Drug-induced Fanconi syndrome in patients with kidney allograft transplantation.

Background: Patients after kidney transplantation need to take long-term immunosuppressive and other drugs. Some of these drug side effects are easily confused with the symptoms of Fanconi syndrome, resulting in misdiagnosis and missed diagnosis, and causing serious consequences to patients. Therefore, improving awareness, early diagnosis and treatment of Fanconi syndrome after kidney transplantation is critical. Methods: This retrospective study analyzed 1728 cases of allogeneic kidney transplant patients admitted to the Second Xiangya Hospital of Central South University from July 2016 to January 2021. Two patients with Fanconi syndrome secondary to drugs, adefovir dipivoxil (ADV) and tacrolimus, were screened. We summarized the diagnostic process, clinical data, and prognosis. Results: The onset of Fanconi syndrome secondary to ADV after renal transplantation was insidious, and the condition developed after long-term medication (>10 years). It mainly manifested as bone pain, osteomalacia, and scoliosis in the late stage and was accompanied by obvious proximal renal tubular damage (severe hypophosphatemia, hypokalemia, hypocalcemia, hypouricemia, glycosuria, protein urine, acidosis, etc.) and renal function damage (increased creatinine and azotemia). The pathological findings included mitochondrial swelling and deformity in renal tubular epithelial cells. The above symptoms and signs were relieved after drug withdrawal, but the scoliosis was difficult to rectify. Fanconi syndrome secondary to tacrolimus has a single manifestation, increased creatinine, which can be easily confused with tacrolimus nephrotoxicity. However, it is often ineffective to reduce the dose of tacrolomus, and proximal renal failure can be found in the later stage of disease development. There was no abnormality in the bone metabolism index and imageological examination findings. The creatinine level decreased rapidly, the proximal renal tubule function returned to normal, and no severe electrolyte imbalance or urinary component loss occurred when the immunosuppression was changed from tacrolimus to cyclosporine A. Conclusions: For the first time, drug-induced Fanconi syndrome after kidney transplantation was reported. These results confirmed that the long-term use of ADV or tacrolimus after kidney transplantation may have serious consequences, some of which are irreversible. Greater understanding of Fanconi syndrome after kidney transplantation is necessary in order to avoid incorrect and missed diagnosis.

Prednisone and deflazacort in Duchenne muscular dystrophy: a patient perspective and plain language summary publication of the Cincinnati study.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about the Cincinnati study, which was published in the Journal of Comparative Effectiveness Research in January 2020. The Cincinnati study reviewed data from 435 males with Duchenne muscular dystrophy, also known as DMD, who were treated at the Cincinnati Children's Hospital Medical Center. DMD is a rare disease that worsens over time. People with DMD experience inflammation in their muscles and muscle loss over time. They also experience bone problems such as an abnormally bent spine, also known as scoliosis, as well as heart and lung problems. WHAT HAPPENED IN THE CINCINNATI STUDY?: Prednisone and deflazacort are steroids that help to reduce muscle inflammation and are used as treatments for DMD. The study researchers wanted to further understand the differences between using prednisone and deflazacort in males with DMD by reviewing data from past medical records of patients seen in clinics rather than in clinical studies. This is known as gathering real-world evidence. In the Cincinnati study, the researchers compared males with DMD who started taking prednisone as their first steroid treatment with males who started taking deflazacort as their first steroid treatment. WHAT WERE THE RESULTS?: Overall, the researchers found that the participants who took deflazacort were able to walk until a later age before they needed to use a wheelchair, compared with those who took prednisone. They also had a lower risk of scoliosis and developed it at a later age. WHAT DO THE RESULTS OF THE STUDY MEAN?: These results helped the researchers to learn more about the differences between how well prednisone and deflazacort work in males with DMD based on their medical records.

Impact of growth hormone treatment on scoliosis development and progression: analysis of 1128 patients with idiopathic short stature.

OBJECTIVES: The purpose of this study was to evaluate the impact of recombinant human growth hormone (rhGH) on the development and progression of scoliosis in patients with idiopathic short stature (ISS). METHODS: Patients with ISS who underwent rhGH treatment from 1997 to 2017 and were followed up for scoliosis screening with serial radiographic examination were included. For assessing scoliosis development, patients who did not have scoliosis at the time of rhGH treatment were included and followed up to determine whether de novo scoliosis developed during the treatment. For evaluating scoliosis progression, patients who already had scoliosis were analyzed. Univariate and multivariate Cox regression analyses of demographic and radiographic variables were performed to determine the related factors in the development and progression of scoliosis. RESULTS: For assessing scoliosis development, 1093 patients were included. The average duration of rhGH treatment was about 2 years. De novo scoliosis developed in 32 patients (3.7%). The analysis revealed that sex (p=0.016) and chronological age (p=0.048) were statistically significant factors associated with scoliosis development. However, no relationship was observed between scoliosis development and rhGH treatment types or duration. Among 67 patients who already had scoliosis at the time of rhGH treatment, 11 (16.4%) showed scoliosis progression. However, the rhGH types and duration also did not affect scoliosis progression. CONCLUSIONS: De novo scoliosis developed in 3.7% and scoliosis progressed in 16.4% of the patients during rhGH treatment. However, scoliosis development or progression was not affected by the types or duration of rhGH treatment in patients with ISS.

Chronic toxicity of 1,3,5-triazine herbicides in the postembryonic development of the western clawed frog Silurana tropicalis.

Seven 1,3,5- triazine (s-triazine) herbicides (ametryn, prometryn, dimethametryn, simazine, atrazine, propazine, and cyanazine) were tested using an amphibian (Silurana tropicalis) metamorphosis assay focusing on morphometric, gravimetric, and thyroid-histological endpoints. Premetamorphic tadpoles were exposed to each s-triazine at 2 concentrations between 1/1000 and 1/10 of the 96-h acute toxicity values, until all tadpoles in the control group reached either the late prometamorphosic stages or the initial stage of metamorphic climax. All s-triazines tested induced significant retardation in growth and development at the higher concentrations (0.2-1.0mg/L), and some of them induced similar effects even at the lower concentrations (0.02-0.1mg/L) while each showing a linear dose-response. Total size of the thyroid glands tended to be reduced corresponding to the delayed development, but without showing histomorphological lesions typical of anti-thyroid chemicals. These consistent results suggest that the s-triazines can act as a chemical stressor inhibiting tadpole growth and development, possibly without disrupting the thyroid axis. In addition, tadpoles exhibiting spinal curvatures appeared in either one or both of the lower and higher concentration groups for each s-triazine tested. The incidence rate in the s-triazine exposure groups where tadpoles with scoliosis were observed ranged from 3.3% to 63.3%, some of which were significantly higher than that in the respective control groups (0-6.7%). It is speculated that the s-triazines may promote to occur axial malformations in developing tadpoles.

Congenital scoliosis: an anomalous association with endosulfan.

Endosulfan is an organochlorine pesticide that is used extensively across the world to kill insects. Incidence of acute and chronic toxicity with endosulfan poisoning has been reported, and nearly 80 countries have banned its use. However, it is still being used in many low-income/middle-income countries. One of the most severe tragedies because of endosulfan poisoning has taken place in the Indian state of Kerala due to persistent aerial spraying of endosulfan. Even though there are reports of skeletal and other congenital abnormalities in humans and experimental animals following exposure to endosulfan, very few have been documented. We report two cases of congenital scoliosis in siblings living in a community affected by high levels of endosulfan in the environment. High index of suspicion is essential during the screening of school children exposed to endosulfan. Congenital scoliosis is a progressive deformity that leads to severe disability, unless detected and corrected at an early stage.

Influence of growth hormone treatment on radiographic indices of the spine: propensity-matched analysis.

BACKGROUND: We performed this study to investigate the influence of recombinant human growth hormone (rhGH) therapy on radiographic indices of the spine using propensity-matched analysis. METHODS: Patients with idiopathic short stature who had undergone both growth hormone therapy and whole-spine radiographs more than twice prior to 15 years of age were included in the patient group. Other patients who had undergone whole-spine radiographs more than twice prior to the same age during regular checkups for idiopathic scoliosis formed the control group. Propensity-matched analysis was performed to reduce the selection bias. The scoliosis Cobb angle, coronal balance, apical vertebral translation, apical rotation, and pelvic obliquity were measured from the radiographs taken at the periodic follow-ups. The rate of progression of the measurements was adjusted by multiple factors using a linear mixed model with sex as the fixed effect and age and each subject as the random effects. RESULTS: Using a propensity-matched analysis, 48 patients were finally included in both groups. The scoliosis Cobb angle increased by 1.0° (p < 0.001) per year in the patient group, whereas there was no significant annual change in the control group (p = 0.496). Female patients showed a greater scoliosis Cobb angle (1.8°, p = 0.039) compared with male patients. There was no significant difference between the patient and control groups in coronal balance (p = 0.264). Apical vertebral translation per year was increased by 1.2 mm (p < 0.001) in the patient group and 0.5 mm in the control group (p = 0.003). CONCLUSION: Radiographic examination revealed that growth hormone therapy for idiopathic short stature affected the progression of the scoliosis Cobb angle and apical vertebral translation on the coronal plane. Physicians should be aware that annual follow-up is required to evaluate the change in the curvature of the spine in patients undergoing rhGH treatment.

Growth Hormone Treatment and Adverse Events.

We compiled the major adverse events included in the Annual Research Reports of the Foundation for Growth Research published in and after 2000. We conducted a review of approximately 32,000 patients treated with growth hormone (GH) who subsequently developed leukemia and who were registered with the Foundation for Growth Research (from 1975 to December 31 1997). We performed a literature review and found that GH therapy was not associated with leukemia onset in patients with no risk factors for leukemia. We also reported the onset of diabetes mellitus (DM), scoliosis, and respiratory problems in patients with Prader-Willi syndrome who were treated with GH. Osteoporosis, Hashimoto thyroiditis, and hyperlipemia were relatively frequent complications of Turner syndrome (TS).

Congenital malformations and other reproductive losses in goats due to poisoning by Poincianella pyramidalis (Tul.) L.P. Queiroz (=Caesalpinia pyramidalis Tul.).

In the semiarid region of Brazil, in areas with vegetation composed mainly of Poincianella pyramidalis, several cases of congenital malformation and reproductive losses were observed in goats and sheep from 2012 to 2014. To determine the teratogenic effect of P. pyramidalis, two groups of eight goats each were used. Goats from Group 1 received fresh P. pyramidalis, harvested daily, as the only roughage during the whole breeding and pregnancy period. Goats in Group 2 (control) received Cynodon dactylon (tifton) hay free choice. Ultrasound examination for pregnancy diagnosis was performed every 28 days. Four goats from Group 1 were pregnant on day 28 but not on day 56, suggesting embryonic death or abortion. Another goat from Group 1 died at day 70 of pregnancy, and the fetuses exhibited micrognathia. The other three goats bore six kids, three of which showed bone malformations in the limbs, spine, ribs, sternum, and head, including arthrogryposis, scoliosis and micrognathia. One kid also showed hypoplasia of the left pulmonary lobes. In the control group, all goats bore a total of 13 kids and none of them exhibited malformations. These results demonstrated that P. pyramidalis causes congenital malformations and other reproductive losses in goats.

Effect of Melatonin and Calmodulin in an Idiopathic Scoliosis Model.

Background. To explore influence of continuous illumination, luzindole, and Tamoxifen on incidence of scoliosis model of rats. Methods. Thirty-two one-month-old female rats were rendered into bipedal rats. The bipedal rats were divided into 4 groups: group A by intraperitoneal injection of luzindole and continuous illumination; group B by intraperitoneal injection of luzindole only; group C by intraperitoneal injection of luzindole and oral administration of Tamoxifen; and group D by intraperitoneal injection of equivalent saline. Radiographs were taken at 8th week and 16th week, and incidence and the Cobb angles of scoliosis were calculated. At 16th week, all rats were sacrificed. Before the sacrifice, the levels of calmodulin were measured in each group. Results. At 8th week, scoliosis occurred in groups A and B, with an incidence of 75% and 12.5%, respectively, while rats in group C or D had no scoliosis. At 16th week, scoliosis incidences in groups A and B were 57% and 62.5%, respectively. No scoliosis occurred in group C or D. Calmodulin in platelets in group B was significantly different, compared with groups A and D. There was no significant difference in calmodulin in platelets in groups B and C. Conclusion. By intraperitoneal injection of luzindole in bipedal rats, scoliosis rat models could be successfully made. Under light, incidence of scoliosis may be increased at an early period but it is reversible. Tamoxifen can suppress natural process of scoliosis.

Change of selenium in environment and risk of adolescent idiopathic scoliosis: a retrospective cohort study.

OBJECTIVES: Scoliosis is the disease which has a long history over one century. However, the pathogenesis remains unclear at present. To demonstrate the effect of different selenium content in environment on the morbidity of adolescent idiopathic scoliosis (AIS). METHODS: Retrospective cohort study (follow-up from 1997 to 2009): compare the difference morbidity between high selenium group and the normal selenium group of AIS. PATIENTS: 9998 cases from three areas in China were participated in this study. There is different selenium content in these three areas. RESULTS: High selenium levels were significant associated with the AIS morbidity. While low selenium level had no significant correlation with the AIS morbidity. CONCLUSIONS: This study confirmed that high selenium content in the environment was one of risk factors for idiopathic scoliosis. We speculated that the excessive growth of the spine and the spinal cord asynchronous growth effect were key factors that high selenium content in the environment leads to scoliosis.

Heated indoor swimming pools, infants, and the pathogenesis of adolescent idiopathic scoliosis: a neurogenic hypothesis.

BACKGROUND: In a case-control study a statistically significant association was recorded between the introduction of infants to heated indoor swimming pools and the development of adolescent idiopathic scoliosis (AIS). In this paper, a neurogenic hypothesis is formulated to explain how toxins produced by chlorine in such pools may act deleteriously on the infant's immature central nervous system, comprising brain and spinal cord, to produce the deformity of AIS. PRESENTATION OF THE HYPOTHESIS: Through vulnerability of the developing central nervous system to circulating toxins, and because of delayed epigenetic effects, the trunk deformity of AIS does not become evident until adolescence. In mature healthy swimmers using such pools, the circulating neurotoxins detected are chloroform, bromodichloromethane, dibromochloromethane, and bromoform. Cyanogen chloride and dichloroacetonitrile have also been detected. TESTING THE HYPOTHESIS: In infants, the putative portals of entry to the blood could be dermal, oral, or respiratory; and entry of such circulating small molecules to the brain are via the blood-brain barrier, blood-cerebrospinal fluid barrier, and circumventricular organs. Barrier mechanisms of the developing brain differ from those of adult brain and have been linked to brain development. During the first 6 months of life cerebrospinal fluid contains higher concentrations of specific proteins relative to plasma, attributed to mechanisms continued from fetal brain development rather than immaturity. IMPLICATIONS OF THE HYPOTHESIS: The hypothesis can be tested. If confirmed, there is potential to prevent some children from developing AIS.

Safety of growth hormone treatment of children with idiopathic short stature: the US experience.

Recombinant human growth hormone (rhGH) is approved in the United States for treatment of idiopathic short stature (ISS). The occurrence of adverse events (AEs) and the long-term safety of rhGH treatment in this patient population are reviewed. Data were analyzed from postmarketing surveillance studies that included ISS patients, prospective ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children. Frequency rates of targeted AEs (i.e., scoliosis, slipped capital femoral epiphysis, intracranial hypertension, pancreatitis) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions. At dosages of 0.24-0.37 mg/kg/week, rhGH treatment in children with ISS does not adversely affect blood glucose levels. At dosages ≥ 0.3 mg/kg/week, a dose-dependent increase in mean fasting and stimulated insulin levels is observed. Current evidence derived from 'on-treatment' surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The safety profile of rhGH at doses ≤ 0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs. Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and/or heightened GH and insulin-like growth factor I exposure on cancer risk, caution and ongoing scrutiny of risks versus benefits are warranted.

Impact of strontium on skeletal deformities in Baltic cod (Gadus morhua callaris L.).

A study was conducted to examine spinal deformities such as lordosis, scoliosis, and dwarfism in cod (Gadus morhua callaris L.) that were caught in the southern Baltic. The bone tissue of the spine and the muscle of the deformed cod were analyzed for concentration of macroelements (Sr, Ca and P) and toxic metals (Cd, Pb and Hg). Healthy specimens of the same body length that were caught in the same hauls were also tested, and these comprised the reference material. The study was undertaken to verify the hypothesis that lowered values of Ca/Sr and P/Sr ratios caused skeletal deformities. Toxic metals were also tested to determine whether they had an impact on the deformities of cod inhabiting Baltic waters. In cod with deformities, a significant decrease in Ca/Sr ratios were noted in 86% of the spine and 97% of the muscle. Decreases in the values of the P/Sr ratios were confirmed in 57% of the bone tissue and 78% of the muscle tissue of individuals with skeletal deformities. Toxic metals (Cd, Pb and Hg) occurred in the bone and muscle tissues of deformed and healthy cod on the low levels. It was not differences in concentrations of these elements, and thus could not have had an impact on the occurrence of deformities. Skeletal deformities could have resulted from lowered values of the Ca/Sr and P/Sr ratios of the spinal bone and muscle tissues of cod. Lower values of these coefficients should be linked to the varied salinity (5-21‰) and strontium (5-15Bqm(-3)) concentrations of Baltic waters.

Orthopedic complications related to growth hormone therapy in a pediatric population.

Since the introduction of recombinant growth hormone, its use has diversified and multiplied. Growth hormone is now the recommended therapy for a growing indication to all forms of short stature because of its direct and indirect role on bone growth. Hereby, we discuss the orthopedic complications associated with growth hormone treatment in pediatric patients. These complications include carpal tunnel syndrome, Legg-Calve-Perthes' disease, scoliosis, and slipped capital femoral epiphysis. Their incidence rates recorded in several growth hormone therapy-related pharmacovigilance studies will be summarized in this study with focused discussion on their occurrence in the pediatric and adolescent age groups. The pathogenesis of these complications is also reviewed.

High selenium may be a risk factor of adolescent idiopathic scoliosis.

The pathogenesis of adolescent idiopathic scoliosis (AIS) remains little understood. Previous work has shown that guppy fish is an ideal animal model of idiopathic scoliosis which has similar epidemiological and morphological characteristic with AIS. However, some research speculated that the high-selenium environment could also induce idiopathic-type scoliosis of fish. We believe that the high-selenium related deformity of spine and guppy curveback syndrome may have the same pathogenesis. And high selenium may be a risk factor of AIS.

Do baclofen pumps influence the development of scoliosis in children?

OBJECT: Intrathecal baclofen is an effective treatment for spasticity in patients with cerebral palsy. There has been increasing concern, however, that intrathecal baclofen may accelerate the development of scoliosis in this population. To this end, the authors reviewed their population of pediatric patients with baclofen pumps to assess the incidence of scoliosis. METHODS: This was a retrospective chart and radiology review of all pediatric patients with baclofen pumps. Cobb angles were measured preoperatively and on follow-up images. RESULTS: Of 38 patients identified, 32 had adequate data available for inclusion in the study (16 with cerebral palsy, 7 with dystonic cerebral palsy, 4 with head injury, and 5 with other diagnoses). The mean age at pump insertion was 10.6 years and the mean follow-up period was 31 months (range 1-118 months). The mean annual Cobb angle progression was 19 degrees (range 0-68 degrees, median 12 degrees). CONCLUSIONS: In the authors' group of patients there was notable development and progression of scoliosis at a greater than previously reported rate for the same patient population, and also greater than previously reported patients with intrathecal baclofen pumps. The largest possible confounding factor in this study was the insertion of the pump before skeletal maturity and therefore coinciding with the time when scoliosis may be developing naturally. A prospective study is recommended to gather further data on the development of scoliosis in this particular population with intrathecal baclofen pumps.

Long-term safety of recombinant human growth hormone in children.

BACKGROUND: Between 1985 and 2006, the National Cooperative Growth Study (NCGS) monitored the safety and efficacy of recombinant human growth hormone (rhGH) in 54,996 children. METHODS: Enrolled patients were followed until rhGH discontinuation. Investigators submitted adverse event reports for targeted events or those potentially rhGH-related. RESULTS: Early concerns about de novo leukemia in patients without risk factors have not been substantiated--three observed vs. 5.6 expected in age-matched general population based on years at risk [standard incidence ratio (SIR), 0.54; 95% confidence interval (CI), 0.11-1.58]. De novo malignancies (intracranial and extracranial) were not significantly increased in patients without risk factors (29 confirmed vs. 26 expected; SIR, 1.12; 95% CI, 0.75-1.61). Second neoplasms occurred in 49 patients, of whom 37 had irradiation for their initial tumors (including five of 16 retinoblastoma patients, three of whom had bilateral retinoblastoma) consistent with an increased risk with rhGH. Thirty-three patients developed type 1 diabetes mellitus (DM) (37 expected; SIR, 0.90; 95% CI, 0.62-1.26). Type 2 DM and nonspecified DM were reported in 20 and eight patients, respectively. Two deaths were reported in patients with Prader-Willi syndrome and five deaths from aortic dissection in patients with Turner syndrome. In patients with organic GH deficiency and idiopathic panhypopituitarism, 11 events of acute adrenal insufficiency occurred, including four deaths, consistent with a reported increased risk for adrenal insufficiency in hypopituitary patients with or without rhGH treatment. CONCLUSION: After more than 20 yr, leukemia, a major safety issue initially believed associated with GH, has not been confirmed, but other signals, including risk of second malignancies in patients previously treated with irradiation, have been detected or confirmed through the NCGS. These data further clarify the events associated with rhGH and, although confirming a favorable overall safety profile, they also highlight specific populations at potential risk.

Long-term safety of recombinant human growth hormone in turner syndrome.

CONTEXT: Turner syndrome (TS) affects more than 50,000 girls and women in the United States. The National Cooperative Growth Study (NCGS) has collected efficacy and safety data for 5220 TS children treated with recombinant human GH (rhGH) during the last 20 yr. OBJECTIVES: Our objective was to determine frequencies of specific targeted adverse events (AEs) and additional AEs of interest in TS patients. Corresponding safety data in non-TS patients or normal populations were compared for selected AEs. METHODS: Patients may be enrolled at rhGH initiation and followed until discontinuation. Investigators submit AE reports describing any event that is potentially rhGH related or is a targeted event. RESULTS: The Genentech Drug Safety department received 442 AE reports for TS NCGS patients as of June 30, 2006, including 117 serious AEs. Seven deaths occurred; five resulted from aortic dissections/ruptures. The incidence of certain events known to be associated with rhGH (targeted events), including intracranial hypertension, slipped capital femoral epiphysis, scoliosis, and pancreatitis, was increased compared with other non-TS patients in NCGS. There were 10 new-onset malignancies that occurred, including six in patients without known risk factors. Type 1 diabetes also appeared to be increased compared with other NCGS groups. CONCLUSIONS: Children with TS who were treated with rhGH exhibit an increased underlying risk for selected AEs associated with rhGH and for type 1 diabetes, which is likely unrelated to rhGH. The aortic dissection/rupture incidence reflects the higher baseline risk for these events in TS, was consistent with current epidemiological data in smaller TS populations, and is likely unrelated to rhGH. It is not known whether the reported malignancies represent an inherently increased risk in TS patients. Twenty years of experience in 5220 patients indicates no new rhGH-related safety signals in the TS population. The NCGS and similar registries, although focused on the years during rhGH treatment, may also be a window into the natural history of TS in childhood.