Tx Population Research Articles

Exercise rehabilitation to treat sarcopenia in pediatric transplant populations.

In adult transplant (Tx) populations, exercise rehabilitation strategies may improve sarcopenia components (muscle mass [MM], strength [MS], and physical performance [PP]). Limited data are available regarding exercise rehabilitation therapy in pediatric Tx populations. The purpose of this review is to critically evaluate the feasibility and impact of exercise programs (EP) that include resistance exercise (RE) on markers of sarcopenia in pediatric Tx populations. Literature searches in SCOPUS and WEB OF SCIENCE were conducted to identify studies applying EP with a RE component in pediatric populations in the Tx setting. Twelve articles (2008-2022) met inclusion criteria. The exercise interventions varied in length (3 weeks-12 months), intensity (low to moderate), time pre/post Tx (0 days-5 years post Tx), age of participants (3-18 years), adherence (63%-94%), and methodologies to measure components of sarcopenia. No studies measured all three components of sarcopenia concurrently. Approximately, 60% of studies found positive effects on MS and PP. Only one pediatric study measured body composition, therefore, the effect of exercise programs with RE components on MM is unknown. Exercise programs may be a beneficial treatment for sarcopenia in Tx populations, particularly in components of MS and PP. Studies measuring all three aspects of sarcopenia together in response to RE training in pediatrics remains an important gap. Studies that include body composition measurements in response to exercise are needed. Special considerations for the development of RE programs in pediatrics Tx populations are safety, supervision, engagement through family/peer involvement and incorporation of game/play-based elements.

Activity of a novel immunotherapy combination of intralesional Coxsackievirus A21 and systemic ipilimumab in advanced melanoma patients previously treated with anti-PD1 blockade therapy.

3014 Background: CAVATAK is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21 (CVA21) that when injected into melanoma lesions can increase immune-cell infiltration, up-regulation of γ-INF response and immune-checkpoint genes, including CD122, which may be a potential marker for enhanced anti-tumor activity by anti-CTLA-4 blockade. Intratumoral replication of CVA21 may act as a strong “immune-sequestration signal” to circulating activated T-cells following CTLA-4 blockade. A large unmet need exists for active therapies in melanoma patients (pts) following treatment (tx) with anti-PD1 therapies. We present in a Phase 1 study, the clinical activity of a CVA21/ ipilimumab (ipi) combination following anti–PD1 therapy in advanced melanoma pts. Methods: The Phase Ib MITCI study (NCT02307149) investigated the efficacy and safety of i.t. CVA21 and i.v. ipi in 26 pts with unresectable Stage IIIB/C-IVM1c melanoma with 13 pts previously treated with anti-PD1 therapies. Pts received up to 3 x 108 TCID50CVA21 i.t. on study days 1, 3, 5, 8 and 22, and then q3w for a further 6 series of injections. Ipi (3 mg/kg) q3w was given as 4 i.v. infusions starting at Day 22. Results: Analysis of the prior anti–PD1 treated pts (n=13) revealed that the combination tx was generally well-tolerated with one case of Gr 3 ipi-related liver toxicity observed. Of the tx population, 54% (7/13) had received prior ipi tx in addition to anti-PD1, 85% (11/13) of pts were stage IV M1b/c, with the median time between the last anti-PD1 and first CVA21 and ipi doses being 5.7 and 8.7 weeks, respectively. The mean number of prior systemic therapies including anti-PD1 tx was 2.6. For all pts completing at least the first investigator response assessment (irWHO criteria at Day 106) we observed a confirmed BORR of 38.0% (3/8) and a DCR (CR+PR+SD) of 88% (7/8). Conclusions: Intratumoral CVA21 + ipilimumab treatment in anti–PD1 treated pts has displayed promising clinical activity together with low adverse toxicity and as such this regimen may represent a valuable tx option for pts that have been administered previous lines of immune checkpoint therapy. Clinical trial information: NCT02307149.

Maximal Metabolic Rates of the Barking Frog (Craugastor augusti)

The Barking frog (Craugastor augusti, Dugès, 1879) is a direct‐developing anuran from Mexico and the Southwestern US. Very little is known about the metabolic characteristics of this species and maximal metabolic rates of adult animals are unknown. We hypothesized that metabolic characteristics of two genetically distinct populations from TX and NM, inferred from mitochondrial and nuclear DNA (Streicher et al. 2014), might show differences in maximal metabolic rates. We used closed respirometry at 20 °C to measure resting and maximal O2 consumption (VO2max) and CO2 production (VCO2max) to compare adult animals from the two populations, and examined the effects of body mass on metabolism. VO2max was 0.40 ± 0.04 ml O2 g‐1 h‐1 and 0.46 ± 0.02 ml O2 g‐1 h‐1 for the NM and TX populations (mean mass = 46.9 g), respectively, but there was no significant difference. The respiratory exchange ratio (VCO2max/VO2max) for the combined groups was 0.85 ± 0.04 and the aerobic scope (VO2max/VO2rest) was 16.9 ‐ 18.3, indicative of a high aerobic capacity. VO2max and VCO2max were significantly related to body mass (ml O2 h‐1 = 0.47 * Mass + 3.2 & ml CO2 h‐1 = 0.35 * Mass + 3.7). Previous work with anurans (32 species) has shown that VO2max scales with body mass to the 0.97 power (Taigen et al. 1992) and C. augusti falls on the predicted line relating VO2max and body mass for anurans. These results indicate that C. augusti is a highly aerobic species, but genetically distinct populations from TX and NM do not exhibit differences in maximal metabolic rates. Supported by NSF‐IOS 0843082 (MSH) and NSF‐CAREER 0845741(DAC).

Clinical Outcomes and Virus Characteristics of Dengue in Kidney Transplant Recipients: Report of 11 Cases From a Single Center.

Introduction: The growing number of transplants (Tx) in developing countries has brought the impact of neglected tropical diseases such as Dengue infection (DI) and the natural course of this disease to the attention of researchers dealing with kidney Tx in tropical areas. Objectives: To report the impact of DI in 11 Tx recipients (KTx) in a single center in Brazil. Methods: From January 2010 to December 2013, all KTx with confirmed diagnosis of DI were studied. Results: Eleven KTx requiring hospitalization were diagnosed as DI in 306 KTx (3.6%). Two cases occurred in 2010 and 9 during the outbreak of 2013. Patients were a mean age of 48 ±17 years, Caucasian (81%), males (63%), and non-diabetics (9%). Immunosuppression protocols consisted of induction therapy in 82% of cases; 72% were using calcineurin inhibitors and all patients were taking steroids. Diagnosis was made 34 ± 26 months after transplantation and the principal clinical features were fever (72%), muscular pain (73%), leucopenia (90%), and thrombocytopenia (81%). Ten (91%) cases were diagnosed as classic dengue fever (DF), and one had dengue hemorrhagic fever/shock syndrome (DHF/DSS). All diagnoses were confirmed by at least one of the following serologic tests: NS1- dengue nonstructural protein 1 antigen (3/4; 27%), dengue-specific immunoglobulin M serology (7/8; 64%), or dengue virus serotype by reverse transcriptase-polymerase chain reaction (7/9; 64%). The viremia time was 6 ± 7 (3-28) days, and co-infection with cytomegalovirus was present in 18% of cases. Dengue type 1 was the main subtype (6 cases). Graft dysfunction occurred in 10 patients, but none lost their grafts after a mean follow-up time of 17±14 months. The only patient with DHF/DSS had fulminant course and died (9%). Conclusions: The most common DI virus affecting our Tx population was type1. It seems that the clinical manifestation disease in KTx is not different from that in the general population. However, KTx seems to carry the risk of life-threatening complications in patients with DHF/DSS.

Restless legs syndrome in patients after renal transplantation

There is an almost complete lack of information on the epidemiology of sleep disorders in kidney-transplanted patients. In this report the authors assess the prevalence and clinical correlates of restless legs syndrome (RLS) in kidney-transplanted (Tx) patients. They also analyze the impact of declining renal function on this condition in the Tx population. Finally, the prevalence of RLS was compared between waitlisted dialysis patients (WL), and the Tx group. In a cross-sectional study enrolling 992 patients (816 Tx and 176 WL), the presence of RLS was assessed using the Restless Legs Syndrome Questionnaire. Clinical and sociodemographic data were collected from the patients' medical records. In transplanted patients, the prevalence of RLS was 4.8%. RLS was associated strongly with declining renal function. In groups formed on the basis of estimated glomerular filtration rate (eGFR), the prevalence of RLS was 1.8%, 5.1%, 6.5%, and 23.5% in patients with eGFR greater than 60 mL/min/1.73 m 2 ; eGFR 30 to 59 mL/min/1.73 m 2 ; eGFR 15 to 29 mL/min/1.73 m 2 ; and eGFR less than 15 mL/min/1.73 m 2 , respectively (P < 0.001). There was also a significant association between RLS and lower serum hemoglobin, higher number of self-reported comorbid conditions, and higher prevalence of iron deficiency. RLS was significantly less frequent in patients taking steroids than in patients not taking this medication (4% versus 9%, P < 0.05). In multivariate analysis, not taking steroids, eGFR, self-reported comorbidity, and iron deficiency were significant and independent predictors of RLS. Dialysis treatment was associated with increased odds for RLS (odds ratio 2.2; 95% confidence interval 1.11 to 4.35; P < 0.05) even after adjusting for serum hemoglobin and comorbidity. The prevalence of RLS is significantly lower in Tx patients than in patients on maintenance dialysis. Declining renal function is associated with increasing prevalence of the condition.

Age-dependent adaptation of the liver thyroid status and recovery of serum levels and hepatic insulin-like growth factor-I expression in neonatal and adult diabetic rats

The effect of treatment with thyroxine (T4) on the hepatic deiodinase (5′D-I) activity and triiodothyronine (T3) content and on insulin-like growth factor-I (IGF-I) secretion and mRNA hepatic expression were studied in neonatal and adult diabetic (D) rats and compared with 4 thyroidectomized (Tx) groups: neonatal and adult Tx rats treated or not with T4. Serum T3 and T4 decreased by 92% in both Tx populations and by 80% to 70% in D adults according to the severity of diabetes: −70 mg/kg body weight (BW) (D70) or 50 mg/kg BW (D50) of streptozotocin (STZ) injected, whereas only a 30% to 33% decrease was found in D neonates. A similar decrease of liver 5′D-I activity and T3 concentrations was found in neonatal and adult Tx rats, whereas a significant reduction in those parameters was observed only in adult diabetics, either D70 or D50, but not in D neonates. Serum levels and liver mRNA expression of IGF-I determined by ribonuclease protection assay, plasma and pituitary growth hormone (GH), plasma insulin, and glycemia were also measured in both D populations. A decrease in circulating IGF-I, previously reported for Tx adult rats, was also found in both D populations. T4 treatment recovered IGF-I and liver T3 in both Tx groups and D neonates, but not in D adults. These results show an age-dependent adaptation of the liver thyroid economy in diabetes, as hepatic 5′D-I does not respond to diabetes in neonates and IGF-I is insensitive to T4 treatment in adult diabetics and suggest a positive correlation between hepatic T3 content and IGF-I expression in conditions of diabetes and Tx.

Effect of thyroxine administration on the IGF/IGF binding protein system in neonatal and adult thyroidectomized rats.

The effects of different doses of thyroxine (T(4)) delivered by injection or s.c. pellet implantation on alterations of the IGF/IGF binding protein (IGFBP) system were studied in neonatal and adult thyroidectomized (Tx) rats. Body weight, blood glucose, plasma insulin, TSH and GH and pituitary GH content, as well as serum IGF-I, IGF-II, IGFBP-1, -2 and -3 and their liver mRNA expression were assayed. Pellet implantation with the smaller dose of T(4) (1.5 microg/100 g body weight (b.w.) per day) in Tx neonatal rats decreased serum IGF-I, -II and the 30 kDa complex of IGFBPs (IGFBP-1 and -2), and increased serum IGFBP-3. Only the larger dose of T(4) (3 microg/100 g b.w. per day) recovered liver mRNA expression of IGF-I and ensured euthyroid status as shown by the normalized levels of plasma TSH. The rapid increase of body weight and serum GH after T(4) administration indicated a high sensitivity to T(4) during the neonatal period. Serum and liver mRNA expression of IGFs and plasma insulin and GH recovered in adult Tx rats after pellet implantation of 1.75 microg/100 g b.w. per day throughout 10 days. The continuous replacement of T(4) by pellet seems to be the most suitable method for thyroid rehabilitation. A very good correlation was found between insulin and IGF-II in Tx neonates treated with T(4) but not between insulin and IGF-I in Tx adults. IGFBP-2 seems to be up-regulated by T(4) deprivation in neonatal and adult rats. Finally, a good correlation as well as a partial correlation were found between IGFs and thyroid hormones in both neonatal and adult Tx populations, suggesting a direct effect in vivo of T(4) on the hepatic secretion of IGFs, as previously suggested in vitro.

Survival of Donor Leukocyte Subpopulations in Immunocompetent Transfusion Recipients: Frequent Long-Term Microchimerism in Severe Trauma Patients

We recently reported detection of a transient increase in circulating donor leukocytes (WBCs) in immunocompetent recipients 3 to 5 days posttransfusion (tx) (Blood 85:1207, 1995). We have now characterized survival kinetics of specific donor WBC subsets in additional tx populations. Eight female elective surgery patients (pts) were sampled pre-tx and on days 1, 3, 5, 7, and 14 post-tx. Ten female trauma pts transfused with a total of 4 to 18 U of relatively fresh red blood cells were sampled up to 1.5 years post-tx. WBC subsets from frozen whole blood were isolated using CD4, CD8 (T cell), CD15 (myeloid), and CD19 (B cell) antibody-coated magnetic beads. Donor WBCs were counted by quantitative polymerase chain reaction (PCR) of male-specific sex determining region (SRY) sequences. PCR HLA typing and mixed leukocyte reaction (MLR) between recipient and donor WBCs were performed on two of the trauma tx recipients who had long-term chimerism of donor cells post-tx. In 6 of 8 female surgery pts, circulating CD4(+) male donor cells peaked at day 3 or 5 (0.01 to 1 cell/microL), followed by clearance by day 14. In 7 of 10 female trauma pts, we observed multilineage persistence of male donor WBCs (CD4, CD8, CD15, CD19) for 6 months to 1.5 years post-tx at concentrations of 10 to 100 cells/microL. In 2 trauma recipients studied, MLR showed no, or very low, response to WBC of the single donor implicated as the source of microchimerism by HLA typing. Establishment of long-term multilineage chimerism in trauma recipients is probably caused by engraftment of donor stem cells and mutual tolerance between recipient and donor leukocytes. A better understanding of factors determining clearance versus chimerism of transfused leukocytes is critical to prevention of alloimmunization and transfusion-induced graft-versus-host disease, and, potentially, to induction of tolerance for transplantation.

Survival of Donor Leukocyte Subpopulations in Immunocompetent Transfusion Recipients: Frequent Long-Term Microchimerism in Severe Trauma Patients

AbstractWe recently reported detection of a transient increase in circulating donor leukocytes (WBCs) in immunocompetent recipients 3 to 5 days posttransfusion (tx) (Blood 85:1207, 1995). We have now characterized survival kinetics of specific donor WBC subsets in additional tx populations. Eight female elective surgery patients (pts) were sampled pre-tx and on days 1, 3, 5, 7, and 14 post-tx. Ten female trauma pts transfused with a total of 4 to 18 U of relatively fresh red blood cells were sampled up to 1.5 years post-tx. WBC subsets from frozen whole blood were isolated using CD4, CD8 (T cell), CD15 (myeloid), and CD19 (B cell) antibody-coated magnetic beads. Donor WBCs were counted by quantitative polymerase chain reaction (PCR) of male-specific sex determining region (SRY) sequences. PCR HLA typing and mixed leukocyte reaction (MLR) between recipient and donor WBCs were performed on two of the trauma tx recipients who had long-term chimerism of donor cells post-tx. In 6 of 8 female surgery pts, circulating CD4+ male donor cells peaked at day 3 or 5 (0.01 to 1 cell/μL), followed by clearance by day 14. In 7 of 10 female trauma pts, we observed multilineage persistence of male donor WBCs (CD4, CD8, CD15, CD19) for 6 months to 1.5 years post-tx at concentrations of 10 to 100 cells/μL. In 2 trauma recipients studied, MLR showed no, or very low, response to WBC of the single donor implicated as the source of microchimerism by HLA typing. Establishment of long-term multilineage chimerism in trauma recipients is probably caused by engraftment of donor stem cells and mutual tolerance between recipient and donor leukocytes. A better understanding of factors determining clearance versus chimerism of transfused leukocytes is critical to prevention of alloimmunization and transfusion-induced graft-versus-host disease, and, potentially, to induction of tolerance for transplantation.

Effect of long-term thyroidectomy on post-prandial plasma calcium changes in man

Five totally thyroidectomized (TX) individuals were compared to age-matched controls and to 20 normal adults, 20 to 30 years of age. All subjects, after an overnight fast, were given a morning meal containing 563 mg calcium and an equal amount of phosphorus. In separate tests some of the young adults were given a meal containing only 280 mg of each of the two elements. Most individuals were studied twice: on one occasion salmon calcitonin (0.1 MCR U/kg body weight) was injected 30 min after the meal; on the other visit only the vehicle was injected. In normal individuals plasma calcium values fluctuated only slightly during the 8 hour post-prandial study period, showing no consistent deviation. In contrast, in the TX population, plasma calcium concentrations changed in a sigmoid pattern. They fell for the first hour after consumption of the meal, then rose gradually to a value statistically higher than controls by the fourth hour. This was followed by a drop in plasma calcium values to levels lower than those in their normal counterparts. A single injection of calcitonin reversed this sigmoid pattern to one not statistically different from normal. It is concluded that the post-prandial presence of calcitonin (secreted or injected) minimizes fluctuations in both directions in plasma calcium concentrations in human subjects.

ASEPTIC NECROSIS OF BONE IN TRANSPLANTED CHILDREN

Aseptic necrosis (AN) of bone was evaluated in 19 renal transplant (Tx) patients (ages 3-17 yrs.). Two were excluded because of early death. The average time from recognition of renal failure to Tx in the remaininq 17 patients (6M; 11F) was 26 mos. Four had minimal X-ray evidence of hyoerparathyroidism prior to Tx but none of the 17 had a parathyroidectomy nor received vitamin D or calcium before or after Tx. With post-Tx follow-up of 6-28 mos., 6 of 17 (35%) had symptoms and X-ray findings of AN. The average duration between Tx and onset of symptoms and positive X-ray findings was 5.5 mos. and 7.6 mos. respectively (range 1-15 mos.). All patients had involvement of 2 or 3 weight bearing joints. Presence of AN was related to duration of recognized renal failure before Tx (p<.001). The average aae at Tx in those with AN was 14.5 yrs., while in those without AN was 11.5 yrs. (p<0.05). Five patients, never receiving a high dose I.V. methylprednisolone (MP) “pulse” for rejection, had no AN; 6 of 12 who were “pulsed” developed AN (p/0.07). The following were found not to be correlated with AN: previous hyperparathyroidism, time on dialysis, prednisone before Tx (4 pts.), or total dosage of prednisone post-Tx. AN has been the major morbidity in this Tx population. Evidence suggests that AN in children is related to the duration of uremia, development of puberty, and to the number of IV MP “pulses”, but not total dosage of steroids.