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Biomedical subjects

R Mendez

Publications and source records attributed to R Mendez.

At least 55 records · Page 3Linked to original sources

FK 506 and mycophenolate mofetil in renal transplant recipients: six-month results of a multicenter, randomized dose ranging trial. FK 506 MMF Dose-Ranging Kidney Transplant Study Group.

The effective dose of MMF with FK 506 has not been previously studied in a prospective, randomized, controlled setting. In the present study, we evaluated two different daily doses of MMF (1 and 2 g) and compared it to the historically conventional therapy of AZA. At 6 months post-transplant, we found no significant difference in the incidence of acute rejection between the AZA group and the MMF 1 g group. However, patients who started on MMF 2 g/d had significantly delayed and lower incidence of acute rejection as compared to the other two groups. We found that patients who were initiated on MMF 2 g frequently had their dose lowered, primarily for gastrointestinal or hematologic symptoms; by 6 months after-transplant, patients in the MMF 2 g group had a mean dose of 1.5 g. It is unclear from this study if initiating patients on MMF 1.5 g in combination with FK 506 would be as effective as initiating a patient on MMF 2 g. Further studies of the combination of FK 506 and MMF in kidney transplant recipients to further define the optimal dosing regimen are warranted. In summary, the combination of FK 506 and MMF is well-tolerated, safe, and effective in cadaveric kidney transplant recipients.

Adolescent↗

Penetrating atherosclerotic aortic ulcer: documentation by transesophageal echocardiography.

OBJECTIVES: This study sought to describe the ability of transesophageal echocardiography (TEE) to document the presence of penetrating atherosclerotic aortic ulcers and their complications. BACKGROUND: TEE has greatly enhanced our ability to assess patients with suspected aortic disease. However, the utility of this technique in the diagnosis of penetrating atherosclerotic aortic ulcers is still undefined. METHODS: TEE was performed prospectively in 194 patients to evaluate aortic disease. Twelve patients with the diagnosis of aortic ulcers or their complications were specifically studied. The diagnosis was confirmed by pathologic studies in six patients and by an additional diagnostic technique (angiography, computed tomography or magnetic resonance imaging) in the other six. All 12 patients were hypertensive and presented with chest or back pain; the mean age was 65 years (range 56 to 79). The initial working diagnosis was acute aortic dissection in nine patients. Aortic ulcers were located in the descending thoracic aorta in eight patients, the aortic arch in two and the ascending aorta in two. RESULTS: TEE could detect aortic ulcers or their complications in 10 patients but failed to detect these lesions in the remaining 2 (1 with aortic ulcers in the distal ascending aorta and 1 with aortic ulcers in the aortic arch). In four patients, aortic ulcers were detected as a calcified focal outpouching of the aortic wall and were associated with concomitant aneurysmal dilation of the aorta in two patients and with a small localized intramural hematoma in one. TEE visualized a partially thrombosed pseudoaneurysm complicating an aortic ulcer in the descending thoracic aorta of two patients. Four patients had an aortic ulcer complicated by a "limited aortic dissection" in the descending aorta that could be detected by TEE. Five patients underwent operation, two because of aneurysmal dilation of the aorta and three because of aortic dissection; two patients died of aortic rupture; the remaining five did well (11-month follow-up) without operation. CONCLUSIONS: Aortic ulcers should be included in the differential diagnosis of chest or back pain, especially in elderly hypertensive patients. These ulcers and their complications may be recognized by TEE.

Aged↗

Specificity of RNA binding by CPEB: requirement for RNA recognition motifs and a novel zinc finger.

CPEB is an RNA binding protein that interacts with the maturation-type cytoplasmic polyadenylation element (CPE) (consensus UUUUUAU) to promote polyadenylation and translational activation of maternal mRNAs in Xenopus laevis. CPEB, which is conserved from mammals to invertebrates, is composed of three regions: an amino-terminal portion with no obvious functional motif, two RNA recognition motifs (RRMs), and a cysteine-histidine region that is reminiscent of a zinc finger. In this study, we investigated the physical properties of CPEB required for RNA binding. CPEB can interact with RNA as a monomer, and phosphorylation, which modifies the protein during oocyte maturation, has little effect on RNA binding. Deletion mutations of CPEB have been overexpressed in Escherichia coli and used in a series of RNA gel shift experiments. Although a full-length and a truncated CPEB that lacks 139 amino-terminal amino acids bind CPE-containing RNA avidly, proteins that have had either RRM deleted bind RNA much less efficiently. CPEB that has had the cysteine-histidine region deleted has no detectable capacity to bind RNA. Single alanine substitutions of specific cysteine or histidine residues within this region also abolish RNA binding, pointing to the importance of this highly conserved domain of the protein. Chelation of metal ions by 1,10-phenanthroline inhibits the ability of CPEB to bind RNA; however, RNA binding is restored if the reaction is supplemented with zinc. CPEB also binds other metals such as cobalt and cadmium, but these destroy RNA binding. These data indicate that the RRMs and a zinc finger region of CPEB are essential for RNA binding.

Amino Acid Sequence↗

Parvovirus B19 infection-related complications in renal transplant recipients: treatment with intravenous immunoglobulin.

BACKGROUND: Chronic red cell aplasia can develop in immunocompromised patients including transplant recipients infected with parvovirus B19 (PV B19). Renal involvement with PV B19 infection is not well-recognized. METHODS: We diagnosed erythroid hypoplasia associated with PV B19 infection in three renal transplant recipients; one of them developed de novo collapsing glomerulopathy. These patients were treated with intravenous immunoglobulin (IVIG). RESULTS: In two patients, anemia responded promptly to IVIG therapy. One of them had recurrence of anemia that responded to a second course of IVIG. Despite IVIG treatment, persistent infection with PV B19, recurrent anemia, and de novo collapsing glomerulopathy leading to allograft failure developed in the third patient, who had received the most intense immunosuppression. CONCLUSIONS: These findings indicate that PV B19 infection in transplant recipients can cause chronic red cell aplasia that generally responds to IVIG therapy. In some patients, particularly those who are heavily immunosuppressed, infection may persist despite treatment. As the cellular receptor for PV B19 is expressed in the kidney, persistent infection may result in development of glomerulopathies in these patients.

Adult↗

Risks of transplanting kidneys from hepatitis B surface antigen-negative, hepatitis B core antibody-positive donors.

BACKGROUND: As the number of patients on the United States kidney transplant list increases, investigation into the utility of transplanting organs formerly considered marginal or undesirable has intensified. Using kidneys from hepatitis B surface antigen (HBsAg)-positive donors is thought to place recipients at excessive risk of graft failure, morbidity, and mortality. However, the risks of using kidneys from HBsAg-negative but hepatitis B core antibody (HBcAb)-positive donors have not been defined. METHODS: Between 1990 and 1994, our group transplanted 1067 cadaveric kidneys, including 38 from HBsAg(-)/HBcAb(+) donors. Of these 38 kidneys, 27 were transplanted into HBcAb(-) recipients (group 1) and 11 were transplanted into HBcAb(+) recipients (group 2). Group 1 and 2 patients received no hepatitis immunoglobulin therapy after transplantation and received the same immunosuppression and rejection therapies as recipients of kidneys from HBcAb(-) donors. RESULTS: After transplantation, none of the group 1 patients became HBsAg(+), three became hepatitis B surface antibody (HBsAb)-positive, and two became HBcAb(+). Of the group 2 patients, none became newly HBsAg(+) or HBsAb(+). No patient receiving a kidney from an HBsAg(-)/HBcAb(+) donor developed signs or symptoms of clinical hepatitis B. Graft and patient survival rates were similar in both groups and similar to the rates of the 1029 recipients of kidneys from HBcAb(-) donors. CONCLUSIONS: Recipients of kidneys from HBsAg(-)/HBcAb(+) donors are at a small risk of hepatitis B seroconversion but are at no excess risk of graft failure or short-term morbidity or mortality.

Adult↗

Outcome of en bloc and single kidney transplantation from very young cadaveric donors.

BACKGROUND: The optimal use of very young cadaveric kidneys (from donors less than 4 years old) remains controversial. High rates of technical complications and poor functional results compared with adult donor kidneys have been reported. The use of en bloc transplantation to overcome these problems has been advocated, although en bloc transplantation halves the number of potential transplants from very young donors. METHODS: We studied the technical and functional results of 91 transplants from very young donors performed at our institution between 1984 and 1995. This included 59 single and 22 en bloc procedures involving first transplants and 7 single and 3 en bloc procedures involving retransplantation. Individual surgeon preference dictated the use of either the single or en bloc technique. Kidneys smaller than 6 cm tended to be transplanted en bloc, and lighter patients were generally given preference for receiving pediatric kidneys. Patients received sequential cyclosporine-based quadruple immunosuppression. RESULTS: En bloc kidneys had a 1-year and 5-year graft survival of 82% and 70%, respectively. Single kidneys had a 1-year and 5-year graft survival of 64% and 40%. Kidneys that avoided acute rejection episodes and that were transplanted into heavier or male recipients had better long-term survival. Kidneys from donors less than 2 years old did poorly whether transplanted en bloc or singly. Better HLA matching improved short-term, but not long-term, graft survival, whereas cold ischemic time did not have statistically significant association with differences in graft survival. Eleven percent of the transplants had ureteral leaks, but only one kidney was lost. Ten transplants had vascular complications leading to graft loss, whereas two episodes of arterial stenosis were successfully treated with percutaneous angioplasty. CONCLUSIONS: En bloc transplantation optimizes the outcome of transplantation with very young kidneys. We recommend induction therapy and cyclosporine immunosuppression with cyclosporine levels similar to adult target levels to minimize rejection episodes and, thus, improve outcome. These kidneys should be distributed nationally, because better HLA matching is associated with improved short-term graft survival. Our high ureteral leak rate indicates that alternatives to unstented ureteroneocystostomy should be considered.

Adult↗

Requirement of protein kinase C zeta for stimulation of protein synthesis by insulin.

The ability of insulin to stimulate protein synthesis and cellular growth is mediated through the insulin receptor (IR), which phosphorylates Tyr residues in the insulin receptor substrate-signaling proteins (IRS-1 and IRS-2), Gab-1, and Shc. These phosphorylated substrates directly bind and activate enzymes such as phosphatidylinositol 3'-kinase (PI3K) and the guanine nucleotide exchange factor for p21Ras (GRB-2/SOS), which are in turn required for insulin-stimulated protein synthesis, cell cycle progression, and prevention of apoptosis. We have now shown that one or more members of the atypical protein kinase C group, as exemplified by the zeta isoform (PKC zeta), are downstream of IRS-1 and P13K and mediate the effect of insulin on general protein synthesis. Ectopic expression of constitutively activated PKC zeta eliminates the requirement of IRS-1 for general protein synthesis but not for insulin-stimulated activation of 70-kDa S6 kinase (p70S6K), synthesis of growth-regulated proteins (e.g., c-Myc), or mitogenesis. The fact that PKC zeta stimulates general protein synthesis but not activation of p70S6K indicates that PKC zeta activation does not involve the proto-oncogene Akt, which is also activated by PI3K. Yet insulin is still required for the stimulation of general protein synthesis in the presence of constitutively active PKC zeta and in the absence of IRS-1, suggesting a requirement for the convergence of the IRS-1/PI3K/PKC zeta pathway with one or more additional pathways emanating from the IR, e.g., Shc/SOS/p21Ras/mitogen-activated protein kinase. Thus, PI3K appears to represent a bifurcation in the insulin signaling pathway, one branch leading through PKC zeta to general protein synthesis and one, through Akt and the target of rapamycin (mTOR), to growth-regulated protein synthesis and cell cycle progression.

Actins↗

Lung reduction surgery in severe COPD decreases central drive and ventilatory response to CO2.

BACKGROUND AND OBJECTIVES: Lung volume reduction surgery (LVRS) improves ventilatory function in selected patients with severe COPD. The reasons for the observed benefits include the following: increased elastic recoil, improved airflow, and lesser dynamic hyperinflation and decreased lung volumes. We reasoned that these changes could also alter respiratory drive. METHODS: Respiratory central drive was prospectively assessed using the mouth occlusion pressure (P0.1), and the P0.1 response to increasing CO2 (P0.1/PETCO2 [end-tidal CO2 pressure]), in eight sequential patients before and 3 to 5 months after LVRS. Results were compared with those from 13 control subjects. RESULTS: LVRS decreased total lung capacity from 7.44+/-1.8 L to 5.92+/-1.3 L (p<0.05) and residual volume from 4.97+/-1.5 L to 3.56+/-1.1 L (p<0.05). It also significantly improved FEV1 from 0.85+/-0.26 L to 0.99+/-0.26 L (p<0.05). Baseline P0.1 (3.4+/-1.8 vs 1.4+/-0.4 cm H2O, p<0.01) and P0.1/PETCO2 (0.24+/-0.07 vs 0.11+/-0.04 cm H2O/mm Hg, p<0.05) were higher in patients than in control subjects. After LVRS, P0.1 decreased from 3.4+/-1.8 to 1.3+/-0.75 cm H2O (p<0.01) and P0.1/PETCO2 from 0.24+/-0.07 to 0.16+/-0.06 cm H2O/mm Hg (p<0.05). These postoperative values were similar to those of control subjects. There were no correlations between changes in the factors known to influence central drive (PaO2, PaCO2, age, weight, height, FVC, and FEV1) and changes in P0.1. CONCLUSIONS: We conclude that decreased ventilatory drive should be added to the list of benefits of LVRS, and may help explain the symptomatic improvement reported by many patients after this surgery.

Age Factors↗

Autotransplantation as an effective therapy for the loin pain-hematuria syndrome: case reports and a review of the literature.

PURPOSE: The loin pain-hematuria syndrome is a well recognized but poorly understood clinical condition in which patients have progressive loin pain accompanied by hematuria but they maintain stable renal function. We present 2 cases effectively treated with renal autotransplantation, as well as a review of the literature, and a coherent algorithm for the diagnosis and treatment of this condition. MATERIALS AND METHODS: The medical literature concerning the loin pain-hematuria syndrome was reviewed. In 1994 we performed renal autotransplantation on 2 patients with the loin pain-hematuria syndrome at our institution. RESULTS: Extensive urological evaluation revealed no obvious underlying abnormalities in patients with the loin pain-hematuria syndrome. Theories for the pathogenesis of this condition range from thrombotic phenomena to autoimmune processes. Treatment efforts have been directed primarily towards pain management. Narcotic dependence becomes progressive as the pain becomes debilitating. In extreme cases nephrectomy is performed despite normal renal function. Several invasive methods of nerve block and enervation provide only temporary relief. Renal autotransplantation provided lasting cessation of loin pain in both of our patients with followup of 1.5 and 2.5 years, and this intervention has been shown to provide the most durable pain relief in other series. CONCLUSIONS: Renal autotransplantation provides the most durable, nonnarcotic, nephron sparing relief for patients with the loin pain-hematuria syndrome. Further investigation is necessary to elucidate the pathophysiology of this debilitating condition.

Adult↗

An open-label, concentration-ranging trial of FK506 in primary kidney transplantation: a report of the United States Multicenter FK506 Kidney Transplant Group.

This was a multicenter, open-label, concentration-ranging trial of FK506 and cyclosporine in 120 patients undergoing primary cadaveric kidney transplant. Patients were randomized to a cyclosporine-based regimen or to one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, and 0.4 mg/kg/day. Patients were evaluated at 42 days after transplant for the occurrence of the first episode of acute rejection or toxicity, necessitating a dosage reduction. There was no significant difference among the three FK506-based regimens and the cyclosporine-based regimen for rejection or toxicity at 42 days. However, the incidence of acute rejection was significantly lower (14% for FK506 and 32% for cyclosporine; P=0.048) for the aggregate of all FK506-treated patients versus cyclosporine. The incidence of neurotoxic and gastrointestinal events was higher among FK506-treated patients during the first month after transplant. A significant trend was observed for increasing toxicity with increasing maximum trough FK506 concentrations (P=0.01) and for decreasing rates of rejection with increasing minimum trough FK506 concentrations (P=0.021). FK506 was effective in preventing early rejection in kidney transplant recipients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients seems to be 0.2 mg/kg/day.

Adult↗

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Acute Disease↗

One-year follow-up of an open-label trial of FK506 for primary kidney transplantation. A report of the U.S. Multicenter FK506 Kidney Transplant Group.

Patients undergoing primary cadaveric kidney transplantation were followed for 1 year as part of a phase II, multicenter, open-label concentration-ranging trial of FK506 and cyclosporine. One hundred twenty patients were randomly assigned to a cyclosporine-based regimen or one of three FK506-based regimens designed to achieve low (5-14 ng/ml), medium (15-25 ng/ml), or high (26-40 ng/ml) trough whole blood levels. Corresponding initial doses of FK506 were 0.2, 0.3, or 0.4 mg(kg/day, respectively. Patients with toxicity to FK506 had their target concentration reduced by lowering the dose of FK506. Ninety-two patients completed a 1-year follow-up to determine patient and graft survival and long-term safety. At 1-year, the patient survival rate was 98% for FK506 and 92% for cyclosporine, and the graft survival rate was 93% and 89% in the FK506 and cyclosporine groups, respectively. The incidence of acute rejection was significantly lower (14% FK506, 32% cyclosporine, P=0.048) at day 42 after transplantation. However, the incidence of rejection episodes requiring treatment at 1 year was similar in both groups (33% for FK506 and 32% for cyclosporine). Nephrotoxicity occurred with a similar frequency with FK506 and cyclosporine, but the incidence of neurotoxic events and the incidence of new insulin use were higher among FK506-treated patients. The target range of whole blood levels that optimizes efficacy and minimizes toxicity seems to be 5-15 ng/ml. The corresponding recommended initial dose of FK506 for kidney transplant recipients is 0.2 mg/kg/day. These results indicate that the efficacy and safety of FK506 were comparable to that for cyclosporine for primary immunosuppression in patients undergoing cadaveric kidney transplantation.

Adult↗

The effect of antibiotics on nitrification processes. Batch assays.

The effect of different antibiotics at several concentrations of ampicillin (0-250 mg/L), benzylpenicillin (0-250 mg/L), novobiocine (0-150 mg/L), oxytetracycline (0-250 mg/L), and chloramphenicol (0-50 mg/L) on a stabilized nitrifying sludge was evaluated under aerated and lithoautotrophic conditions. No effect resulting from the presence of antibiotics on the biomass and nitrate production was noticed. The specific growth rate and volumetric nitrification rate average values for the controls were 8.28 x 10-3/h-1 and 2.74 x 10-3 g/L.h, respectively. Similar rate values were found when different kinds of antibiotic and concentrations were tested. These results may be explained by the nature of the floc or the instability of the antibiotics.

Aerobiosis↗

Phosphorylation of eukaryotic protein synthesis initiation factor 4E at Ser-209.

Initiation factor 4E (eIF-4E) binds to the m7GTP-containing cap of eukaryotic mRNA and facilitates the entry of mRNA into the initiation cycle of protein synthesis. eIF-4E is a phosphoprotein, and the phosphorylated form binds to mRNA caps 3-4-fold more tightly than the nonphosphorylated form. A previous study indicated that the major phosphorylation site was Ser-53 (Rychlik, W., Russ, M. A., and Rhoads, R. E. (1987) J. Biol. Chem. 262, 10434-10437). In the present study, we synthesized the phosphopeptide expected to result from tryptic digestion of eIF-4E, O-phosphoseryllysine. Surprisingly, the tryptic and synthetic phosphopeptides did not comigrate electrophoretically. Accordingly, we redetermined the phosphorylation site by isolating a chymotryptic phosphopeptide on reverse phase high performance liquid chromatography. The peptide was sequenced by Edman degradation and corresponded to 198QSHADTATKSGSTTKNRF215. The site of phosphorylation was determined to be Ser-209 by four methods: the increase in the ratio of dehydroalanine to serine derivatives during Edman degradation, the release of 32P, the further digestion of the chymotryptic phosphopeptide with trypsin, Glu-C, and Asp-N, and site-directed mutagenesis of eIF-4E cDNA. The S209A variant was not phosphorylated in a rabbit reticulocyte lysate system, whereas the wild-type, S53A, and S207A variants were. This site falls within the consensus sequence for phosphorylation by protein kinase C.

Amino Acid Sequence↗

Renal transplantation in systemic lupus erythematosus: a single-center experience with sixty-four cases.

The outcome of renal transplantation in 64 patients with end-stage renal disease (ESRD) secondary to lupus nephritis is the subject of this report. The patients were transplanted over a 150-month (12.5-year) period (between July 5, 1979, and January 30, 1992). The study population is predominantly made up of young females (mean age, 34.7 +/- 9 years, n = 54, 81.3%). Fifty-one transplants (79.7%) are cadaveric, and 13 (20.3%) are from living-related donors. Fifty-eight patients (90.6%) had primary (first) allografts, and 6 (9.4%) received a second allograft. Posttransplantation immunosuppression consisted of azathioprine and prednisone (AZA group, n = 22, 34.3%) or AZA, prednisone and cyclosporine (CsA group, n = 42, 65.6%). For all 64 patients combined, the 1-year graft and patient survival rates are 68.8 and 86.5%, respectively, whereas 5-year graft and patient survival rates are 60.9 and 85.9%, respectively. Patients whose immunosuppressive regimen was CsA-based had a 1-year graft survival of 71.5 versus 63.6% in the AZA group. However, this 7.9% difference did not reach statistical significance (p = 0.95). The 5-year graft survival of the CsA-based group was 69.1 versus 45.5% for the AZA group, p < 0.05. One-year patient survival was 77.3% for the AZA group and 92.9% for the CsA group, p < 0.05). The data show that patients with ESRD secondary to lupus nephritis can undergo renal transplantation with satisfactory outcome. Immunosuppression based upon CsA improves first-year patient and allograft survival by 15.6 and 7.9%. respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗