Updated evidence of the effectiveness and safety of transanal drainage tube for the prevention of anastomotic leakage after rectal low anterior resection: a systematic review and meta-analysis.

BACKGROUNDS: Anastomotic leakage (AL) represents a major complication after rectal low anterior resection (LAR). Transanal drainage tube (TDT) placement offers a potential strategy for AL prevention; however, its efficacy and safety remain contentious. METHODS: A systematic review and meta-analysis were used to evaluate the influence of TDT subsequent to LAR as part of the revision of the surgical site infection prevention guidelines of the Japanese Society of Surgical Infectious Diseases (PROSPERO registration; CRD42023476655). We searched each database, and included randomized controlled trials (RCTs) and observational studies (OBSs) comparing TDT and non-TDT outcomes. The main outcome was AL. Data were independently extracted by three authors and random-effects models were implemented. RESULTS: A total of three RCTs and 18 OBSs were included. RCTs reported no significant difference in AL rate between the TDT and non-TDT groups [relative risk (RR): 0.69, 95% confidence interval (CI) 0.42-1.15]. OBSs reported that TDT reduced AL risk [odds ratio (OR): 0.45, 95% CI 0.31-0.64]. In the subgroup excluding diverting stoma (DS), TDT significantly lowered the AL rate in RCTs (RR: 0.57, 95% CI 0.33-0.99) and OBSs (OR: 0.41, 95% CI 0.27-0.62). Reoperation rates were significantly lower in the TDT without DS groups in both RCTs (RR: 0.26, 95% CI 0.07-0.94) and OBSs (OR: 0.40, 95% CI 0.24-0.66). TDT groups exhibited a higher anastomotic bleeding rate only in RCTs (RR: 4.28, 95% CI 2.14-8.54), while shorter hospital stays were observed in RCTs [standard mean difference (SMD): -0.44, 95% CI -0.65 to -0.23] and OBSs (SMD: -0.54, 95% CI -0.97 to -0.11) compared with the non-TDT group. CONCLUSIONS: A universal TDT placement cannot be recommended for all rectal LAR patients. Some patients may benefit from TDT, such as patients without DS creation. Further investigation is necessary to identify the specific beneficiaries.

Association between skin suture devices and incidence of incisional surgical site infection after gastrointestinal surgery: systematic review and network meta-analysis.

BACKGROUND: Surgical site infections (SSIs) are common complications after abdominal surgery. AIM: To compare which suture devices could reduce the incidence of incisional surgical site infections (SSIs) after gastrointestinal surgery using a systematic review and network meta-analysis. METHODS: The CENTRAL, PubMed, and ICHUSHI-Web databases were searched from January 1st, 2000, to December 31st, 2022, for randomized clinical trials (RCTs) comparing the incidence of incisional SSI after gastrointestinal surgery among patients treated with different surgical suture devices, including non-absorbable sutures, absorbable sutures, skin staplers, and tissue adhesives (last searched in August 23th, 2023). The risk of bias was assessed using the criteria of the Cochrane Handbook for Systematic Reviews of Interventions. To estimate the pooled odds ratios (ORs) for each comparison, a fixed-effect inverse-variance model based on the Mantel-Haenszel approach was employed. FINDINGS: A total of 18 RCTs with 5496 patients were included in this study. The overall SSIs in absorbable sutures were significantly lower than those in skin staplers (OR: 0.77; 95% confidence intervals (CI): 0.63-0.95) and non-absorbable sutures (OR: 0.62; 95% CI: 0.39-0.99), whereas SSIs in absorbable sutures were not significantly different from the SSIs in tissue adhesive. The highest P-score was 0.91 for absorbable sutures. A funnel plot for estimating the heterogeneity of the studies revealed that a publication bias would be minimal (Egger test, P = 0.271). CONCLUSION: This study showed that absorbable sutures reduced incisional SSIs in gastrointestinal surgical operations compared to any other suture devices.

The effectiveness of fascial closure with antimicrobial-coated sutures in preventing incisional surgical site infections in gastrointestinal surgery: a systematic review and meta-analysis.

The aim of this study was to conduct a systematic review and meta-analysis of the efficacy of fascial closure using antimicrobial-sutures specifically for the prevention of surgical site infections (SSIs) in gastrointestinal surgery, as part of the revision of the SSI prevention guidelines of the Japanese Society of Surgical Infectious Diseases (JSSI). We searched CENTRAL, PubMed and ICHUSHI-Web in May 2023, and included randomized controlled trials (RCTs) comparing antimicrobial-coated and non-coated sutures for fascial closure in gastrointestinal surgery (PROSPERO No. CRD42023430377). Three authors independently screened the RCTs. We assessed the risk of bias and the GRADE criteria for the extracted data. The primary outcome was incisional SSI and the secondary outcomes were abdominal wall dehiscence and the length of postoperative hospital stay. This study was supported partially by the JSSI. A total of 10 RCTs and 5396 patients were included. The use of antimicrobial-coated sutures significantly lowered the risk of incisional SSIs compared with non-coated suture (risk ratio: 0.79, 95% confidence intervals: 0.64-0.98). In subgroup analyses, antimicrobial-coated sutures reduced the risk of SSIs for open surgeries, and when monofilament sutures were used. Antimicrobial-coated sutures did not reduce the incidence of abdominal wall dehiscence and the length of hospital stay compared with non-coated sutures. The certainty of the evidence was rated as moderate according to the GRADE criteria, because of risk of bias. In conclusion, the use of antimicrobial-coated sutures for fascial closure in gastrointestinal surgery is associated with a significantly lower risk of SSI than non-coated sutures.

Enhanced proliferation and differentiation of rat hepatocytes cultured with bone marrow stromal cells.

Liver transplantation is the only clinically effective method of treating acute liver failure. However, wider application of this therapeutic modality is restricted primarily by shortage of donor organs. In the search for alternative methods of liver replacement therapy, investigators have focused on transplantation of normal allogeneic hepatocytes and on the development of liver support systems utilizing isolated hepatocytes. Since all human livers suitable for cell harvest are being used for transplantation, hepatocyte therapy using human tissue would require growing of cells in vitro. Unfortunately, although hepatocytes have tremendous capacity to proliferate in vivo, their ability to grow in culture is severely limited. Stromal cells from bone marrow and other blood-forming organs have been found to support hematopoiesis. In this paper, we show that bone marrow-derived stromal cells (BMSCs) enhance proliferation and support differentiation of rat hepatocytes in culture. Further, we demonstrate that in hepatocyte/BMSC co-cultures, clonal expansion of small hepatocytes (SH) is increased. Using semipermeable membrane cultures, we established that direct cell-cell contact is necessary for stimulation of cell proliferation. We also show that BMSCs which are in direct contact with hepatocytes and SH colonies express Jagged1. This suggests a potential role for Notch signaling in the observed effects. Finally, we present evidence that the expression and activity of liver specific transcription factors, CCAAT/enhancer binding proteins and liver specific key enzymes such as tryptophan 2,3-dioxygenase, are improved in hepatocyte/BMSC co-cultures. In conclusion, results of this study indicate that BMSCs could facilitate proliferation and differentiation of primary rat hepatocytes and their progenitors (SH) in vitro.

Regulation of c-met expression in rats with acute hepatic failure.

BACKGROUND: Earlier we described a model of fulminant hepatic failure (FHF) in the rat where partial hepatectomy is combined with induction of right liver lobe necrosis. In FHF rats, lack of hepatocyte proliferation was associated with delayed expression of HGF and HGF receptor c-met. Since the c-met promoter region has Sp1 binding sites, we decided to examine whether in FHF rats down-regulation of c-met is associated with decreased Sp1 function and whether changes in blood HGF, IL-6, and TGFbeta1 levels might be responsible for these effects. MATERIALS AND METHODS: Induction of FHF, partial (2/3) hepatectomy (PH), and sham hepatectomy (SH) was performed in adult Sprague-Dawley rats. The levels of c-met mRNA and Sp1 DNA binding activity were studied in rat liver remnants at different time points after surgery. Blood levels of HGF, IL-6, and TGFbeta1 were also measured in these rats. Additionally, the effects of treatment with TGF-beta1, IL-6, or a combination of both on c-met expression and Sp1 DNA binding were studied in HGF-induced rat hepatocyte cultures. RESULTS: Compared to SH rats, in PH rat livers c-met was up-regulated after 6 h and Sp1 DNA binding was at or only slightly lower than levels at all time points studied. In FHF rat livers, c-met expression was markedly reduced after 2 and 6 h, moderate after 12 h, and undetectable after 24 h. At the same time, Sp1 DNA binding was detected at 2 h postinduction only. In FHF rats, blood levels of all three cytokines showed early and sustained elevation. In vitro, IL-6 had no effect on c-met expression, whereas TGFbeta1 up-regulated c-met. When used alone, none of the cytokines affected Sp1 DNA binding activity. In contrast, a combination of IL-6 and TGFbeta1 down-regulated c-met expression as well as Sp1 DNA binding activity. These effects were dependent on the IL-6 concentration used. This study suggests that following massive loss of hepatocyte mass in rats, early increase in blood IL-6 and TGFbeta1 levels may weaken the expression of HGF receptor c-met in surviving hepatocytes through suppression of Sp1 DNA binding.

Acute fatty liver of pregnancy complicated with anterior pituitary insufficiency.

Acute fatty liver of pregnancy complicated with anterior pituitary insufficiency in a 24-year-old nullipara woman who presented fever and progressing liver damage after the delivery by Cesarean section is described. The liver biopsy revealed severe fatty changes with microvesicular fat drops in the hepatocytes. Serum growth hormone and adrenocorticotropic hormone levels were low, and did not respond to the stimulation. The daily urinary excretion of 17-hydroxycorticosteroid was also low. Acute fatty liver of pregnancy and antehypophyseal insufficiency were diagnosed. Secondary adrenal failure was also suspected. The co-existing hypercoagulable state could cause an ischemic attack on the pituitary gland.

Inhibition of signal transducer and activator transcription factor 3 in rats with acute hepatic failure.

In fulminant hepatic failure, survival is not possible without recovery of sufficient hepatocyte mass. Remarkably, only a few studies exist that provide insight into the mechanisms that control proliferation of residual hepatocytes after extensive hepatocyte loss. In this regard, the role of growth-regulatory factors, including pro-inflammatory cytokines such as interleukin-6 (IL-6), is not well understood. In the present study we show that in rats with critically low (10%) hepatocyte mass, whether with or without ongoing liver cell necrosis, inhibition of liver regeneration is associated with early and sustained increase in blood IL-6 levels. Under these conditions, the signal transducer and activator of transcription (Stat3) DNA binding activity was lowered at the time of G1/S cell-cycle transition. We further demonstrate that the protein inhibitor of activated Stat3 (PIAS3) and the suppressor of cytokine signaling (SOCS-1) were up-regulated early after induction of liver failure (6-12 h). In vitro, IL-6 induced PIAS3 expression in HGF stimulated rat hepatocytes. These findings suggest that after massive hepatocyte loss, an early and rapid rise in blood IL-6 levels may weaken the hepatic regenerative response through up-regulation of Stat3 inhibitors PIAS3 and SOCS-1.

Reconstruction of hepatic organoid by rat small hepatocytes and hepatic nonparenchymal cells.

Hepatic cells isolated from an adult rat liver, consisting of small hepatocytes (SHs), mature hepatocytes (MHs), liver epithelial cells (LECs), Kupffer cells, sinusoidal endothelial cells, and stellate cells, were cultured in a medium supplemented with 10% fetal bovine serum, 10 mmol/L nicotinamide, 1 mmol/L ascorbic acid 2-phosphate, 10 ng/mL epidermal growth factor, and 1% dimethyl sulfoxide. The SHs rapidly proliferated and formed a colony. About 10% of cytokeratin 8 (CK8)-positive cells formed SH colonies. All SHs at day 10 immunocytochemically showed positivity for albumin, transferrin, CK8, and CK18, which are markers for hepatocytes. In contrast, alpha-fetoprotein (AFP)-, CK14-, OC2-, and glutathione S-transferase placental type (GST-P)-positive cells, which are thought to be markers for hepatic immature cells, were rarely observed. At day 20 some cells in the colonies were positive for AFP, CK7, CK19, and GST-P. LECs and stellate cells proliferated and surrounded the colonies. About 2 weeks after plating, piled up cells were often observed on the SH colonies. In those colonies LECs and stellate cells invaded under the colonies. The invasion of the cells and gradual deposits of extracellular matrix (ECM) such as type I collagen, type IV collagen, and laminin induced alteration of the shape of the SHs from relatively flat to cuboidal or rectangular. With the cellular structural changes, the expression of albumin, connexin 32 (Cx32), and tryptophan 2,3-dioxygenase (TO) messenger RNAs increased. In addition, overlapping nonparenchymal cells (NPCs) on the piled up cells induced the formation of duct- or cyst-like structures consisting of MHs. In the present experiment we showed that SHs could differentiate to MHs by interacting with NPCs and ECM. Thus, SHs may be "committed progenitor cells" that can further differentiate into MHs.

[Serum transferrin receptor level as an index of the response to erythropoietin therapy for anemia in pre-dialysis patients with chronic renal failure].

In order to reveal whether serum transferrin receptor (sTfR) can serve as an index in erythropoiesis during recombinant human erythropoietin (rHuEpo) therapy for anemia in pre-dialysis patients with chronic renal failure, we analyzed hematopoietic parameters and sTfR levels in 26 patients who were newly administered rHuEpo. sTfR was determined as sTfR transferrin complex (TRC) using the enzyme linked immunosolvent assay (ELISA) and the latex agglutination nephelometric immunoassay (LA). The therapeutic effect of rHuEpo was expressed as the change in the Ht from the start of treatment to 8 weeks later. (delta Ht). Ht, RBC and Hb levels were significantly increased at 4 and 8 weeks after initiating rHuEpo treatment. Furthermore, sTfR levels were significantly increased at 2 and 4 weeks after the start of rHuEpo treatment. Absolute changes in the sTfR level (sTfR before - sTfR after) and rates of change (absolute change/sTfR before x 100) at, 2, 4 weeks after the start of rHuEpo treatment showed a significant positive correlation with delta Ht. These results indicate that sTfR is a useful marker as an index of therapeutic effect of rHuEpo for anemia in pre-dialysis patients with chronic renal failure.

Effects of oxygen radical scavengers on connexins 32 and 26 expression in primary cultures of adult rat hepatocytes.

Although we recently reported our success in inducing and maintaining the gap junction proteins connexin 26 (Cx26) and connexin 32 (Cx32) in adult rat hepatocytes cultured in serum-free L-15 medium supplemented with epidermal growth factor, dimethylsulfoxide (DMSO) and glucagon, the mechanisms by which DMSO induces gap junctions are still not clear. It is known that DMSO is not only a differentiation reagent for various cells but also a powerful scavenger of oxygen radicals. In the present study, by using this culture system and the measurement of oxidative stress by the nitro blue tetrazolium (NBT) formazan assay, we have examined the effect of oxygen radical scavengers such as DMSO, dimethylthiourea (DMTU) and alpha-tocopherol on the expression of both Cxs and on gap junctional intercellular communication (GJIC), as compared to another differentiation reagent, hexamethylene-bis-acetamide (HMBA). DMSO and DMTU clearly inhibited the oxidative stress of the cultured hepatocytes, while alpha-tocopherol and HMBA did not. The expression of Cx26 and Cx32 in the cultured hepatocytes was markedly induced by DMSO and DMTU. Furthermore, extensive GJIC was also observed with DMSO and DMTU. These results suggest that the expression of gap junctions in the hepatocytes may be closely related to oxidative stress and that oxygen radical scavengers may be important substances in inducing this expression.

High-dose fentanyl does not suppress interleukin-1 beta-induced increases in plasma ACTH and corticosterone in rats.

BACKGROUND: High-dose fentanyl anesthesia is reported to attenuate the metabolic and endocrinal responses to surgery. Interleukin-1 (IL-1) is one of the key mediators in the immunoneuroendocrine system, and may be involved in the stress responses to surgery. We studied whether high-dose fentanyl may influence the IL-1 beta-induced alterations in plasma ACTH and corticosterone in rats. METHODS: Plasma ACTH, corticosterone, blood pressure, heart rate and acid-base status were determined in either awake or fentanyl-anesthetized animals immediately before and after either phosphate buffered saline or IL-1 beta administration. Fentanyl anesthesia was induced by bolus intravenous injections of fentanyl at 50 micrograms/kg and pancuronium bromide at 0.2 mg/kg, and maintained by continuous administrations of fentanyl at 100 or 200 micrograms.kg-1.h-1 and pancuronium bromide at 0.4 microgram.kg-1.h-1. RESULTS: In awake rats, IL-1 beta at incremental doses of 0.25, 0.5 and 1 microgram/kg increased plasma ACTH in a dose-dependent manner, but heat-inactivated IL-1 beta at 4 micrograms/kg did not influence plasma ACTH. A noxious stimulus with tail clamping for 30 min did not significantly alter plasma ACTH in fentanyl-anesthetized rats. Fentanyl reduced the basal plasma corticosterone, but it did not modulate the increases in plasma ACTH and corticosterone after the administration of IL-1 beta at 1 microgram/kg. Fentanyl moderately increased the basal blood pressure and heart rate, but it moderately attenuated the IL-1 beta-induced elevations of blood pressure and heart rate. IL-1 beta moderately decreased PCO2 in awake animals. CONCLUSIONS: Fentanyl anesthesia, which is able to suppress the endocrine responses to noxious stimuli, does not attenuate the IL-1 beta-mediated activation of the pituitary-adrenal axis in rats.

Analysis of circulating hematopoietic progenitors in patients with chronic renal failure under hemodialysis.

Circulating hematopoietic progenitors were analyzed in patients with chronic renal failure (CRF) under hemodialysis (HD) by methylcellulose culture containing interleukin-3 (IL-3) to clarify the differences in hematopoiesis between patients with and without CRF-associated anemia and between good responder whose hematocrit (Ht) was preserved in more than 25% under erythropoietin (Epo) treatment and poor responders whose Ht remained less than 25% even under Epo treatment. The numbers of peripheral blood (PB) erythroid burst-forming units (BFU-E) and granulocyte-macrophage colony-forming units (CFU-GM) in HD patients without Epo treatment, whose Ht levels were greater than 30%, were similar to those in normal subjects. However, these numbers in HD patients who required Epo treatment were significantly lower than those in normal subjects. The number of PB BFU-E in HD patients who showed a poor response to Epo was significantly lower than that in HD patients who showed a good response to Epo. The number of PB BFU-E was well correlated with the number of PB CFU-GM in all groups of HD patients. There also existed a definite correlation between these numbers and the Ht levels in HD patients without Epo treatment, but not those in HD patients with Epo treatment. The sensitivity of PB BFU-E to IL-3 was lower in HD patients who showed a poor response to Epo than in the other HD patients and normal subjects. These findings indicate that hematopoiesis in HD patients with CRF associated anemia is suppressed in both the erythroid and myeloid lineage at primitive stages, and that the lower sensitivity of PB BFU-E to IL-3 in HD patients with a poor response to Epo may be associated with this poor response. In addition, the level of the serum transferrin receptor (sTfR) in HD patients without severe anemia was higher than that in normal subjects and HD patients who required Epo treatment, indicating that erythropoiesis in HD patients who do not require Epo treatment is more active than that in normal subjects and other HD patients.

[Cancer-pain management in home care].

Patient was 58 year old female with severe uterus cancer pain who refused to take the oral morphine in hospital because doctor should be hesitated to discharged patient whose pain is particularly difficult to manage in home. A few days later, she returned back home with her family irritably and recovered from hallucination by morphine-intake in home. The oral morphine is the prepared route of analgesic administration in home care. When patient can not take medications orally, continuous intravenous infusion provides the most consistent level of analgesia. In future, transdermal route offers a practical alternative in the hospice and home.

Functional and high level expression of human dopamine beta-hydroxylase in transgenic mice.

Dopamine beta-hydroxylase (DBH; EC 1.14.17.1) catalyzes the production of the neurotransmitter and hormone norepinephrine in the third step of the catecholamine biosynthesis pathway. Transgenic mice were generated with multiple copies of a human DBH minigene construct containing the full-length cDNA connected downstream of the 4-kilobase upstream promoter region to achieve overexpression of DBH. Human DBH mRNA and immunoreactivity were detected tissue-specifically in the brain and adrenal gland of these transgenic mice. The transgene products were correctly processed to a glycosylated mature polypeptide with a molecular mass of 72 kDa and existed in the secretory vesicles as both soluble and membrane-bound forms. We detected a marked increase in DBH activity in various catecholamine-containing tissues of the mice that occurred as a consequence of expression of the catalytically active human DBH enzyme. However, in these transgenics the steady-state levels of norepinephrine and epinephrine were normally maintained without the acceleration of the catecholamine turnover rate, suggesting that there are some regulatory mechanisms to preserve a constant rate of norepinephrine synthesis in spite of the increased amount of DBH protein. These transgenic mice with the minigene construct provide one approach to study the mechanisms underlying biogenesis of the DBH polypeptide and regulation of norepinephrine synthesis.

[Differential effects of isoflurane, sevoflurane and halothane on autonomic function determined by spectral analysis of heart rate variability].

The effects of isoflurane, sevoflurane and halothane on heart rate variability were studied in 18 patients scheduled for minor otolaryngeal surgery. After the surgery, R-R intervals were determined at minimum alveolar concentrations of 2.0, 1.5, 1.0 and 0.5 under mechanical ventilation. The data were plotted on a one-dimensional map and analyzed further by autoregressive spectral analysis. All three anesthetics suppressed both the low frequency component (Mayer wave related sinus arrhythmia; MWSA) and the high frequency component (respiratory sinus arrhythmia; RSA). The MWSA reflecting sympathetic activity was less affected by sevoflurane while the RSA reflecting parasympathetic function was less influenced by halothane. The one-dimensional map was useful to visualize the depth of anesthesia.

Nicotine-induced regulation of tyrosine hydroxylase activity in adrenal gland of transgenic mouse carrying human tyrosine hydroxylase gene.

We investigated the effect of subcutaneous injection of nicotine on in vitro tyrosine hydroxylase (TH) activity in adrenal gland and brain of the transgenic mice carrying an 11-kb fragment containing the entire human TH gene. Injection of 5 mg nicotine/kg (as free base) for 3 days caused a statistically significant increase in vitro TH activity in the adrenal gland, whereas brain TH activity was not affected at all. The adrenal gland of non-transgenic C57BL/6J mice treated in the same way as for transgenic mice tended to enhance TH activity, although not to a significant level. This observation might indicate the possibility that the machinery used by nicotine in regulating the properties or expression of TH in the adrenal gland should be similar between transgenic and non-transgenic mice.

Effects of subacute administration of methamphetamine and nicotine on locomotor activity in transgenic mice expressing the human tyrosine hydroxylase gene.

We produced transgenic (Tg) mice carrying the human tyrosine hydroxylase (TH) gene. To investigate differences in the dopaminergic (DAergic) neuronal activity between the Tg and nTg mice, we examined changes in the locomotor activity induced by methamphetamine (MAP) and nicotine (NIC), which enhances DA release and induces TH enzyme activation, respectively. Surprisingly, however, the intensity of MAP (2.5 mg/kg, once a day for 14 days)-induced hyperlocomotion in the nTg mice was greater than that in the Tg mice, and, furthermore, the Tg mice were less sensitive to subacute administration of NIC (0.5 mg/kg, once a day for 14 days) than the nTg mice. These results suggest that DAergic neuronal function is suppressed in Tg mice to compensate for the overexpression of TH.

Effect of erythroid differentiation factor on maintenance of human hematopoietic cells in co-cultures with allogenic stromal cells.

The effect of erythroid differentiation factor (EDF) on the maintenance of human hematopoietic progenitors in a microenvironment was examined by co-culture of adherent- and E rosette-depleted mononuclear cells from the bone marrow (BM) or peripheral blood (PB) with allogenic stromal cells. EDF had no effect on colony formation of erythroid burst-forming units (BFU-E) from the BM cultured without a stromal layer. The number of BFU-E cultured with the stromal layer was decreased less in the presence of EDF than in its absence. This activity of EDF was also observed when the mononuclear cells were separated from the stromal layer by a filter membrane. These data suggest that EDF facilitates maintenance of the number of BFU-E through a humoral factor(s) secreted by the stromal layer. The number of BM erythroid colony-forming units (CFU-E) was decreased on addition of EDF, which promotes differentiation of CFU-E. The number of PB CFU-E was increased irrespective of the presence or absence of EDF over 2 weeks, suggesting that BFU-E, which are more abundant in PB than in BM, differentiate to supply CFU-E. However, the addition of EDF resulted in less increase of PB CFU-E, indicating that it inhibited the proliferation of CFU-E progenitors to suppress colony formation. On the other hand, CFU-GM was consistently decreased by addition of EDF to this culture system. These data indicate that EDF acts as a commitment factor and/or a promoter of erythroid progenitors in a hematopoietic microenvironment.