Early onset of primary hypogonadism revealed by serum anti-Mullerian hormone determination during infancy and childhood in trisomy 21

Male patients with an extra sex chromosome or autosome are expected to present primary hypogonadism at puberty owing to meiotic germ-cell failure. Scarce information is available on trisomy 21, a frequent autosomal aneuploidy. Our objective was to assess whether trisomy 21 presents with pubertal-onset, germ-cell specific, primary hypogonadism in males, or whether the hypogonadism is established earlier and affects other testicular cell populations. We assessed the functional status of the pituitary-testicular axis, especially Sertoli cell function, in 117 boys with trisomy 21 (ages: 2 months-20 year). To compare with an adequate control population, we established reference levels for serum anti-Mullerian hormone (AMH) in 421 normal males, from birth to adulthood, using a recently developed ultrasensitive assay. In trisomy 21, AMH was lower than normal, indicating Sertoli cell dysfunction, from early infancy, independently of the existence of cryptorchidism. The overall prevalence rate of AMH below the 3rd percentile was 64.3% in infants with trisomy 21. Follicle-stimulating hormone was elevated in patients <6 months and after pubertal onset. Testosterone was within the normal range, but luteinizing hormone was elevated in most patients <6 months and after pubertal onset, indicating a mild Leydig cell dysfunction. We conclude that in trisomy 21, primary hypogonadism involves a combined dysfunction of Sertoli and Leydig cells, which can be observed independently of cryptorchidism soon after birth, thus prompting the search for new hypotheses to explain the pathophysiology of gonadal dysfunction in autosomal trisomy.

Comparative study of Botox (R) injection treatment for upper eyelid retraction with 6-month follow-up in patients with thyroid eye disease in the congestive or fibrotic stage

Aim To compare morphometric data of the eyelid fissure and the levator muscle function (LF) before and up to 6 months after transcutaneous injection with five units of Botox (R) in patients with upper lid retraction (ULR) from congestive or fibrotic thyroid eye disease (TED). Methods Twenty-four patients with ULR from TED were submitted to transcutaneous injection of 5 units (0.1 ml) of Botox in one eye only. Patients were divided into two groups: 12 with congestive-stage TED (CG), and 12 with fibrotic-stage TED (FG). Bilateral lid fissure measurements using digital imaging and computer-aided analysis were taken at baseline and at regular intervals 2 weeks, 1 month, 3 months and 6 months after unilateral Botox injection. Mean values taken at different follow-up points were compared for the two groups. Results Most patients experienced marked improvement in ULR, with a mean reduction of 3.81 mm in FG and 3.05 mm in CG. The upper eyelid margin reflex distance, fissure height and total area of exposed interpalpebral fissure were significantly smaller during 1 month in CG and during 3 months in FG. Reduction in LF and in the difference between lateral and medial lid fissure measurements was observed in both groups. The treatment lasted significantly longer in FG than in CG. Conclusions A single 5-unit Botox injection improved ULR, reduced LF and produced an adequate lid contour in patients with congestive or fibrotic TED. The effect lasts longer in patients with fibrotic orbitopathy than in patients with congestive orbitopathy.

Microduplication of the ICR2 Domain at Chromosome 11p15 and Familial Silver-Russell Syndrome

Silver-Russell syndrome (SRS) is characterized by severe intrauterine and postnatal growth retardation in association with a typical small triangular face and other variable features. Genetic and epigenetic disturbances are detected in about 50% of the patients. Most frequently, SRS is caused by altered gene expression on chromosome 11p15 due to hypomethylation of the telomeric imprinting center (ICR1) that is present in at least 40% of the patients. Maternally inherited duplications encompassing ICR1 and ICR2 domains at 11p15 were found in a few patients, and a microduplication restricted to ICR2 was described in a single SRS child. We report on a microduplication of the ICR2 domain encompassing the KCNQ1, KCNQ1OT1, and CDKN1C genes in a three-generation family: there were four instances of paternal transmissions of the microduplication from a single male uniformly resulting in normal offspring, and five maternal transmissions, via two clinically normal sisters, with all the children exhibiting SRS. This report provides confirmatory evidence that a microduplication restricted to the ICR2 domain results in SRS when maternally transmitted. (C) 2011 Wiley-Liss, Inc.

Improvements in the 6-Min Walk Test and Spirometry Following Thoracentesis for Symptomatic Pleural Effusions

Background: Impairment in pulmonary capacity due to pleural effusion compromises daily activity. Removal of fluid improves symptoms, but the impact, especially on exercise capacity, has not been determined. Methods: Twenty-five patients with unilateral pleural effusion documented by chest radiograph were included. The 6-min walk test, Borg modified dyspnea score, FVC, and FEV, were analyzed before and 48 h after the removal of large pleural effusions. Results: The mean fluid removed was 1,564 +/- 695 mL. After the procedure, values of FVC, FEV and 6-min walk distance increased (P<.001), whereas dyspnea decreased (P<.001). Statistical correlations (P<.001) between 6-min walk distance and FVC (r=0.725) and between 6-min walk distance and FEV, (r=0.661) were observed. Correlations also were observed between the deltas (prethoracentesis X postthoracentesis) of the 6-min walk test and the percentage of FVC (r=0.450) and of FEV, (r=0.472) divided by the volume of fluid removed (P<.05). Conclusion: In addition to the improvement in lung function after thoracentesis, the benefits of fluid removal are more evident in situations of exertion, allowing better readaptation of patients to routine activities. CHEST 2011; 139(6):1424-1429

Primary retroperitoneal lipoma: A soft tissue pathology heresy? Report of a case with classic histologic, cytogenetics, and molecular genetic features

Adipose tissue tumors of the retroperitoneum showing no identifiable cytologic atypia are usually classified as lipoma-like well-differentiated liposarcoma. Whether a subset of these tumors represents true examples of retroperitoneal lipoma remains a controversial subject, because the diagnostic liposarcoma cells may be of difficult identification, even after extensive sampling. Herein, we describe a large retroperitoneal lipoma with classic histopathologic, cytogenetic, molecular cytogenetic, and molecular genetic features. Extensive morphologic inspection showed no evidence of cytologic atypia. Cytogenetic analysis performed on fresh tissue material revealed the classic lipoma chromosome t(3;12)(q27;q14-15). Fluorescence in situ hybridization on multiple sections excluded the presence of MDM2 and CDK4 amplification, but showed HMGA2 balanced rearrangement in most cells. Reverse-transcriptase polymerase chain reaction followed by sequencing analysis confirmed the presence of the HMGA2-LPP fusion gene, a characteristic and the most common fusion product found in lipoma. The patient has been followed for 2.5 years without evidence of recurrence or metastasis. These results indicate that retroperitoneal lipomata do exist, but their diagnosis must rely on stringent histologic, cytogenetic, and molecular genetic analysis.

Toxoplasma gondii: The severity of toxoplasmic encephalitis in C57BL/6 mice is associated with increased ALCAM and VCAM-1 expression in the central nervous system and higher blood-brain barrier permeability

In order to investigate the differential ALCAM, ICAM-1 and VCAM-1 adhesion molecules mRNA expression and the blood-brain barrier (BBB) permeability in C57BL/6 and BALB/c mice in Toxoplasma gondii infection, animals were infected with ME-49 strain. It was observed higher ALCAM on day 9 and VCAM-1 expression on days 9 and 14 of infection in the central nervous system (CNS) of C57BL/6 compared to BALB/c mice. The expression of ICAM-1 was high and similar in the CNS of both lineages of infected mice. In addition, C57BL/6 presented higher BBB permeability and higher IFN-gamma and iNOS expression in the CNS compared to BALB/c mice. The CNS of C578L/6 mice presented elevated tissue pathology and parasitism. In conclusion, our data suggest that the higher adhesion molecules expression and higher BBB permeability contributed to the major inflammatory cell infiltration into the CNS of C57BL/6 mice that was not efficient to control the parasite. (C) 2010 Elsevier Inc. All rights reserved.

Childhood radiation-associated atypical meningioma with novel complex rearrangements involving chromosomes 1 and 12

Meningiomas are recognized as the most common late complication following radiotherapy. However, cytogenetic studies in childhood atypical radiation-induced meningioma are sporadic, mainly because this condition generally occurs after a long latent period. In the present study we show the results of conventional and molecular cytogenetics in a 14-year-old boy with a secondary atypical meningioma. Apart from numerical changes, we found complex aberrations with the participation of chromosomes 1, 6 and 12. The invariable presence of loss of 1p was demonstrated by fluorescent in situ hybridization (FISH) analysis with probes directed to telomeric regions and by comparative genome hybridization (CGH). Previous cytogenetic studies on adult spontaneous and radiation-associated meningiomas showed loss of chromosome 22 as the most frequent change, followed by loss of the short arm of chromosome 1. To the best of our knowledge this is the first report of highly complex chromosome aberrations in the pediatric setting of meningioma.

An INDEL polymorphism at the X-STR GATA172D05 flanking region

A new polymorphic INDEL was detected at the X-STR GATA172D05 flanking region, which corresponds to an 18-bp deletion, 141 bp upstream the TAGA repeat motif. This INDEL was found to be polymorphic in different population samples from Native Americans, Africans, and Europeans as well as in an admixed population from the Amazonia (Bel,m). Gene diversities varied between 37.5% in Native Americans and 49.9% in Africans. Comparison between human and chimpanzee sequences showed that the ancestral state corresponds to the presence of two copies of 18 bp, detected in both species; and the mutated allele has lost one of these two copies. The simultaneous analysis of the short tandem repeat (STR) and INDEL variation showed an association between the INDEL ancestral allele with the shorter STR alleles. High diversities were found in all population groups when combining the information provided by the INDEL and STR variation. Gene diversities varied between 76.7% in Native Americans and 80.6% in both Portugal and Bel,m.

Estimates of Interethnic Admixture in the Brazilian Population Using a Panel of 24 X-Linked Insertion/Deletion Markers

Objectives. In this study, we aimed to identify ancestry informative haplotypes and make interethnic admixture estimates using X-chromosome markers. Methods. A significant sample (461 individuals) of European, African, and Native American populations was analyzed, and four linkage groups were identified. The data obtained were used to describe the ancestral contribution of populations from four different geographical regions of Brazil (745 individuals). Results. The global interethnic admixture estimates of the four mixed populations under investigation were calculated applying all the 24 insertion/deletion (INDEL) markers. In the North region, a larger Native Americans ancestry was observed (42%). The Northeast and Southeast regions had smaller Native American contribution (27% in both of them). In the South region, there was a large European contribution (46%). Conclusions. The estimates obtained are compatible with expectations for a colonization model with biased admixture between European men (one X chromosome) and Native American and African women (two X chromosomes), so the 24 X-INDEL panel described here can be a useful to make admixture interethnic estimates in Brazilian populations. Am. J. Hum. Biol. 22:849-852,2010. (C) 2010 Wiley-Liss, Inc.

Diagnostic value of interleukin-6 and C-reactive protein on early onset bacterial infection in preterm neonates with respiratory distress

Aims: To evaluate the C-reactive protein (CRP) and interleukin-6 (IL-6) as diagnostic tools for early onset infection in preterm infants with early respiratory distress (RD). Methods: CRP and IL-6 were quantified at identification of RD and 24 h after in 186 newborns. Effects of maternal hypertension, mode of delivery, Apgar score, birth weight, gestational age, mechanical ventilation, being small for gestational age (SGA), and the presence of infection were analyzed. Results: Forty-four infants were classified as infected, 42 as possibly infected, and 100 as uninfected. Serum levels of IL-6 (0 h), CRP (0 h), and CRP (24 h), but not IL-6 (24 h) were significantly higher in infected infants compared to the remaining groups. The best test for identification of infection was the combination of IL-6 (0 h) 36 pg/dL and/or CRP (24 h) 0.6 mg/dL, which yielded 93% sensitivity and 37% specificity. The presence of infection and vaginal delivery independently increased IL-6 (0 h), CRP (0 h) and CRP (24 h) levels. Being SGA also increased the CRP (24 h) levels. IL-6 (24 h) was independently increased by mechanical ventilation. Conclusions: The combination of IL-6 (0 h) and/or CRP (24 h) is helpful for excluding early onset infection in preterm infants with RD but the poor specificity limits its potential benefit as a diagnostic tool.

Roux-en-Y Bypass Gastroplasty: Markers of Oxidative Stress 6 Months After Surgery

This study examined the effect of weight loss on energy intake, vitamin C, E, beta-carotene (diet/blood), reduced glutathione (GSH), C-reactive protein (CRP), thiobarbituric acid reactive substances (TBARS), catalase, and myeloperoxidase, in patients with Roux-en-Y bypass gastroplasty. Prospective clinical study with control (C) and bariatric (B) groups (n = 20 each). Age was 38.8 +/- 11.1 (C) and 37.8 +/- 11.2 years (B), and body mass indices (BMI) were 22.4 +/- 2.4 and 48.1 +/- 8.7 kg/m(2), respectively. Group C was assessed on a single occasion and B at three time points (basal period and 3 and 6 months after gastroplasty). BMI was decreased at three (38.3 +/- 1.7, P = 0.018) and 6 months after surgery (34.9 +/- 1.7, P < 0.001). Mean weight loss was 20.53 +/- 1.1 after three and 27.96 +/- 1.3 kg after 6 months. Serum vitamin C and beta-carotene (P < 0.01 and P < 0.001, respectively) were increased at 6 months compared to basal. Basal serum vitamin C (P = 0.001) and beta-carotene (P < 0.001) were lower compared to controls. Serum vitamin E corrected for cholesterol and triglycerides was higher in group B at three (P = 0.01) and 6 months (P = 0.001) and lower at basal (P < 0.001) compared to controls. GSH was higher in controls (P < 0.001) compared to basal. Catalase (P = 0.01) and TBARS (P < 0.001) were higher in group B at 6 months. TBARS were higher (P < 0.001) at basal compared to controls. Myeloperoxidase and CRP decreased in group B after three (P = 0.028, P = 0.010) and 6 months (P < 0.001, P = 0.001), respectively. Roux-en-Y bypass gastroplasty led to decreased proinflammatory parameters together with increased nutritional antioxidants, catalase, and TBARS, and decreased GSH 6 months after surgery.

5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors recruitment in tonic-clonic seizure-induced antinociception: Role of dorsal raphe nucleus

Pharmacological studies have been focused on the involvement of different neural pathways in the organization of antinociception that follows tonic-clonic seizures, including 5-hydroxytryptamine (5-HT)-, norepinephrine-, acetylcholine- and endogenous opioid peptide-mediated mechanisms, giving rise to more in-depth comprehension of this interesting post-ictal antinociceptive phenomenon. The present work investigated the involvement of 5-HT(1A/1B), 5-HT(6), and 5-HT(7) serotonergic receptors through peripheral pretreatment with methiothepin at doses of 0.5, 1.0, 2.0 and 3.0 mg/kg in the organization of the post-ictal antinociception elicited by pharmacologically (with pentylenetetrazole at 64 mg/kg)-induced tonic-clonic seizures. Methiothepin at 1.0 mg/kg blocked the post-ictal antinociception recorded after the end of seizures, whereas doses of 2.0 and 3.0 mg/kg potentiated the post-ictal antinociception. The nociceptive thresholds were kept higher than those of the control group. However, when the same 5-hydroxytryptamine receptors antagonist was microinjected (at 1.0, 3.0 and 5.0 mu g/0.2 mu L) in the dorsal raphe nucleus, a mesencephalic structure rich in serotonergic neurons and 5-HT receptors, the post-ictal hypo-analgesia was consistently antagonized. The present findings suggest a dual effect of methiothepin, characterized by a disinhibitory effect on the post-ictal antinociception when peripherally administered (possibly due to an antagonism of pre-synaptic 5-HT(1A) serotonergic autoreceptors in the pain endogenous inhibitory system) and an inhibitory effect (possibly due to a DRN post-synaptic 5-HT(1B), 5-HT(6), and 5-HT(7) serotonergic receptors blockade) when centrally administered. The present data also Suggest that serotonin-mediated mechanisms of the dorsal raphe nucleus exert a key-role in the modulation of the post-ictal antinociception. (C) 2009 Elsevier Inc. All rights reserved.

Nitric Oxide-Induced Vasorelaxation in Response to PnTx2-6 Toxin from Phoneutria nigriventer Spider in Rat Cavernosal Tissue

Introduction. Priapism is one of several symptoms observed in accidental bites by the spider Phoneutria nigriventer. The venom of this spider is comprised of many toxins, and the majority has been shown to affect excitable ion channels, mainly sodium (Na+) channels. It has been demonstrated that PnTx2-6, a peptide extracted from the venom of P. nigriventer, causes erection in anesthetized rats and mice. Aim. We investigated the mechanism by which PnTx2-6 evokes relaxation in rat corpus cavernosum. Main Outcome Measures. PnTx2-6 toxin potentiates nitric oxide (NO)-dependent cavernosal relaxation. Methods. Rat cavernosal strips were incubated with bretylium (3 x 10-5 M) and contracted with phenylephrine (PE; 10-5 M). Relaxation responses were evoked by electrical field stimulation (EFS) or sodium nitroprusside (SNP) before and after 4 minutes of incubation with PnTx2-6 (10-8 M). The effect of PnTx2-6 on relaxation induced by EFS was also tested in the presence of atropine (10-6 M), a muscarinic receptor antagonist, N-type Ca2+ channel blockers (omega-conotoxin GVIA, 10-6 M) and sildenafil (3 x 10-8 M). Technetium99m radiolabeled PnTx2-6 subcutaneous injection was administrated in the penis. Results. Whereas relaxation induced by SNP was not affected by PnTx2-6, EFS-induced relaxation was significantly potentiated by this toxin as well as PnTx2-6 plus SNP. This potentiating effect was further increased by sildenafil, not altered by atropine, however was completely blocked by the N-type Ca2+ channels. High concentrated levels of radiolabeled PnTx2-6 was specifically found in the cavernosum tissue, suggesting PnTx2-6 is an important toxin responsible for P. nigriventer spider accident-induced priapism. Conclusion. We show that PnTx2-6 slows Na+ channels inactivation in nitrergic neurons, allowing Ca2+ influx to facilitate NO/cGMP signalling, which promotes increased NO production. In addition, this relaxation effect is independent of phosphodiesterase enzyme type 5 inhibition. Our data displays PnTx2-6 as possible pharmacological tool to study alternative treatments for erectile dysfunction. Nunes KP, Cordeiro MN, Richardson M, Borges MN, Diniz SOF, Cardoso VN, Tostes R, De Lima ME, Webb RC, and Leite R. Nitric oxide-induced vasorelaxation in response to PnTx2-6 toxin from Phoneutria nigriventer spider in rat cavernosal tissue. J Sex Med 2010;7:3879-3888.

Dysregulation of renal transient receptor potential melastatin 6/7 but not paracellin-1 in aldosterone-induced hypertension and kidney damage in a model of hereditary hypomagnesemia

Rationale Hyperaldosteronism, important in hypertension, is associated with electrolyte alterations, including hypomagnesemia, through unknown mechanisms. Objective To test whether aldosterone influences renal Mg(2+) transporters, (transient receptor potential melastatin (TRPM) 6, TRPM7, paracellin-1) leading to hypomagnesemia, hypertension and target organ damage and whether in a background of magnesium deficiency, this is exaggerated. Methods and results Aldosterone effects in mice selectively bred for high-normal (MgH) or low (MgL) intracellular Mg(2+) were studied. Male MgH and MgL mice received aldosterone (350 mu g/kg per day, 3 weeks). SBP was elevated in MgL. Aldosterone increased blood pressure and albuminuria and increased urinary Mg(2+) concentration in MgH and MgL, with greater effects in MgL. Activity of renal TRPM6 and TRPM7 was lower in vehicle-treated MgL than MgH. Aldosterone increased activity of TRPM6 in MgH and inhibited activity in MgL. TRPM7 and paracellin-1 were unaffected by aldosterone. Aldosterone-induced albuminuria in MgL was associated with increased renal fibrosis, increased oxidative stress, activation of mitogen-activated protein kinases and nuclear factor-NF-kappa B and podocyte injury. Mg(2+) supplementation (0.75% Mg(2+)) in aldosterone-treated MgL normalized plasma Mg(2+), increased TRPM6 activity and ameliorated hypertension and renal injury. Hence, in a model of inherited hypomagnesemia, TRPM6 and TRPM7, but not paracellin-1, are downregulated. Aldosterone further decreased TRPM6 activity in hypomagnesemic mice, a phenomenon associated with hypertension and kidney damage. Such effects were prevented by Mg(2+) supplementation. Conclusion Amplified target organ damage in aldosterone-induced hypertension in hypomagnesemic conditions is associated with dysfunctional Mg(2+)-sensitive renal TRPM6 channels. Novel mechanisms for renal effects of aldosterone and insights into putative beneficial actions of Mg(2+), particularly in hyperaldosteronism, are identified. J Hypertens 29: 1400-1410 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.