Sphenoid sinus brown tumor, a mass lesion of occipital bone and hypercalcemia: an unusual presentation of primary hyperparathyroidism.

Brown tumor is a focal lesion of the bone caused by primary or, less commonly, secondary or tertiary hyperparathyroidism (HPT). While the mandible is the most frequently involved bone in the head and neck region, atypical involvement of the cranium in the area of the sphenoid sinus is exceedingly rare. In the literature, a unique case of brown tumor of the sphenoid sinus was reported in a patient with primary HPT. We present a case of sphenoid sinus and occipital bone brown tumor associated with primary HPT. A 47-yr-old woman presented a 2-yr history of headaches, dizziness, diffuse body and articular pain, fatigue, and a 6-month history of intermittent nausea and vomiting, polydipsia, and polyuria. Magnetic resonance imaging (MRI) demonstrated an expansive mass lesion in the sphenoid sinus with erosion of the sellar floor and medial wall of the right orbit, and expansion in the medulla of bone. Examination of biopsy specimens obtained from sphenoid sinus mass confirmed the diagnosis of brown tumor. The biochemical laboratory studies showed elevation of parathyroid hormone and confirmed the diagnosis of primary HPT. Excision of a parathyroid adenoma affected the metabolic status into normalizing. At the follow-up of 12 months postoperatively, the size of sphenoid sinus brown tumor decreased and the mass of occipital bone disappeared. In conclusion, this is a first report of primary HPT masquerading as a destructive fibrous sphenoid sinus brown tumor associated with a mass lesion of occipital bone and hypercalcemia in the literature.

Effect of low-dose metoprolol in combination with sibutramine therapy in normotensive obese patients: a randomized controlled study.

OBJECTIVE: Sibutramine is an effective appetite suppresser agent, but treatment is often complicated with side effects, including palpitations and hypertension. In this study, we aimed to assess the effect of low-dose cardio-selective beta blocker combination with sibutramine treatment. METHODS: In total, 57 obese subjects were enrolled in the study and separated into two groups in order to receive sibutramine 10 mg/day plus placebo (group P) or sibutramine 10 mg/day plus metoprolol 25 mg/day (group M). Patients were evaluated in the beginning and at the end of the third month with anthropometric measurements, biochemical analysis, peripheral insulin resistance, and ambulatory 24 h blood pressure monitoring. Side effects were evaluated with a visual analog scale. RESULTS: During the study period, the drop-out rate was significantly higher in group P compared with group M (55 and 21%, respectively, P=0.014). Palpitations and headache were prominent symptoms in group P. Diastolic blood pressure (78.6+/-11.6 and 70.6+/-4.8 mmHg, respectively, P=0.013) and mean heart rate (84.3+/-6.1 and 75.8+/-8.4 beats/min, respectively, P=0.003) were significantly higher in group P compared with group M at the end of the third month. Weight loss was similar between the two groups (100.9+/-11.5 to 91.8+/-12.8 kg for group P, P<0.0001 and 97.9+/-13.2 to 88.9+/-13.8 kg for group M, P<0.0001). We did not find any deleterious effect of metoprolol on metabolic parameters. CONCLUSION: Addition of low-dose metoprolol to sibutramine therapy increased patient compliance to the treatment, and decreased the frequency and severity of side effects including hypertension and palpitations, without decreasing the drug efficacy or causing significant deleterious changes in metabolic parameters.

Blood coagulation and fibrinolysis in patients with hyperthyroidism.

Several papers concerning abnormalities of blood coagulation and fibrinolysis during hyperthyroidism, have been published. Increased von Willebrand Factor (vWF) activity and high fibrinogen levels have been reported. However, there is controversy concerning the presence of a hypercoagulable state in hyperthyroidism. We investigated various hemostatic parameters in 41 hyperthyroid patients and compared them to 20 euthyroid controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, factors V, VII, VIII, IX and X activities, vWF, antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA) and tissue plasminogen activator inhibitor-1 (PAI-1), as well as common lipid variables, were measured. The relationships between serum thyroid hormones and these hemostatic parameters were examined. Compared with control subjects, fibrinogen, factor IX, vWF, AT III and PAI-1 were significantly increased in patients (p<0.05, p<0.0001, p<0.05, p<0.01 and p<0.0001; respectively), whereas factor X and t-PA were decreased (p<0.05). We showed that free T4 (FT3) levels were correlated with factor VIII activity (r=0.35, p<0.05). FT4, FT3 and TSH did not correlate with fibrinogen, vWF, AT III, t-PA, or PAI-1. AT III was inversely correlated with factor VII activity (r=-0.48, p<0.01). Protein C and S were correlated with vWF levels (r=0.58, p<0.0001; r=0.55, p<0.0001, respectively). Protein C was inversely correlated with t-PA (r=-0.39, p<0.01). There was a negative correlation between triglycerides, LDL-C and F X (r=-0.45, p<0.05; r=-64, p<0.01, respectively). Mean platelet volume (MPV) was correlated with anti-thyroid peroxidase (TPO) antibodies (in Graves'disease) and F IX activity (r=0.57, p<0.05 and r=0.39, p<0.05; respectively). We found important differences in the coagulatory /fibrinolytic parameters between the hyperthyroid patients and healthy controls. Hyperthyroid patients may experience vascular endothelial dysfunction and decreased fibrinolytic activity in blood. This endothelial activation may represent a situation with a higher thromboembolic potential.

Prevalence of diabetes, obesity and hypertension in a Turkish population (Trabzon city).

OBJECTIVE: The objectives of this study were to determine the prevalence of diabetes mellitus in Trabzon city, Turkey, using standardized diagnostic criteria, and to evaluate associated factors. METHODS: A total of 3000 eligible study subjects were selected. Of those, 2646 subjects participated in the study. Individuals aged > or =20 years were selected from their family health cards and were invited to the health station. Anthropometric and demographic data were obtained for each subject. Plasma glucose was measured by an autoanalyser. People without previously diagnosed diabetes were categorized according to WHO diagnostic criteria as follows. Diabetes: a fasting plasma glucose (FPG)> or =140 mg/dl or 2-h plasma glucose > or =200 mg/dl after a 75-g oral glucose load. RESULTS: The overall prevalence of diabetes in those > or =20 years of age was 6.0% (n=160). Among diabetic subjects, 69 were newly diagnosed diabetes mellitus. Age, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP) and FPG were higher in diabetic subjects than in non-diabetic subjects. The prevalence of diabetes showed significant association with increased age (P<0.0001). The overall prevalence of obesity was 19.2%. The combined prevalence of both overweight and obesity was 60.6%. The prevalence of obesity was 27.4% among women and 10.7% among men (P<0.0001). Prevalence of diabetes increased with degree of obesity (P<0.0001). The rate of obesity in diabetic subjects was 35.6%. In the study population as a whole, the prevalence of obesity increased with age, being highest in the 50-59 years age group, but lower again in the 60+ age group. Prevalence of SBP> or =140 mmHg was 12.0% and of DBP> or =90 mmHg was 8.2%.

Thyroid function tests in pregnant women with and without goiter in the eastern Black Sea region.

Maternal thyroid function was investigated in 29 pregnant women with goiter and 51 pregnant women without goiter in the eastern Black Sea region of Turkey, which is an endemic goiter area. Ten women with goiter and 10 healthy women without goiter were used as controls in the study. In all of the pregnant women, increased concentrations of total and free thyroxine, total and free tri-iodothyronine and thyroxine-binding globulin were found. Serum thyroid-stimulating hormone levels showed a decrease in pregnant women without goiter compared with non-pregnant women without goiter.

Detection of bcl-2/IgH rearrangements by quantitative-competitive PCR and capillary electrophoresis.

BACKGROUND: PCR is the primary method for detecting minimal residual disease in hematologic cancers. One such gene target is the bcl-2/immunoglobulin heavy chain (IgH) translocation found in a majority of cases of follicular lymphoma. METHODS AND RESULTS: We report an accurate method for quantitative detection of the bcl-2/IgH translocation marker of follicular lymphoma in a series of patients in various stages of remission and relapse who had been treated with a combination of ifosfamide, mitoxantrone, and etoposide (MINE) chemotherapy and monoclonal anti-CD20 antibody (Rituximab). The approach uses seminested PCR followed by analysis of the products on a fluorescent capillary electrophoresis system. The quantitation of bcl-2/IgH translocation-positive cells was sensitive and reproducible, capable of detecting as few as five malignant cells out of 300,000 normal cells. CONCLUSION: Quantitative PCR enables one to monitor the kinetics of tumor reduction in patients treated with MINE chemotherapy in combination with Rituximab.

Excellent tolerance of rituximab when given after mitoxantrone/cyclophosphamide: an effective and safe combination for indolent non-Hodgkin's lymphoma.

Treatment for extensive indolent lymphoma should provide optimization of efficacy while avoiding excessive toxicity. Rituximab may be an ideal agent to combine with chemotherapy because of its lack of classical myelotoxicity. In this study, 27 patients with a variety of histologies of indolent B-cell non-Hodgkin's lymphoma have been treated utilizing a novel three-drug combination. Nine patients had relapsed disease and 18 were previously untreated. Patients first received cyclophosphamide 800 mg/m(2) and mitoxantrone 8 mg/m(2) i.v. on day 1, every 3 weeks for 2 cycles. Subsequently, patients received rituximab 375 mg/m(2) followed by mitoxantrone 8 mg/m2 every 2 weeks for 4 cycles. This regimen and, in particular, the rituximab infusion were extremely well tolerated. Only two of 27 patients experienced a grade 1/2, infusion-related reaction during the first rituximab infusion. Grade 4 neutropenia was noted at some point in 16 patients who were then offered granulocyte-macrophage colony-stimulating factor support for improvement of neutropenia. No infections were noted. Alopecia was minimal. Of 27 patients, 19 achieved a complete response (CR), one achieved an unconfirmed CR (CRu), and five patients achieved a partial response, for an overall response rate of 92.5%. Molecular remissions were noted in seven of 12 tested patients in CR. We concluded that the cyclophosphamide/mitoxantrone/rituximab (CyMiR) regimen is effective and extremely well tolerated. Furthermore, rituximab infusion-associated morbidity is markedly reduced.

Value of resistive index in patients with clinical diabetic nephropathy.

OBJECTIVE: To determine whether the intrarenal resistive index (RI) can be used as a predictor in patients with advanced clinical diabetic nephropathy. METHODS: Sixty-eight kidneys belonging to 34 patients with type II diabetes mellitus and 100 kidneys of 50 healthy persons (control group) were evaluated with Doppler ultrasonography. RI values were obtained from intraparenchymal arteries, either the arcuate or interlobar arteries. Patients with diabetes were divided into two groups based on serum creatinine concentration: group 1 (n = 21 patients, 42 kidneys) had a serum creatinine concentration <1.4 mg/dL and group 2 (n = 13 patients, 26 kidneys) had a serum creatinine concentration >1.4 mg/dL. Regression analysis was used to examine the relations between intrarenal RI and age, serum creatinine concentration, and creatinine clearance rate. RESULTS: The mean RI value (0.69+/-0.1) in patients with diabetes was significantly different from that of healthy subjects (0.56+/-023) (P < 0.00001). The RI value of the patients in group 2 (0.79+/-0.07) was significantly different from that of the patients in group 1 (0.61+/-0.04, P < 0.00001). Serum creatinine concentration and creatinine clearance rate showed high correlations (r = 0.84 and r = -0.76, respectively) with intrarenal RI values. CONCLUSIONS: Because the intrarenal RI shows a high level of correlation with serum creatinine concentration and creatinine clearance rate, it can be used as a predictor in patients with advanced clinical diabetic nephropathy. Intrarenal RI does not offer any advantage over serum creatinine concentration and creatinine clearance rate in patients with early-stage diabetic nephropathy with normal renal function.

Plasma lipoprotein (a) levels in Turkish NIDDM patients with and without vascular diabetic complications.

OBJECTIVE: Plasma concentrations of lipoprotein (a) [Lp(a)], an independent risk factor for atherosclerosis, were measured in 59 non-insulin-dependent diabetes mellitus (NIDDM) patients with and without vascular complications, and 21 non-diabetic healthy subjects. RESULTS: The plasma log Lp(a) levels were found to be significantly increased in the NIDDM patients (1.40 +/- 0.36) compared with the healthy subjects (1.02 +/- 0.53; p < 0.05). Plasma Lp(a) levels in NIDDM patients with diabetic vascular complications (1.51 +/- 0.27) were significantly higher than those of the NIDDM patients without diabetic vascular complications (1.23 +/- 0.43) and healthy subjects (p < 0.05). There were significant correlations between plasma log Lp(a) levels and apolipoprotein B (apo B) in all NIDDM patients (r: 0.68, p < 0.05). No correlation was observed between Lp(a) levels and age, sex, duration of diabetes, fasting blood glucose, haemoglobin Alc, the mode of treatment, triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and apolipoprotein Al levels in all patients. CONCLUSIONS: It was concluded that Lp(a) was a risk factor for angiopathy in NIDDM patients and the patients who have a high plasma Lp(a) concentration should be kept under strict glycaemic control.

Absence of mutations in the ATM gene in forty-seven cases of sporadic breast cancer.

Epidemiological evidence points to an increased risk of breast cancer in ataxia telangiectasia (AT) heterozygote women. Previous attempts to screen early onset or familial breast cancer patients failed to confirm an association. The issue of AT and late onset sporadic breast cancer remained unresolved. We screened 47 women who developed later onset, sporadic breast cancer for ataxia telangiectasia mutated (ATM) mutations. No mutations were found.

New mutations, polymorphisms, and rare variants in the ATM gene detected by a novel SSCP strategy.

The gene for ataxia-telangiectasia, ATM, spans about 150 kb of genomic DNA. ATM mutations are found along the entire gene, with no evidence of a mutational hot spot. Using DNA as the starting material, we screened the ATM gene in 92 A-T patients, using an optimized single-strand conformation polymorphism (SSCP) technique that detected all previously known mutations in the polymerase chain reaction (PCR) segments being analyzed. To expedite screening, we sequentially loaded the SSCP gels with three different sets of PCR products that were pretested to avoid overlapping patterns. Many of the DNA changes we detected were intragenic polymorphisms. Of an expected 177 unknown mutations, we detected approximately 70%, mostly protein truncating mutations (that would have been detectable by protein truncation testing if RNA starting material had been available). Mutations have now been defined for every exon of the ATM gene. Herein, we present 35 new mutations and 34 new intragenic polymorphisms or rare variants within the ATM gene. This is the most comprehensive compilation of ATM polymorphisms assembled to date. Defining polymorphic sites as well as mutations in the ATM gene will be of great importance in designing automated methods for detecting mutations.

Plasma lipoprotein (a) concentrations in hypothyroid, euthyroid and hyperthyroid subjects.

OBJECTIVE: Alterations of the lipid profile are a well known phenomenon in thyroid dysfunction. Thyroid hormones regulate lipid metabolism through various mechanisms, but a key role is played by the LDL receptor pathway. Thyroid hormone influence on lipoprotein (a) [Lp(a)] metabolism is known. METHODS AND RESULTS: Therefore we studied Lp(a) concentrations in a group of 16 hypothyroid patients and in a group of 22 hyperthyroid patients. Twenty-six euthyroid subjects were used as a control group. Plasma Lp(a) concentrations in hyperthyroid patients (23.2 +/- 28.1 mg/dl) were significantly lower than those of the hypothyroid patients (27.1 +/- 19.2, p < 0.05). There were negative correlations between plasma Lp(a) concentrations and total T4 levels in patients with hyperthyroidism and hypothyroidism (r: -0.49, p < 0.05; r: -0.40, p < 0.05, respectively). Also, decreased HDL-C levels, increased LDL-C, total cholesterol and apo B levels in the hypothyroid patients according to euthyroid subjects were observed (p < 0.05). Decreased LDL-C levels, increased HDL-C and apo Al levels in the hyperthyroid patients according to euthyroid subjects were determined (p < 0.05). CONCLUSIONS: It was concluded that plasma Lp(a) concentrations increase in hypothyroid patients and the observed relationships between thyroid status and Lp(a) levels can be explained by impaired catabolism of apo B and Lp(a) in hypothyroidism.

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

Mutations resulting in defective splicing constitute a significant proportion (30/62 [48%]) of a new series of mutations in the ATM gene in patients with ataxia-telangiectasia (AT) that were detected by the protein-truncation assay followed by sequence analysis of genomic DNA. Fewer than half of the splicing mutations involved the canonical AG splice-acceptor site or GT splice-donor site. A higher percentage of mutations occurred at less stringently conserved sites, including silent mutations of the last nucleotide of exons, mutations in nucleotides other than the conserved AG and GT in the consensus splice sites, and creation of splice-acceptor or splice-donor sites in either introns or exons. These splicing mutations led to a variety of consequences, including exon skipping and, to a lesser degree, intron retention, activation of cryptic splice sites, or creation of new splice sites. In addition, 5 of 12 nonsense mutations and 1 missense mutation were associated with deletion in the cDNA of the exons in which the mutations occurred. No ATM protein was detected by western blotting in any AT cell line in which splicing mutations were identified. Several cases of exon skipping in both normal controls and patients for whom no underlying defect could be found in genomic DNA were also observed, suggesting caution in the interpretation of exon deletions observed in ATM cDNA when there is no accompanying identification of genomic mutations.

Identical mutation in 55% of the ATM alleles in 11 Norwegian AT families: evidence for a founder effect.

The ATM gene is responsible for the autosomal recessive disorder Ataxia-Telangiectasia (AT). Many different mutations, located all across the gene, have been reported with a predominance of truncating mutations. By using PTT (protein truncation test) a mutation was found in one Norwegian AT family. Sequencing revealed that the mutation affected nucleotides 3245-3247, codon 1082, and changed the sequence from ATC to TGAT, inducing a stop codon downstream at codon 1095 and leading to early truncation of the ATM protein. Perpendicular DGGE (denaturing gradient gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes. Haplotype analyses were performed using eight microsatellite markers, within and flanking the ATM gene. All carriers of the mutation described were found to have a common haplotype of the five closest CA-repeat microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common ancestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now allows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cancer risk can be evaluated.

A model for ATM heterozygote identification in a large population: four founder-effect ATM mutations identify most of Costa Rican patients with ataxia telangiectasia.

Ataxia telangiectasia (A-T) is an autosomal recessive disorder with a broad range of clinical manifestations and a frequency of 1:40,000-100,000 live births. Epidemiological studies have suggested that A-T heterozygotes are at an elevated risk of breast cancer. ATM mutations occur worldwide over the entire ATM gene, making it difficult to identify heterozygotes in large populations. However, some founder-effect mutations are specific for certain populations. Here, we present four mutations in Costa Rican A-T patients that accounted for 86-93% of 41 patients studied in two batches. We have developed assays for rapid detection of these four mutations which can be used diagnostically. They will also enable the Costa Rican population to be used as a model for analyzing the role of ATM heterozygosity in cancer development and other disorders.

Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.

To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases, such as breast cancer, we have attempted to define the most common mutations and their frequencies in ataxia-telangiectasia (A-T) homozygotes from 10 ethnic populations. Both genomic mutations and their effects on cDNA were characterized. Protein-truncation testing of the entire ATM cDNA detected 92 (66%) truncating mutations in 140 mutant alleles screened. The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist. Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations. These rapid assays detected mutations in 76% of Costa Rican patients (3), 50% of Norwegian patients (1), 25% of Polish patients (4), and 14% of Italian patients (1), as well as in patients of Amish/Mennonite and Irish English backgrounds. Additional mutations were observed in Japanese, Utah Mormon, and African American patients. These assays should facilitate screening for A-T heterozygotes in the populations studied.

Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic ataxia.

To explore the clinical heterogeneity associated with the Friedreich's ataxia (FRDA) expanded repeat and provide preliminary guidance for future gene testing in patients suspected of having FRDA, we tested patients with typical FRDA (group I), late-onset FRDA or FRDA with retained reflexes (group II), as well as those with early onset "non-Friedreich's" recessive or sporadic ataxia (group III). Eighty-seven percent of families in group I tested positive for the FRDA triplet repeat expansion. Thirty-six percent of families in group II demonstrated the FRDA expansion. Only one of 11 patients in group III had the FRDA expansion. Clinical criteria did not clearly distinguish between expansion-positive and expansion-negative individuals in groups I and II. Minimal criteria that were present in all the patients who tested positive were recessive or sporadic inheritance, progressive caudal-rostral gait and limb ataxia, and at least one of the following: dysarthria, Babinski sign, or cardiomyopathy. This study confirms recent findings that some patients in group II can carry the FRDA mutation. However, we did not observe the FRDA expansion in 64% of group II families or in 13% of families with typical FRDA (group I), suggesting other genetic or environmental causes for their ataxia.

CAND3: a ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 11q23.1.

Using a magnetic beads-mediated cDNA selection procedure and a fetal brain expression library, we identified a transcriptional unit within a cosmid positive for the marker D11S384. Pursuit of its full-length cDNA led to the cloning of the third candidate gene (CAND3) we studied in our quest for the ataxia-telangiectasia (A-T) gene, ATM. CAND3 spans approximately 140 kb of genomic DNA and is located immediately centrimeric to ATM, with 544 bp of DNA separating the two genes. CAND3 encodes two ubiquitously expressed transcripts of approximately 5.8 kb and approximately 4.6 kb that are divergently transcribed from a promoter region common to ATM. Nucleotide sequence was determined for one of its alternately spliced transcripts. The predicted protein has 1175 amino acids and is novel in sequence, with only weak homologies to transcriptional factors, nucleoporin protein, and protein kinases, including members of the phosphatidylinositol 3-kinase (PI-3 kinase) family. Although neither homology to ATM nor any mutation of CAND3 in A-T patients has been found, the head-to-head arrangement of CAND3 and ATM, with expression of both housekeeping genes from a common stretch of 544 bp intergenic DNA, suggests a bi-directional promoter possibly for co-regulation of biologically related functions. YACs, BACs, cosmids, and STSs are defined to aid in further study of this gene.

CAND3: A ubiquitously expressed gene immediately adjacent and in opposite transcriptional orientation to the ATM gene at 1lq23.1.

Using a magnetic beads-mediated cDNA selection procedure and a fetal brain expression library, we identified a transcriptional unit within a cosmid positive for the marker D11S384. Pursuit of its full-length cDNA led to the cloning of the third candidate gene (CAND3) we studied in our quest for the ataxiatelangiectasia (A-T) gene, ATM. CAND3 spans ~140 kb of genomic DNA and is located immediately centrimeric to ATM, with 544 bp of DNA separating the two genes. CAND3 encodes two ubiquitously expressed transcripts of ~5.8 kb and ~4.6 kb that are divergently transcribed from a promoter region common to ATM. Nucleotide sequence was determined for one of its alternately spliced transcripts. The predicted protein has 1175 amino acids and is novel in sequence, with only weak homologies to transcriptional factors, nucleoporin protein, and protein kinases, including members of the phosphatidylinositol 3-kinase (PI-3 kinase) family. Although neither homology to ATM nor any mutation of CAND3 in A-T patients has been found, the head-to-head arrangement of CAND3 and ATM, with expression of both housekeeping genes from a common stretch of 544 bp intergenic DNA, suggests a bi-directional promoter possibly for co-regulation of biologically related functions. YACs, BACs, cosmids, and STSs are defined to aid in the further study of this gene.