Additive antinociceptive action of intrathecal anandamide reuptake inhibitor and morphine in the management of post-incisional pain in rats.

Spinal opioids have mixed efficacy and their adverse effects force treatment cessation of postoperative pain. Consequently, there is an ongoing search for new therapeutic strategies. Here, we evaluated the analgesic efficacy of intrathecal UCM707, an anandamide reuptake inhibitor, and morphine combination. Firstly, we assessed the effects of morphine (1, 5 and 10 µg), UCM707 (75 µg) and its combination in the hot plate. Then, morphine + UCM707 at sub-effective doses was evaluated in a rat post-incisional pain model. In addition, µ-, CB1r-, CB2r- and TRPV1-antagonists were pre-administered before the combination. Activation of µ-opioid and CB1r, and Cnr1, Cnr2, Oprm1 and TRPV1 expressions were evaluated in the lumbar sacra and periaqueductal grey by [35 S]-GTPγS binding autoradiography and qPCR studies. In the hot plate, morphine (1 µg) and UCM707 (75 µg) induced a more robust analgesic effect than each drug alone. Morphine plus UCM707 did not modify µ-opioid nor CB1 receptor function in the PAG or LS. Cnr1 and TRPV1 expression increased in the lumbar sacra (LS). Morphine plus UCM707 significantly reduced post-incisional pain at 1 and 4 days after surgery. Cnr1, Cnr2 and TRPV1 expressions increased in the LS. Blockade of µ-opioid receptor reduced combination effects on days 1 and 4. CB1r- and CB2r-antagonism reduced morphine + UCM707 effects on days 1 and 4, respectively. CB1r and TRPV1-antagonism improved their antinociceptive effects on day 4. These results revealed a synergistic/additive analgesic effect of UCM707 and morphine combination controlling postincisional pain. CB1r, CB2r and TRPV1 contribute differently as central sensitization occurs.

Isolated pulmonary interstitial glycogenosis associated with alveolar growth abnormalities: A long-term follow-up study.

INTRODUCTION: Pulmonary interstitial glycogenosis (PIG) is a rare infant interstitial lung disease characterized by an increase in the number of interstitial mesenchymal cells, presenting as enhanced cytoplasmic glycogen, and is considered to represent the expression of an underlying lung development disorder. METHODS: This study describes the clinical, radiological, and functional characteristics and long-term outcomes (median 12 years) of nine infants diagnosed with isolated PIG associated with alveolar simplification in the absence of other diseases. RESULTS: All patients presented with tachypnea. Additionally, seven patients had breathing difficulties and hypoxemia. Abnormalities in chest-computerized tomography (CT) with a pattern of ground-glass opacity, septal thickening, and air trapping were observed in all individuals, with images suggesting abnormal alveolar growth (parenchymal bands and architectural distortion). All lung biopsies showed alveolar simplification associated with an increased number of interstitial cells, which appeared as accumulated cytoplasmic glycogen. In the follow-up, all patients were asymptomatic. The respiratory function test was normal in only two patients. Five children showed an obstructive pattern, and two children showed a restrictive pattern. Chest-CT, performed after an average of 6.5 years since the initial investigation, revealed a partial improvement of the ground-glass opacity pattern; however, relevant alterations persisted. CONCLUSION: Although the patients with PIG in the absence of other associated pathologies had a good clinical outcome, significant radiographic alterations and sequelae in lung function were still observed after a median follow-up of 12 years, suggesting that PIG is a marker of some other persistent abnormalities in lung growth, which have effects beyond the symptomatic period.

Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients.

17α-hydroxylase/17,20-lyase deficiency is a rare form of congenital adrenal hyperplasia caused by mutations in CYP17A1. Two phenotypic female sisters, aged 17 and 15 years and with 46,XY and 46,XX karyotypes, respectively, presented with primary amenorrhea and absent secondary sexual characteristics. The elder sib also presented with high blood pressure. Both patients had elevated levels of ACTH, gonadotropins, progesterone, corticosterone, and deoxycorticosterone, and reduced levels of estradiol, testosterone, androstenedione, 17-OH-P, DHEA-S, cortisol, aldosterone, and renin activity. The CYP17A1 gene was sequenced, and polymorphic haplotypes were further analyzed in the Spanish family and in Brazilian patients. The 2 sisters were compound heterozygous for p.Arg362Cys and p.Trp406Arg mutations, previously described as the most prevalent mutations in Brazilian families of Spanish (p.Trp406Arg) or Portuguese (p.Arg362Cys) origin. Analysis of polymorphisms in CYP17A1 suggested that the paternal allele with p.Arg362Cys may share a common origin with the Brazilian carriers, while the maternal allele with p.Trp406Arg did not. Hydrocortisone and sex hormone replacement therapy was initiated in both patients. In conclusion, one CYP17A1 mutation (p.Arg362Cys) may share a common ancestry in Brazilian and our present Spanish patients, while p.Trp406Arg may have arisen separately. The elder patient (46,XY) developed a more severe phenotype and a poorer response to estradiol replacement therapy.

Hysteroscopic myomectomy outcomes after 3-month treatment with either Ulipristal Acetate or GnRH analogues: a retrospective comparative study.

Ulipristal Acetate (UPA) modifies the endometrium, as well as fibroids, and therefore it might make hysteroscopic surgery more difficult. To confirm that pre-treatment with UPA is as safe and effective an option as pre-treatment with GnRH analogues, considered the gold standard. We present the first series of 26 hysteroscopic myomectomies after 3 months treatment with UPA and we compare the results with a series of 24 cases pretreated with GnRH analogues. This was a retrospective cohort study between July 2013 and May 2015. We analyszed patients with submucous myomas >2.5 in diameter. Hysteroscopic myomectomy was performed after 3 months of treatment with either UPA (5mg daily) or the GnRH agonist (3.75mg/month). Both groups were similar in age, myoma initial size and classification. There were no significant differences between UPA and GnRHa treated groups in terms of percentage of myomas resected (93% vs 98%), duration of surgery (38 vs 37min), fluid deficit (200 vs 350ml) and complications. In the surgeon's subjective opinion, UPA treatment was associated with an easier resection. Based on our experience, previous treatment with UPA does not difficult Hhysteroscopic myomectomy. Endometrial changes have no impact on surgery. Safety and feasibility are comparable to hysteroscopic myomectomies with previous treatment with GnRH analogues. This allows us to take advantage of the reduction in size of fibroids before surgery with less side effects.

Familial short stature and intrauterine growth retardation associated with a novel mutation in the IGF-I receptor (IGF1R) gene.

CONTEXT: IGF-I is essential for normal human growth and mediates its effects through the IGF1R. IGF1R mutations have been associated with varying degrees of intrauterine and postnatal growth retardation. OBJECTIVE: To identify IGF1R gene mutations in a short-statured family with intrauterine growth retardation and microcephaly. METHODS: Direct DNA sequencing was used to identify IGF1R mutations. Multiplex ligation-dependent probe amplification analyses were performed for deletions and duplications of all IGF1R exons. Functional studies were conducted to assess mutation pathogenicity. RESULTS: A novel heterozygous IGF1R missense mutation in exon 7 (c.A1549T, p.Y487F) was identified in a short-statured girl with severe prenatal growth retardation and microcephaly. The same mutation was also identified in her mother, who presented prenatal and postnatal growth failure, and her short-statured maternal grandmother, both of whom exhibited microcephaly. The index case showed a partial response to rhGH. Functional studies performed in dermal fibroblasts from the index case and her mother showed normal IGF-I binding; however, IGF-I activation of intracellular signalling measured as AKT and extracellular signal-regulated kinase phosphorylation was markedly reduced, with patients' values being lower than those of her mother. IGF-I stimulation of DNA synthesis was significantly reduced compared with controls. CONCLUSION: Our results show a novel missense mutation in the IGF1R gene (c.A1549T, p.Y487F) associated with prenatal and postnatal growth failure and microcephaly in the context of familial short stature. The functional studies are in line with the inactivation of one copy of the IGF1R gene with variable expression within the same family.

Mesenchymal hamartoma: prenatal and postnatal diagnosis by imaging.

We present a case of a twin pregnancy in which one fetus developed a rapidly growing unilateral intrathoracic tumor. While a cystic adenomatoid malformation was suspected in the ultrasound scan, the magnetic resonance scan suggested a pulmonary blastoma or a bronchioalveolar carcinoma. Postnatal chest radiography and contrast-enhanced computed tomography of the affected newborn were performed, and it was ruled out the possibility of malignant origin. Finally, the anatomopathologic exam revealed the presence of a mesenchymal hamartoma in the chest wall. Nevertheless, parents refused any treatment for the newborn.

Macroorchidism and panhypopituitarism: two different forms of presentation of FSH-secreting pituitary adenomas in adolescence.

BACKGROUND: FSH-secreting pituitary adenomas are extremely rare in children and are seldom associated with clinical manifestations of high serum gonadotrophin levels. Thus, most patients have a late presentation, usually as macroadenomas. CASE REPORTS: Two different clinical forms of presentation of FSH-secreting pituitary adenomas are reported: one in a 12-year-old boy with macroorchidism due to a pituitary microadenoma, probably FSH-secreting, and the other in a 15-year-old boy with panhypopituitarism due to an FSH-producing macroadenoma. Both patients presented slightly high or high FSH with low LH and high inhibin B levels. In the first case, the microadenoma was treated medically with cabergoline, which failed to reduce FSH and inhibin B levels. No radiological progression has been observed despite increasing testicular volume. In the second case, surgery was performed on the macroadenoma, leading to a decrease in FSH and inhibin B levels. The patient developed severe hypothalamic obesity and is currently under treatment with somatostatin. CONCLUSIONS: FSH-secreting pituitary tumors have an extremely variable clinical expression. The discrepancy between normal or slightly increased FSH and low LH values, together with high inhibin B levels, strongly suggests FSH hypersecretion which should be studied.

Glycogen storage disease type III with hypoketosis.

A rare case of glycogen storage disease type III with unusually absent ketone body production during hypoglycemia is presented. A 10-month-old boy presented with asymptomatic hepatomegaly. GOT/GPT 2555/1160 IU/L, CK 302 IU/L, triglycerides 1223 mg/dL, cholesterol 702 mg/dL and uric acid 7.9 mg/dL. After a 9-hour fast, glucose was 27 mg/dL and adequate lipolysis without ketogenesis was observed (total/free carnitine 34.5/20 micromol/L, free fatty acids 1620 micromol/L and beta-hydroxybutyrate 172 micromol/L). Result of MCT (medium-chain triglycerides) load test: basal hydroxybutyrate 29 micromol/L rose to 5748 micromol/L. Treatment with a fat-restricted diet supplemented with formula containing MCT was initiated and the patient presented a satisfactory initial evolution. Three months later, CK were 3000 IU/L. Muscle biopsy was diagnostic of glycogenosis. Enzymatic activity in skin fibroblasts was 0% for amylo-1,6-glucosidase. The diagnosis of glycogenosis type III was established. Echocardiography performed at that time showed non-obstructive ventricular hypertrophy. Until now hypoketosis during hypoglycemia has only been described in glycogenosis type I.

Twelve-month neurodevelopmental outcome in preterm infants with and without intrauterine growth restriction.

AIM: To evaluate the neurodevelopmental outcome at 12 months' corrected age in preterm infants with and without severe intrauterine growth restriction. METHODS: This prospective follow-up study included 37 infants with severe intrauterine growth restriction and 36 appropriate-for-gestational-age infants born between 26 and 34 weeks. Neonatal and infant data were prospectively recorded. Infants were assessed at 12 ± 2 months' corrected age with the Hammersmith Infant Neurological Examination and the Bayley Scale for Infant Development version-II. RESULTS: Both groups were similar in demographic characteristics and perinatal status. No significant differences in neurodevelopmental performance were found. The mental development index was 98.8 (SD 9.0) vs 98.4 (SD 13.1) (p = 0.9) and the psychomotor development index was 91.7 (SD 9.9) vs 95.5 (SD 13.4) (p = 0.2) for the study and reference groups respectively. Neurological assessment showed no significant differences between the two groups. CONCLUSION: Although the study group showed a non-significant trend towards a lower score in the psychomotor development index than the reference group, significant differences at 12 months could not be demonstrated. IUGR infants continued to have significantly lower weight, length and head circumference at 1 year.

ACTH-dependent precocious pseudopuberty in an infant with DAX1 gene mutation.

DAX1 gene (Xp21) expression is involved in the development of the hypothalamo-pituitary-gonadal and adrenal axes, and acts as a negative regulator of steroidogenesis. Mutations of this gene determine adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. We report the case of a 9-month-old boy referred for the study of macrogenitosomia and pubic hair development. He had presented acute adrenal crises in the neonatal period and, later, a clinical picture of peripheral precocious puberty. A mutation in the DAX1 gene was found (Trp291Arg) and a diagnosis of AHC was made. Replacement doses of hydrocortisone (HC) (10 mg/m2/day) failed to produce a feedback inhibition of adrenocorticotropic hormone (ACTH), and testosterone levels remained high. Testosterone and ACTH values normalized after HC was progressively increased to 18 mg/m2/day. In conclusion, peripheral precocious puberty in patients with DAX1 gene mutations appears to be secondary to the stimulus exerted by ACTH on melanocortin receptors in Leydig cells and to the overexpression of testicular steroidogenesis activators by the loss of transcriptional repression.

Glucose intolerance and diabetes are observed in the long-term follow-up of nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene.

OBJECTIVE: To report the long-term follow-up of three nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene. RESEARCH DESIGN AND METHODS: Oral glucose tolerance test (OGTT) and venous 24-h glucose-insulin profile were performed yearly from adolescence. RESULTS: Patient 1 (now aged 31 years) developed insulin-dependent diabetes at the age of 25 years. In patient 2 (now aged 17 years), impaired fasting glucose and a diabetic OGTT response with normal A1C values have been observed since the age of 10 years. In patient 3 (now aged 24 years), intolerant OGTT response and hyperglycemic episodes with normal A1C have been observed since the age of 16 years. All patients presented relatively low insulin levels during hyperglycemia, normal BMI, and negative autoantibodies (GAD antibody, insulinoma-associated protein 2, and islet cell antibody). CONCLUSIONS: Development of glucose metabolism impairment ranging from glucose intolerance to insulin-dependent diabetes is observed in the evolution of these patients.

Tamoxifen treatment in a patient with blepharophimosis-ptosis-epicanthus inversus syndrome and peripheral precocious puberty.

Patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) can be classified as types 1 or 2, according to the presence or not of ovarian failure. We report a 5 year-old girl with BPES and large multicystic ovaries who developed peripheral precocious puberty with thelarche (Tanner stage III) and pubarche (Tanner stage II). Pelvic ultrasound revealed pubertal uterus and enlarged multicystic ovaries. Fibrous dysplasia and McCune-Albright syndrome were ruled out. Treatment with an estrogen antagonist was started (tamoxifen, 10 mg/day), achieving regression of thelarche. Tamoxifen treatment was stopped at 10-(7/12) years, and growth velocity and skeletal maturation rate returned to normal. No treatment-associated adverse effects were observed.

Thyroid function in seventy-five healthy preterm infants thirty to thirty-five weeks of gestational age: a prospective and longitudinal study during the first year of life.

Thyroid function was evaluated in 75 healthy preterm infants, 30-35 weeks of gestational age. Serum thyrotropin (TSH), thyroxine (T(4)), triiodothyronine (T(3)), free T(4) (immunochemoluminescence) and reverse triiodothyronine (rT(3)) (radioimmunoassay) were measured in the mother and in the cord at delivery and in the preterm infants at 1 hour, 24 hours, 1 week, 3 weeks, 2 months, 4 months, 6 months, and 12 months of postnatal age. These values were compared to those of healthy full-term infants of the same postnatal age (22 at 24 hours from our hospital and from previously reported data at others times). Mean 24-hour TSH values were significantly lower (p < 0.001) in preterm than in full-term infant populations (12.38 +/- 6.13 microIU/mL versus 22.02 +/- 13.28 microIU/mL); however, all TSH values of preterm infants were in the range of the full-term values. Mean 24-hour free T(4) values were similar in preterm and full-term infants (1.88 +/- 0.46 ng/dL versus 2.01 +/- 0.54 ng/dL) and all preterm infants had free T(4) values within the range of those of full-term infants at 24 hours. Mean T(4) and T(3) values were significantly lower in preterm than in full-term neonates at 1 hour and 24 hours of age. Mean 24-hour rT(3) values were significantly higher in preterm than in full-term newborns. From 1 week onwards, all thyroid function values were in the same range in both populations. In conclusion, individual thyroid function was similar in healthy preterms and full-terms from the first 24 hours of life. Normative data in preterm infants during the first year of life applying the latest luminescence techniques currently used worldwide are reported.

Biomarkers of diabetes-associated oxidative stress and antioxidant status in young diabetic patients with or without subclinical complications.

The aims of the study were to ascertain the potential role of oxidative stress in the onset of disease-related pathophysiological complications in young type 1 diabetes patients. Indicative parameters of lipoperoxidation, protein oxidation, and changes in antioxidant defense system status were measured in blood samples from 26 young diabetic patients with recently diagnosed (< 6 months) microangiopathy (+DC), 28 diabetic patients without complications (-DC), and 40 healthy age-matched controls (CR). Both diabetic groups presented similar fructosamine and glycated hemoglobin (HbA1c) values. Results showed erythrocyte glutathione peroxidase activity, glutathione content, and plasma beta-carotene to be significantly lower in diabetic patients compared with control subjects, but with no significant differences between -DC and +DC groups. Antioxidant enzyme superoxide dismutase activity was significantly higher in the erythrocytes of diabetic patients independently of the presence of microvascular complications. However, the plasma alpha-tocopherol/total lipids ratio was significantly diminished in +DC group compared with -DC (p =.008). Lipid peroxidation indices measured in plasma included malondialdehyde, lipid hydroperoxides, and lipoperoxides, which were significantly elevated in our diabetic patients regardless of the presence of complications. Evidence of oxidative damage to proteins was shown both through the quantification of plasma protein carbonyl levels, which were significantly higher in -DC (0.61 +/- 0.09 mmol/mg prot), and higher still in the +DC patients (0.75 +/- 0.09 mmol/mg prot) compared with those of controls (0.32 +/- 0.03 mmol/mg prot; p <.01) and immunoblot analysis of protein-bound carbonyls. Additionally, a marked increase in protein oxidation was observed in +DC patients through assessment of advanced oxidation protein products (AOPP) considered to be an oxidized albumin index; AOPP values were significantly higher in +DC than in -DC patients (p <.01) and CR (p <.0001). These results point to oxidatively modified proteins as a differential factor possibly related to the pathogenesis of diabetic complications.

Clinical and biochemical determinants of bone metabolism and bone mass in adolescent female patients with anorexia nervosa.

Among pathologies prevalent in western societies, anorexia nervosa has increased over the last decade. Its effects on bone mass need to be defined, and prognostic factors, either clinical or biochemical, could aid clinicians in individual patient management. To determine which clinical and/or biochemical parameters could be related to bone mass status in adolescent female anorexia nervosa patients, 73 female patients were classified according to different stages of their illness and studied in terms of clinical and biochemical parameters and bone densitometric mineral content at lumbar spine. Patients (age 17.2 +/- 1.7 y, mean +/- SD) with Tanner pubertal stage 5, regular menstruation for more than 3 mo before the onset of secondary amenorrhea, and diagnosed with anorexia nervosa were consecutively studied and classified in three clinical situations: I) active phase (34 patients): undernourished and amenorrheic; II) weight recovered but still amenorrheic (20 patients); III) fully recovered (19 patients). Clinical data were recorded at the time of bone density measurement, concomitant with blood sample extraction for study of IGF-I, IGF-binding protein 3 (IGFBP-3), IGFBP-1, estradiol, sex hormone-binding globulin, dehydroepiandrosterone sulfate, prealbumin, amino-terminal propeptide of procollagen III, osteocalcin, bone alkaline phosphatase, carboxy-terminal propeptide of procollagen I, amino-terminal propeptide of procollagen I, carboxy-terminal telopeptide of collagen I, 25-OH-vitamin D, 1,25(OH)(2)-vitamin D, and parathormone. In addition, a 24-h urine collection was made for cortisol, GH, deoxypyridinoline, amino-terminal telopeptide of collagen I, and calcium and creatinine content analysis. IGF-I, estradiol, and biochemical bone formation markers were higher and IGFBP-1, sex hormone-binding globulin, and biochemical bone resorption markers were lower in the weight-recovered stages (stages II and III) compared with the active phase (stage I). Bone formation markers correlated positively with body mass index SD score and IGF-I, whereas bone resorption markers correlated negatively with body mass index SD score and estradiol. Although no statistically significant differences regarding lumbar spine bone mineral density SD score values were recorded among the three stages of the illness, the proportion of osteopenic patients was clearly lower among stage III patients. The actual bone mineral density was inversely related to the duration of amenorrhea and directly related to duration of postmenarcheal menses before amenorrhea. In addition, a subset of osteopenic patients (five of 19) in the fully clinically recovered group with accelerated bone turnover was identified. Normal circulating estrogen level exposure time predicts actual bone mineral density at lumbar spine in young adolescent anorexia nervosa patients. In addition to psychiatric and nutritional interventions, estrogen-deprivation periods must be shortened to less than 20 mo. Patients remaining osteopenic at full clinical recovery require additional follow-up studies.