a leucine-restricted diet. She had episodes of febrile illness several times in infancy but did not develop febrile convulsions or encephalopathy. She is now two years and six months old, and her physical growth and psychomotor development have progressed normally. In a review of the literature and our case, four children with MGCA1 identified during the neonatal period were asymptomatic or exhibited speech delay, regardless of whether or not they had been managed with specific treatments. Treatments such as dietary leucine restriction and carnitine supplementation may have little effect on MGCA1 in childhood; however, further investigation is warranted to evaluate the benefits of specific treatments to prevent potential long-term neurological complications.

Edoxaban eliminates hypercoagulability evoked by transient temperature changes in human whole blood.

Background: Thrombosis is a common critical complication relating to radiofrequency catheter ablation and cryoablation. There is a possibility that high-temperature stimulation during radiofrequency ablation or low-temperature stimulation during cryoablation may affect the coagulability of blood. In this study, we aimed to determine the impacts of transient temperature stimulations on the coagulability of whole blood and to clarify if edoxaban suppressed the hypercoagulability. Methods: Citrated blood samples were drawn from 41 healthy subjects. Some blood samples were mixed with tissue factor (TF) and several concentrations of edoxaban (50, 100, and 200 ng/mL). Blood samples were exposed to several temperature stimulations for 1 min: heat stimulation (50°C) or cryostimulation (-20°C), and compared with control (37°C). Repeated cryostimulations or sequential cryo- and heat stimulation were also applied. Coagulability of whole blood was measured using a dielectric blood coagulometry. As an index of coagulability, the end of acceleration time (EAT) was used. Results: Both heat- and cryostimulations significantly shortened the EAT compared to the control, indicating that hypercoagulability was induced by temperature stimulations. Application of TF enhanced and extended the hypercoagulability after the temperature stimulations. Sequential application of cryo- followed by heat stimulation further enhanced the hypercoagulability of blood. Application of edoxaban increased the EAT in a concentration-dependent manner in control condition. Edoxaban at 100 or 200 ng/mL completely suppressed the shortening of EAT evoked by these temperature stimulations. Conclusion: Transient temperature stimulations evoked hypercoagulability regardless of cryo- or heat stimulation. Edoxaban with 100 ng/mL or more eliminated this temperature-stimulated hypercoagulability.

Prediction models for the recipients' ideal perioperative estimated glomerular filtration rates for predicting graft survival after adult living-donor kidney transplantation.

Introduction: The impact of the perioperative estimated glomerular filtration rate (eGFR) on graft survival in kidney transplant recipients is yet to be evaluated. In this study, we developed prediction models for the ideal perioperative eGFRs in recipients. Methods: We evaluated the impact of perioperative predicted ideal and actual eGFRs on graft survival by including 1,174 consecutive adult patients who underwent living-donor kidney transplantation (LDKT) between January 2008 and December 2020. Prediction models for the ideal perioperative eGFR were developed for 676 recipients who were randomly assigned to the training and validation sets (ratio: 7:3). The prediction models for the ideal best eGFR within 3 weeks and those at 1, 2, and 3 weeks after LDKT in 474 recipients were developed using 10-fold validation and stepwise multiple regression model analyzes. The developed prediction models were validated in 202 recipients. Finally, the impact of perioperative predicted ideal eGFRs/actual eGFRs on graft survival was investigated using Fine-Gray regression analysis. Results: The correlation coefficients of the predicted ideal best eGFR within 3 weeks and the predicted ideal eGFRs at 1, 2, and 3 weeks after LDKT were 0.651, 0.600, 0.598, and 0.617, respectively. Multivariate analyzes for graft loss demonstrated significant differences in the predicted ideal best eGFR/actual best eGFR within 3 weeks and the predicted ideal eGFRs/actual eGFRs at 1, 2, and 3 weeks after LDKT. Discussion: The predicted ideal best eGFR/actual best eGFR within 3 weeks and the predicted ideal eGFRs/actual eGFRs at 1, 2, and 3 weeks after LDKT were independent prognostic factors for graft loss. Therefore, the perioperative predicted ideal eGFR/actual eGFR may be useful for predicting graft survival after adult LDKT.

Maximal parathyroid gland diameter as a predictive factor for autograft-dependent recurrent secondary hyperparathyroidism after total parathyroidectomy.

Introduction: Following total parathyroidectomy (PTx), transcervical thymectomy, and forearm autograft for secondary hyperparathyroidism (SHPT), recurrent SHPT can occur in the autografted forearm. However, few studies have investigated the factors contributing to re-PTx due to autograft-dependent recurrent SHPT before the completion of the initial PTx. Methods: A total of 770 patients who had autografted parathyroid fragments derived from only one of the resected parathyroid glands (PTGs) and who had undergone successful initial total PTx and transcervical thymectomy-defined by serum intact parathyroid hormone level < 60 pg/mL on postoperative day 1-between January 2001 and December 2022 were included in this retrospective cohort study. Factors contributing to re-PTx due to graft-dependent recurrent SHPT before the completion of the initial PTx were investigated using multivariate Cox regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to obtain the optimal maximum diameter of PTG for autograft. Results: Univariate analysis showed that dialysis vintage and maximum diameter and weight of the PTG for autograft were significant factors contributing to graft-dependent recurrent SHPT. However, multivariate analysis revealed that dialysis vintage (P=0.010; hazard ratio [HR], 0.995; 95% confidence interval [CI], 0.992-0.999) and the maximum diameter of the PTG for autograft (P=0.046; HR, 1.107; 95% CI, 1.002-1.224) significantly contributed to graft-dependent recurrent SHPT. ROC curve analysis showed that < 14 mm was the optimal maximum diameter of PTG for autograft (area under the curve, 0.628; 95% CI, 0.551-0.705). Conclusions: The dialysis vintage and maximum diameter of PTG for autograft may contribute to re-PTx due to autograft-dependent recurrent SHPT, which can be prevented by using PTGs with a maximum diameter of < 14 mm for autograft.

Improved electrochemical properties of graphite electrodes incubated with iron powders in rice-paddy fields boost power outputs from microbial fuel cells.

Studies have shown that the supplementation of anode-surrounding soil with zero-valent iron (ZVI) boosts power outputs from rice paddy-field microbial fuel cells (RP-MFCs). In order to understand mechanisms by which ZVI boosts outputs from RP-MFCs, the present study operated RP-MFCs with and without ZVI, and compositions of anode-associated bacteria and electrochemical properties of graphite anodes were analyzed after 3-month operation. Metabarcoding using 16S rRNA gene fragments showed that bacterial compositions did not largely differ among these RP-MFCs. Cyclic voltammetry showed improved electrochemical properties of anodes recovered from ZVI-supplemented RP-MFCs, and this was attributed to the adhesion of iron-oxide films onto graphite surfaces. Bioelectrochemical devices equipped with graphite anodes recovered from ZVI-supplemented RP-MFCs generated higher currents than those with fresh graphite anodes. These results suggest that ZVI is oxidized to iron oxides in paddy-field soil and adheres onto graphite anodes, resulting in the boost of power outputs from RP-MFCs.

Persistent hyperparathyroidism after preemptive kidney transplantation.

BACKGROUND: Long-term dialysis vintage is a predictor of persistent hyperparathyroidism (HPT) after kidney transplantation (KTx). Recently, preemptive kidney transplantation (PKT) has increased. However, the incidence, predictors, and clinical implications of HPT after PKT are unclear. Here, we aimed to elucidate these considerations. METHODS: In this retrospective cohort study, we enrolled patients who underwent PKT between 2000 and 2016. Those who lost their graft within 1 year posttransplant were excluded. HPT was defined as an intact parathyroid hormone (PTH) level exceeding 80 pg/mL or hypercalcemia unexplained by causes other than HPT. Patients were divided into two groups based on the presence of HPT 1 year after PKT. The primary outcome was the predictors of HPT after PKT, and the secondary outcome was graft survival. RESULTS: Among the 340 consecutive patients who underwent PKT, 188 did not have HPT (HPT-free group) and 152 had HPT (HPT group). Multivariate logistic regression analysis revealed that pretransplant PTH level (P < 0.001; odds ratio [OR], 5.480; 95% confidence interval [CI], 2.070-14.50) and preoperative donor-estimated glomerular filtration rate (P = 0.033; OR, 0.978; 95% CI, 0.957-0.998) were independent predictors of HPT after PKT. Death-censored graft survival was significantly lower in the HPT group than that in the HPT-free group (90.4% vs. 96.4% at 10 years, P = 0.009). CONCLUSIONS: Pretransplant PTH levels and donor kidney function were independent predictors of HPT after PKT. In addition, HPT was associated with worse graft outcomes even after PKT.

Treatment for secondary hyperparathyroidism focusing on parathyroidectomy.

Secondary hyperparathyroidism (SHPT) is a major problem for patients with chronic kidney disease and can cause many complications, including osteodystrophy, fractures, and cardiovascular diseases. Treatment for SHPT has changed radically with the advent of calcimimetics; however, parathyroidectomy (PTx) remains one of the most important treatments. For successful PTx, removing all parathyroid glands (PTGs) without complications is essential to prevent persistent or recurrent SHPT. Preoperative imaging studies for the localization of PTGs, such as ultrasonography, computed tomography, and 99mTc-Sestamibi scintigraphy, and intraoperative evaluation methods to confirm the removal of all PTGs, including, intraoperative intact parathyroid hormone monitoring and frozen section diagnosis, are useful. Functional and anatomical preservation of the recurrent laryngeal nerves can be confirmed via intraoperative nerve monitoring. Total or subtotal PTx with or without transcervical thymectomy and autotransplantation can also be performed. Appropriate operative methods for PTx should be selected according to the patients' need for kidney transplantation. In the case of persistent or recurrent SHPT after the initial PTx, localization of the causative PTGs with autotransplantation is challenging as causative PTGs can exist in the neck, mediastinum, or autotransplanted areas. Additionally, the efficacy and cost-effectiveness of calcimimetics and PTx are increasingly being discussed. In this review, medical and surgical treatments for SHPT are described.

High Capacity Li2 S-Li2 O-LiI Positive Electrodes with Nanoscale Ion-Conduction Pathways for All-Solid-State Li/S Batteries.

All-solid-state lithium-sulfur (Li/S) batteries are promising next-generation energy-storage devices owing to their high capacities and long cycle lives. The Li2 S active material used in the positive electrode has a high theoretical capacity; consequently, nanocomposites composed of Li2 S, solid electrolytes, and conductive carbon can be used to fabricate high-energy-density batteries. Moreover, the active material should be constructed with both micro- and nanoscale ion-conduction pathways to ensure high power. Herein, a Li2 S-Li2 O-LiI positive electrode is developed in which the active material is dispersed in an amorphous matrix. Li2 S-Li2 O-LiI exhibits high charge-discharge capacities and a high specific capacity of 998 mAh g-1 at a 2 C rate and 25 °C. X-ray photoelectron spectroscopy, X-ray diffractometry, and transmission electron microscopy observation suggest that Li2 O-LiI provides nanoscale ion-conduction pathways during cycling that activate Li2 S and deliver large capacities; it also exhibits an appropriate onset oxidation voltage for high capacity. Furthermore, a cell with a high areal capacity of 10.6 mAh cm-2 is demonstrated to successfully operate at 25 °C using a Li2 S-Li2 O-LiI positive electrode. This study represents a major step toward the commercialization of all-solid-state Li/S batteries.

Treatment outcome of local injection of botulinum toxin for claw toe: Differences between cerebral hemorrhage and infarction.

BACKGROUND: Some patients with post-stroke claw toe respond well to botulinum toxin (BoNT) treatment while others do not. This study was designed to assess the impact of stroke type (cerebral hemorrhage and cerebral infarction) on the outcome of BoNT treatment for claw toe. METHODS: We retrospectively examined the medical records of patients who received local BoNT (onabotulinumtoxin A) injections into the flexor hallucis longus (FHL) and flexor digitorum longus (FDL) muscles. All patients suffered stroke-related leg paralysis and spasticity. RESULTS: The study participants were 58 patients (mean age, 61.4 ± 10.3 years, ± SD) with time since stroke of 6.7 ± 4.4 years. The stroke type was cerebral hemorrhage (n = 38) and cerebral infarction (n = 20). After a total of 124 BoNT administrations with medical records entries on the subjective symptoms, the odds for symptomatic improvement was approximately 5.8 times higher in patients of the infarction group compared with the hemorrhage group (OR = 5.787, 95% CI = 2.369-14.134, p = 0. 000). Fifty-one patients (32 with cerebral hemorrhage, 19 with cerebral infarction) received the first local BoNT injection and had available medical records, analysis of which showed a significantly higher rate of symptomatic improvement in patients of the infarction group than those of the hemorrhage group (p = 0.006). After adjustment by factors known to influence treatment outcome (degree of spasticity and paralysis, BoNT dosage, and extent of FDL muscle control of toe movements), the treatment effect was predominantly higher in patients with cerebral infarction. CONCLUSION: The BoNT treatment response was better for claw toes in cerebral infarction patients than in hemorrhage patients, possibly suggesting that claw toe is associated with more severe spasticity in this group of patients.

The Atrial Natriuretic Peptide-to-brain Natriuretic Peptide Ratio Predicts Left Atrial Reverse Remodeling after Rhythm Control Therapy in Patients with Persistent Atrial Fibrillation.

Objective The association between natriuretic peptide levels in atrial fibrillation (AF) patients with advanced left atrial (LA) remodeling and reverse remodeling after rhythm control therapy has not been clarified. The present study assessed the role of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) measurements to predict LA reverse remodeling after catheter ablation (CA) in persistent AF patients with LA enlargement. Methods This study included 88 persistent AF patients with LA enlargement (volume index >48 mL/m2) who underwent CA. Plasma ANP and BNP levels were analyzed before CA in all patients. The study population was divided into 2 groups according to the extent of decrease in the LA volume index (LAVI) at 6 months after CA responders were those with a ≥15% reduction in the LAVI, and all others were non-responders. Results At follow-up, 58 patients (66%) were classified as responders. The preprocedural ANP level was significantly higher in the responders than in the non-responders (p=0.03). Furthermore, the ANP-to-BNP ratio (ANP/BNP) was significantly higher in the responders than in the non-responders (p<0.01). The ANP/BNP was correlated with the percentage decrease in the LAVI (r=0.391, p<0.01). A multivariate linear regression analysis revealed that the ANP/BNP before CA was an independent predictor of LA reverse remodeling (p<0.01). Conclusion The preprocedural ANP/BNP was a robust predictor of reverse remodeling of the enlarged LA after sinus rhythm restoration by rhythm control therapy in persistent AF patients.

Optimal dose of rituximab in ABO-incompatible kidney transplantation in patients with low anti-A/B antibody titers: A single-center retrospective cohort study.

BACKGROUND: The clinical outcomes of ABO-incompatible (ABOi) kidney transplantation have improved with the introduction of desensitization therapy with rituximab. However, rituximab prevents not only antibody-mediated rejection (AMR) but also increases the risk of adverse events, such as infection. For ABOi kidney transplantation in patients with low anti-A/B antibody titers, we previously used a rituximab-free desensitization protocol and then initiated a single dose of 100 mg rituximab in 2016. We retrospectively compared the outcomes of ABOi kidney transplantation in patients with low anti-A/B antibody titers before and after the introduction of rituximab. METHODS: ABOi kidney transplantations (n = 142) in patients with low anti-A/B antibody titers between 2007 and 2021 were included. Patients were divided into two groups (with and without rituximab) for desensitization. The primary outcomes were the incidence of acute AMR and infection. RESULTS: Sixty-six patients were desensitized without rituximab (rituximab-free group), and 76 were pretreated with 100 mg rituximab (rituximab group) before transplantation. The incidence of acute AMR was significantly lower in the rituximab group than in the rituximab-free group (.0% [0/76] vs. 7.6% [5/66], respectively; p = .047). Post-transplantation anti-A/B antibody titers were also lower in the rituximab group than in the rituximab-free group. There was no significant difference in the incidence of adverse events, including infections, between the two groups. CONCLUSION: In ABOi kidney transplantation patients with low anti-A/B antibody titers, the desensitization protocol with a single dose of 100 mg rituximab was effective in preventing acute AMR without increasing the risk of other adverse events.

Clinical and molecular investigation of 37 Japanese patients with multiple acyl-CoA dehydrogenase deficiency: p.Y507D in ETFDH, a common Japanese variant, causes a mortal phenotype.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited metabolic disease caused by a defect in electron transfer flavoprotein alpha (ETFA), ETF beta (ETFB), or ETF dehydrogenase (ETFDH), and riboflavin metabolism disorders have recently been reported to present as mimicking MADD. MADD is roughly classified into neonatal (type 1 or 2) and later-onset (type 3) forms. To identify clinicogenetic characteristics in Japan, we investigated 37 Japanese patients with MADD diagnosed from 1997 to 2020. The causes of MADD were ETFDH deficiency in 26 patients, ETFA deficiency in four, ETFB deficiency in six, and riboflavin metabolism disorder in one. All 15 patients with the neonatal-onset type died by 2 years of age, while five of 22 patients with the later-onset form died by 3 years of age. Furthermore, 8 of 15 patients with the later-onset form of ETFDH deficiency treated with riboflavin were riboflavin non-responders. p.Y507D in ETFDH was identified as the most common variant (9 of 48 alleles, 18.8%). Of two patients with a homozygous p.Y507D variant, one experienced disease onset and died in the neonatal period, while the other experienced disease onset at two months of age and died at two years old, suggesting that the p.Y507D variant results in fatal outcomes. Our study concluded that more than half of Japanese patients with MADD died by three years old, and more than half of patients with the later-onset form had poor responsiveness to riboflavin, partly due to the unique Japanese p.Y507D variant in ETFDH.

Intraoperative intact parathyroid hormone monitoring and frozen section diagnosis are essential for successful parathyroidectomy in secondary hyperparathyroidism.

Background: Total parathyroidectomy (PTx) is often performed to treat secondary hyperparathyroidism (SHPT). Successful PTx is essential to prevent recurrent and persistent SHPT because remnant parathyroid glands (PTGs) in the neck can be stimulated and may secrete excessive parathyroid hormone (PTH) in end-stage renal disease. However, to date, few studies have investigated factors contributing to successful PTx before the completion of surgery. Materials and methods: Between August 2010 and February 2020, 344 patients underwent total PTx, transcervical thymectomy, and forearm autograft for SHPT at our institute. Factors contributing to successful PTx before the completion of surgery were investigated. Preoperative imaging diagnoses, including computed tomography, ultrasonography, technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy, intraoperative intact PTH (IOIPTH) monitoring, and frozen section histologic diagnosis, were performed. Successful PTx was defined as intact PTH level < 60 pg/mL on postoperative day 1. A sufficient decrease in IOIPTH level was defined as > 70% decrease in intact PTH levels measured 10 min after total PTx and transcervical thymectomy compared to intact PTH levels measured before skin incision. Logistic regression analysis was conducted to investigate factors contributing to PTx success. Results: Univariate analysis showed that the number of all PTGs identified preoperatively by imaging modalities and the specimens submitted for frozen section diagnosis, which surgeon presumed to be PTGs, were not significant factors contributing to successful PTx. However, multivariate analysis revealed that the number of PTGs identified by frozen section diagnosis (P < 0.001, odds ratio [OR] 4.356, 95% confidence interval [CI] 2.499-7.592) and sufficient decrease in IOIPTH levels (P = 0.001, OR 7.847, 95% CI 2.443-25.204) significantly contributed to successful PTx. Conclusion: Sufficient intact PTH level decrease observed on IOIPTH monitoring and the number of PTGs identified by frozen section diagnosis contributed to successful PTx for SHPT. IOIPTH monitoring and frozen section diagnosis are essential for achieving successful PTx for SHPT.

Intratumoral heterogeneity of c-KIT mutations in a feline splenic mast cell tumor and their functional effects on cell proliferation.

A cat was presented with mast cell tumors (MCTs) of the skin and spleen. During the initial diagnosis, the exon 8 mutation of c-KIT was detected in the masses from skin and spleen by a commercial laboratory test. Consequently, treatment with toceranib was started. After complete remission, because of recurrence on day 117, the spleen and skin tumors were removed, but the cat eventually died on day 191. The analysis of ten cDNA clones of the c-KIT gene cloned from the surgically removed spleen revealed that seven different cDNA patterns were included, indicating the heterogeneity of this gene in the splenic MCT. The seven cDNA nucleotide patterns can be classified into four protein sequence patterns. In addition to the previously known mutations in exon 8, we identified novel mutations in exons 9, 10, and 18; four amino acids deletion in exon 9, and a point mutation in exons 10 and 18. Mouse IL-3-dependent cell line, Ba/F3, was transduced with these mutant clones, and c-KIT phosphorylation and proliferation assays were performed. We found that certain mutations affected the c-KIT phosphorylation status and cell proliferation. This suggests that heterogeneity among the population of tumor cells exists in MCTs, and that the dominant clones of this heterogeneity may contribute to the subsequent tumor cell growth.