Immigrants' access to health care: Problems identified in a high-risk tuberculosis population.

INTRODUCTION: Immigrants may utilize health care services differently than other residents and may also have a greater risk for tuberculosis (TB). OBJECTIVE: Identify barriers to healthcare access by immigrants, factors associated with these barriers, and discuss strategies that may reduce these barriers. MATERIAL AND METHODS: Anonymous questionnaires were given to immigrants at National Immigrant Support Centres between 2015 and 2016. Barriers to healthcare were identified using logistic regression. RESULTS: One-hundred and nineteen questionnaires were administered to immigrants, 9 of whom (8%) presented with TB while in Portugal. Twenty-one percent of immigrants reported barriers to healthcare access, and 69% had general practitioners (GPs). The presence of barriers to healthcare access was negatively associated with having a GP and with being married or in a de facto union. CONCLUSIONS: A considerable proportion of immigrants reported having difficulties accessing healthcare services in Portugal where legally these barriers are nonexistent. Certain factors were associated with these difficulties.

Increased circulating PEDF and low sICAM-1 are associated with sickle cell retinopathy.

Sickle cell retinopathy (SCR) develops in up to 30% of sickle cell disease patients (SCD) during the second decade of life. Treatment for this affection remains palliative, so studies on its pathophysiology may contribute to the future development of novel therapies. SCR is more frequently observed in hemoglobin SC disease and derives from vaso-occlusion in the microvasculature of the retina leading to neovascularization and, eventually, to blindness. Circulating inflammatory cytokines, angiogenic factors, and their interaction may contribute to the pathophysiology of this complication. Angiopoietin (Ang)-1, Ang-2, soluble vascular cell adhesion molecule-1, intercellular adhesion molecule (ICAM)-1, E-selectin, P-selectin, IL1-ß, TNF-α, pigment epithelium derived factor (PEDF) and vascular endothelial growth factor plasmatic levels were determined in 37 SCD patients with retinopathy, 34 without retinopathy, and healthy controls. We observed that sICAM-1 is significantly decreased, whereas PEDF is elevated in HbSC patients with retinopathy (P=0.012 and P=0.031, respectively). Ang-1, Ang-2 and IL1-ß levels were elevated in SCD patients (P=0.001, P<0.001 and P=0.001, respectively), compared to controls, and HbSS patients presented higher levels of Ang-2 compared to HbSC (P<0.001). Our study supports the possible influence of sICAM-1 and PEDF on the pathophysiology of retinal neovascularization in SCD patients.

GSTT1, GSTM1, and GSTP1 polymorphisms and chemotherapy response in locally advanced breast cancer.

The glutathione S-transferase (GST) family consists of phase II detoxification enzymes that catalyze the conjugation of toxic substances, such as chemotherapeutic agents, to glutathione. We examined whether GSTT1/GSTT1"null", GSTM1/GSTM1"null" and GSTP1Ile105Ile/GSTP1Ile105Val polymorphisms are associated with different response rates to neoadjuvant chemotherapy in the treatment of stage II and III breast cancer. Forty Brazilian women with invasive ductal adenocarcinoma of the breast submitted to neoadjuvant chemotherapy, using 5-fluorouracil, epirubicin and cyclophosphamide, were genotyped for the GSTT1, GSTM1 and GSTP1 genes. Clinical response was assessed by RECIST criteria. Comparisons were made for the three genes alone and in pairs, as polymorphic and as wild-type combinations and polymorphic/wild-type combinations. We analyzed all possible combinations and their response rate. Patients with the GSTT1/GSTP1105Ile combination were found to have a significantly better response than GSTT1"null"/GSTP1105Val (P = 0.0209) and GSTT1/GSTM1 (P = 0.0376) combinations. Analysis of all possible combinations showed the GSTM1"null" polymorphic genotype to be present in four, and the wild-type GSTP1105Ile in six of the combinations associated with the largest number of responding patients. We found that patients with the GSTT1/GSTP1105Ile wild-type combination had a significantly higher response rate to chemotherapy than patients with the respective polymorphic GSTT1"null"/GSTP1105Val combination or patients with the wild-type GSTT1/GSTM1. The six gene combinations associated with the largest number of responding patients were found to contain the wild-type GSTP1105Ile and the polymorphic-type GSTM1"null". These specific combinations were virtually absent in the combinations with few responding patients.

Tityus fasciolatus envenomation induced cardio-respiratory alterations in rats.

The present study characterized envenomation in young rats by Tityus fasciolatus, an endemic scorpion to Central Brazilian and state of Minas Gerais. Electrocardiographic examinations were performed prior to treatment and every 5 min during the first 30 min after envenomation. The cardiac blood profile [creatine kinase, CK isoenzyme MB, lactate dehydrogenase, aspartate aminotransferase and troponina] together with macroscopic and microscopic alterations in the lungs and heart were evaluated. Envenomated animals showed ECG changes suggesting electrolytic imbalance, myocarditis and venom interference on the conduction tissue. Biochemical analyses indicated myocardial damage with high levels of CK, CK-MB and LDH. Macroscopic and microscopic findings included detection of pulmonary haemorrhages. In conclusion, T. fasciolatus venom leads to acute cardio-respiratory changes in young rats.

Early endosome localization and activity of RasGEF1b, a toll-like receptor-inducible Ras guanine-nucleotide exchange factor.

Guanine-nucleotide exchange factors (GEFs) stimulate the intrinsic GDP/GTP exchange activity of Ras and promote the formation of active Ras-GTP, which in turn controls diverse signalling networks important for the regulation of cell proliferation, survival, differentiation, vesicular trafficking, and gene expression. RasGEF1b is a GEF, whose expression is induced in macrophages on stimulation with toll-like receptor (TLR) agonists. Here, we showed that in vitro RasGEF1b expression by macrophages is mostly induced by TLR3 (poly I:C) and TLR4 (lipopolysaccharyde) through the MyD88-independent pathway. In vivo infection with the protozoan parasites Trypanosoma cruzi and Plasmodium chabaudi induced RasGEF1b in an MyD88-, TRIF-, and IFN-gamma-dependent manner. Ectopically expressed RasGEF1b was found, mostly, in the heavy membrane fraction of HEK 293T, and by confocal microscopy, it was found to be located at early endosomes. Computational modelling of the RasGEF1b-Ras interaction revealed that RasGEF1b interacts with the binding domain site of Ras, a critical region for interacting with GEFs involved in the activation of Ras-Raf-MEK-ERK pathway. More important, RasGEF1b was found to be closely associated with Ras in live cells and to trigger Ras activity. Altogether, these results indicate that on TLR activation, RasGEF1b may trigger Ras-like proteins and regulate specific biological activities described for this subtype of GTPases.

Amygdalae and striatum calcification in lipoid proteinosis.

Lipoid proteinosis is a rare genodermatosis characterized by multisystem involvement due to intracellular deposition of an amorphous hyaline material. Lipoid proteinosis is caused by mutations in the ECM1 gene. In many patients, skin and mucosa abnormalities are the first manifestation. When the CNS is affected, a wide variety of neurologic abnormalities may be present. The hallmark findings are calcifications, mostly occurring in the amygdalae, hippocampus, parahippocampal gyrus, or even the striatum. Present in half of the patients, moniliform blepharosis is considered a pathognomonic finding. In the other half of patients imaging could assist in the diagnosis. The authors present a series of 3 cases of lipoid proteinosis with brief clinical data and imaging findings.

Cardiorespiratory evaluation of juvenile rats experimentally envenomed with Tityus serrulatus venom

Accidental envenomation caused by Tityus serrulatus scorpions is very common in Brazil and may result in serious cardiorespiratory alterations that are frequently fatal to children. In the present study, the effects of T. serrulatus venom on the cardiorespiratory system of recently weaned male Wistar rats were evaluated. Fifteen animals were distributed into three groups (n = 5). The control group A received 400 miuL ultrapure water by subcutaneous injection, while the experimental groups B and C were injected with scorpion venom (100 and 450 miug, respectively, in 400 miuL water). Electrocardiogram (ECG) traces were obtained prior to the experiment, at five-minute intervals up to 30 minutes after treatment. At 40 minutes after envenomation, the animals had severe acute symptoms and were subsequently anesthetized for blood collection by means of intracardiac puncture. Biochemical profiles for the cardiac muscle were established by colorimetric analysis of creatine kinase (CK) and CK-MB isoenzyme. Semiquantitative analysis of troponin was performed using the immunochromatographic assay. Following euthanasia, the lungs and hearts were removed and subjected to histopathological examination. All experimental animals had ECG alterations compatible with electrolytic imbalance, myocarditis and alterations of the cardiac conduction system. Envenomed animals had accentuated bradycardia at 25 and 30 minutes after venom inoculation. All experimental animals had myocardial lesions, which were confirmed by increased serum levels of CK and CK-MB, although there were no alterations in the serum concentration of troponin. Pulmonary hemorrhage was detected in whole lungs and microscopically confirmed by the presence of congested capillaries and erythrocytes in the alveolar parenchyma. In conclusion, T. serrulatus venom caused great cardiorespiratory damage to weaned rats.

Perfis eletrocardiográfico e ecodopplercardiográfico de ovinos após ingestão da suspensão aquosa de Mascagnia rigida Griseb. (Malpighiaceae). / Electrocardiographical and echocardiographical profiles in experimental Mascagnia rigida Griseb. (Malpighiaceae) toxicosis in sheep

Estudou-se o perfil eletrocardiográfico e ecodopplercardiográfico de ovinos intoxicados experimentalmente pela Mascagnia rigida Griseb (Malpighiaceae). Quinze ovinos machos da raça Santa Inês, com sete meses de idade e pesando, em média, 27kg, foram distribuídos em três grupos (G) com cinco animais cada: No G1 (controle), os animais receberam apenas água; nos G2, receberam 20g/kg de M. rigida durante três dias; e no G3, 20g/kg de M. rigida, durante sete dias. As folhas de M. rigida foram trituradas com água e administradas na forma de suspensão, por via oral, por meio de sonda. M. rigida promoveu aumento da FC em repouso e, principalmente, durante o esforço físico e diminuiu a fração de ejeção e o percentual de encurtamento sistólico do ventrículo esquerdo.

The electrocardiographical and echocardiographical alterations produced by intraruminal administration of Mascagnia rigida griseb. (Malpighiaceae) in sheep were studied. Fifteen male Santa Inês sheep were randomly allotted to three groups: G1 - animals only received water (control); G2 - animals were treated with M. rigida, 20g/kg/day, for three days; and G3 - animals were treated with M. rigida, 20g/kg/day, for seven days. All treatments were administered by an orogastric tube. M. rigida administration produced increase in heart rate during rest and exercise, and decreased in fractional ejection, and fractional shortening.

Perfis eletrocardiográfico e ecodopplercardiográfico de ovinos após ingestão da suspensão aquosa de Mascagnia rigida Griseb. (Malpighiaceae) / Electrocardiographical and echocardiographical profiles in experimental Mascagnia rigida Griseb. (Malpighiaceae) toxicosis in sheep

Estudou-se o perfil eletrocardiográfico e ecodopplercardiográfico de ovinos intoxicados experimentalmente pela Mascagnia rigida Griseb (Malpighiaceae). Quinze ovinos machos da raça Santa Inês, com sete meses de idade e pesando, em média, 27kg, foram distribuídos em três grupos (G) com cinco animais cada: No G1 (controle), os animais receberam apenas água; nos G2, receberam 20g/kg de M. rigida durante três dias; e no G3, 20g/kg de M. rigida, durante sete dias. As folhas de M. rigida foram trituradas com água e administradas na forma de suspensão, por via oral, por meio de sonda. M. rigida promoveu aumento da FC em repouso e, principalmente, durante o esforço físico e diminuiu a fração de ejeção e o percentual de encurtamento sistólico do ventrículo esquerdo.

The electrocardiographical and echocardiographical alterations produced by intraruminal administration of Mascagnia rigida griseb. (Malpighiaceae) in sheep were studied. Fifteen male Santa Inês sheep were randomly allotted to three groups: G1 - animals only received water (control); G2 - animals were treated with M. rigida, 20g/kg/day, for three days; and G3 - animals were treated with M. rigida, 20g/kg/day, for seven days. All treatments were administered by an orogastric tube. M. rigida administration produced increase in heart rate during rest and exercise, and decreased in fractional ejection, and fractional shortening.

Structural evaluation of type 3 dopaminergic receptor gene (DRD3) in chronic anovulatory women.

Dopamine receptor type 3 (DRD3) expressed in the limbic system sites involved in the regulation of GnRH seems to play a role in neuroendocrine control. We hypothesized that women with chronic anovulation should show exacerbated secretion of prolactin (PRL) after thyrotropin-releasing hormone (TRH) stimulation test, having more chances for dopamine inhibitory dysfunction due to alterations in the structure of DRD3. The DRD3-coding region was evaluated in 60 women with chronic anovulation (35 without and 25 with hyperresponse of PRL after TRH stimulation), and in 34 controls. Statistically similar frequencies of homozygous AGC polymorphism (43.4 and 33.4%) and heterozygous polymorphism (33.4 and 47.9%) at position 9 were found in controls and patients, respectively. Homozygous GCG polymorphism at position 17 was identified in 3.4% of the patients, while heterozygosis occurred in 20.8% of the patients and in 6.6% of the controls. The novel 41563_41567delTAAGT polymorphism of DRD3 was identified in 14.7% of the controls and 8.6% of the women with chronic anovulation displaying hyperresponse of PRL after TRH stimulation. Alteration 41563_41567delTAAGT of DRD3 was not found in patients who did not show hyperresponse of PRL after TRH stimulation. Normal baseline and peak levels of PRL and thyroid-stimulating hormone were similar for women with and without 41563_41567delTAAGT in the DRD3 gene. It is concluded that the novel polymorphism in DRD3 identified in this study is not associated with the response of PRL to TRH stimulation in women with chronic anovulation.

Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer.

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug's action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.

Índices ecoDopplercardiográficos de função ventricular esquerda em cães das raças Boxer e Schnauzer Miniatura / EchoDopplercardiographic indexes of left ventricular function in Boxer and Miniature Schnauzer dogs

Avaliaram-se o índice de performance do miocárdio (IPM) e outros índices ecoDopplercardiográficos de função ventricular em cães de duas raças de diferentes biotipos. Foram utilizados 24 cães da raça Schnauzer Miniatura, com média de peso de 8,4±1,6kg, e 24 cães da raça Boxer, com média de peso de 25,1±2,6kg. O IPM na raça Schnauzer Miniatura foi 0,32 e na raça Boxer 0,48. Os valores do IPM, dos índices de fase de ejeção, do período de pré-ejeção, da relação período de pré-ejeção/período de ejeção e do tempo de desaceleração da onda E do fluxo mitral diferiram entre as duas raças. Observou-se correlação entre o peso corporal e esses índices, e o peso corporal foi considerado a principal característica racial responsável pelas diferenças observadas. O tempo de ejeção (r=-0,51), o período de pré-ejeção (r=-0,44) e o tempo de relaxamento isovolumétrico (r=-0,38) foram os únicos parâmetros a apresentar correlação com a freqüência cardíaca (FC). O uso da relação período de pré-ejeção/tempo de ejeção e do tempo de ejeção corrigido pela freqüência cardíaca diminui o efeito da FC sobre esses parâmetros.

The index of myocardial performance (IMP) and others ecoDopplercardiographic indexes of ventricular function were evaluated in dogs of two different breeds and somatotypes. Twenty-four Miniature Schnauzer dogs averaging 8.4±1.6kg and 24 Boxer dogs averaging 25.1±2.6kg were used. IPM, ejection phase indexes, pre-ejection period, pre-ejection period/ejection time relation, and E wave deceleration time of mitral inflow showed correlation to body weight with significant differences between the breeds. Body weight was considered the main breed characteristic responsible for the observed differences. Ejection time (r=-0.51), pre-ejection time (r=-0.44), and isovolumetric relaxation time (r=-0.38) presented correlation with heart rate. The use of pre-ejection period/ejection time relation and ejection time correct by heart rate diminishes the influence of heart rate on the parameters.

Structural evaluation of type 3 dopaminergic receptor gene (DRD3) in chronic anovulatory women

Dopamine receptor type 3 (DRD3) expressed in the limbic system sites involved in the regulation of GnRH seems to play a role in neuroendocrine control. We hypothesized that women with chronic anovulation should show exacerbated secretion of prolactin (PRL) after thyrotropin-releasing hormone (TRH) stimulation test, having more chances for dopamine inhibitory dysfunction due to alterations in the structure of DRD3. The DRD3-coding region was evaluated in 60 women with chronic anovulation (35 without and 25 with hyperresponse of PRL after TRH stimulation), and in 34 controls. Statistically similar frequencies of homozygous AGC polymorphism (43.4 and 33.4%) and heterozygous polymorphism (33.4 and 47.9%) at position 9 were found in controls and patients, respectively. Homozygous GCG polymorphism at position 17 was identified in 3.4% Type 3 dopaminergic receptor in chronic anovulationof the patients, while heterozygosis occurred in 20.8% of the patients and in 6.6% of the controls. The novel 41563_41567delTAAGT polymorphismof DRD3 was identified in 14.7% of the controls and 8.6% of the women with chronic anovulation displaying hyperresponse of PRL after TRH stimulation. Alteration 41563_41567delTAAGT of DRD3 was not found in patients who did not show hyperresponse of PRL after TRH stimulation. Normal baseline and peak levels of PRL and thyroid-stimulating hormone were similar for women with and without 41563_41567delTAAGT in the DRD3 gene. It is concluded that the novel polymorphism in DRD3 identified in this study is not associated with the response of PRL to TRH stimulation in women with chronic anovulation.

Correlation of polymorphism C3435T of the MDR-1 gene and the response of primary chemotherapy in women with locally advanced breast cancer

Primary chemotherapy is a useful strategy for the treatment of locally advanced breast cancer and therefore allows in vivo evaluation of the action of cytotoxic drugs and the possibility of accomplishing conservative breast surgeries, as well as the early treatment of metastasis. Mechanisms of resistance to the drugs include the action of protein associated with the efflux of drugs from the intracellular environment hindering their activity; one of the most studied proteins is P-glycoprotein codified by the MDR-1 gene. The presence of polymorphisms can determine different physiological actions of these proteins, intervening with the response of the drug’s action. We evaluated the presence of single nucleotide polymorphism (SNP) C3435T of the MDR-1 gene and its correlation with the response to primary chemotherapy using the RECIST criteria. Forty-one Brazilian women with stages II and III breast cancer using the PCR-RFLP analysis were evaluated. Thirty-three patients with the SNP genotype (TT and CT) and eight patients with the wild genotype (CC) were found; there was no statistically significant correlation between the diverse genotypes and the clinical and pathological responses according to the Cramer correlation coefficient (V = 0.14). The parameters: nuclear and histological degree, and estrogens, progesterone and c-erb B2 receptors did not demonstrate a statistical correlation with the SNP C3435T. Patients with complete pathological response (12.5%) showed only the polymorphic genotype and not the wild genotype. The characteristics of miscegenation in our population could explain the absence of the characterization of a sub-group of individuals where the presence of the polymorphic genotype influenced the response to the primary chemotherapy.

A novel mutation in DAX1 gene causing different phenotypes in three siblings with adrenal hypoplasia congenita.

Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.

The influence of parental origin of X chromosome genes on the stature of patients with 45 X Turner syndrome.

Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents' stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informative families through the analysis of the exon 1-CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients' and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.

The influence of parental origin of X chromosome genes on the stature of patients with 45 X Turner syndrome

Thirty-seven 45 X Turner syndrome patients with confirmed peripheral blood lymphocyte karyotype were initially selected to determine the origin of the retained X chromosome and to correlate it with their parents’ stature. Blood samples were available in 25 families. The parental origin of the X chromosome was determined in 24 informativefamilies through the analysis of the exon 1 - CAG repeat variation of the androgen receptor gene. In 70.8% of the cases, the retained X chromosome was maternal in origin and 29.2% was paternal. When we classified the patients according to maternal (Xm) or paternal (Xp) X chromosome, there was a positive correlation between patients’ and maternal heights only in the Xm group. There was no correlation with paternal height in either group, and a significant correlation with target height was only observed in the Xm group. In conclusion, maternal height is the best variable correlating with the height of 45 X Turner syndrome patients who retain the maternal X chromosome, suggesting a strong influence of genes located on the maternal X chromosome on stature.

A novel mutation in DAX1 gene causing different phenotypes in three siblings with adrenal hypoplasia congenita

Adrenal hypoplasia congenita (AHC) is a rare disease that can be caused by many abnormalities, including an X-linked form. Mutations in the DAX1 gene have been assigned as the genetic cause of AHC. We describe here three siblings with AHC, clinically presented at different ages, two in the neonatal period and one oligosymptomatic during infancy. Molecular analysis was able to detect a novel mutation in exon 1 of the DAX1 gene, consisting of a transition of C to T at position 359, determining a stop codon at position 359 (Q359X). The mutated gene encodes a truncated protein missing a large portion of the ligand-binding domain (C-terminal domain). The recognition of the disease in the index case suggested the diagnosis in the other siblings. Interestingly, the same mutation is presented with different phenotypes, suggesting that first-degree family members of patients with DAX1 mutations should be carefully evaluated routinely.

Dopplerfluxometria das artérias renais: valores normais das velocidades sistólica e diastólica e do índice resistivo nas artérias renais principais / Renal arteries Dopplerfluxometry: normal systolic and diastolic flow velocities and resistive index values in the main renal arteries / Renal arteries Dopplerfluxometry: normal systolic and diastolic flow velocities and resistive index values in the main renal arteries

Dopplerfluxometry of renal arteries has been used to estimate renal perfusion in humans. The aim of this study was to use Dopplerfluxometry technique to calculate the resistive index of main renal arteries in dogs, measuring their systolic and diastolic blood flow velocities. Twenty (10 males, 10 females), adult mongrel dogs, were used in this study. The dogs were submitted to Doppler sonographic evaluation of left and right main renal arteries. The systolic and diastolic blood flow velocities, expressed (in centimeters per second) as mean and standard deviation were 79.96± 8.82 and 28.86± 5.11 in the right main renal artery and 80.22± 6.99 and 29.62± 4.14 in the left main renal artery. The value of resistive index expressed as mean ± standard deviation was 0.64± 0.04 for the right main renal artery and 0.63± 0.028 in the left main renal artery.

Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers.

The R337H TP53 mutation is a low-penetrance molecular defect that predisposes to adrenocortical tumour (ACT) formation in Brazilian and possibly other populations. Additional genetic defects may be responsible for the variable expression of ACTs in these cases. The inhibin alpha-subunit gene (INHA) on 2q33-qter has been implicated in mouse adrenocortical tumourigenesis. We studied 46 pediatric patients with ACTs from Brazil for INHA genetic alterations; 39 of these patients were heterozygous carriers of the R337H TP53 mutation. We first mapped the INHA gene by radiation hybrid analysis and determined 10 linked microsatellite markers in an area flanked by D2S1371 and D2S206 on 2q33-qter. These markers were then used for loss of heterozygozity (LOH) studies in nine paired germline and tumour DNA samples. Mapping placed the INHA gene in close proximity to D2S2848 (SHGC11864) with a log of odds (LOD) score of 5.84. LOH for at least one marker in the region was identified in 8/9 tumours (89%). Six patients were heterozygous for three INHA mutations: one in exon 1, 127C>G, and two in exon 2, 3998G>A and 4088G>A, all leading to amino acid substitutions (P43A, G227R, and A257T, respectively). A257T is located in a conserved INHA region, highly homologous to transforming growth factor-beta; both G227R and A257T change polarity, and, in addition, G227R changes the pH. We conclude that these sequence alterations and the detected 2q allelic changes suggest that INHA may be one of the contributing factors needed for ACT formation in pediatric patient carriers of the R337H TP53 mutation.