STAT3 expression is correlated with pathological stage in luminal subtypes of breast carcinoma.

AIM: STATs and HIFs in human solid tumors play an important role in mechanisms of tumor growth. The aim of this study was to determine the prognostic role of STATs and HIFs in breast cancers. METHODS: Twenty­four breast carcinoma cases who underwent mastectomy and axillary dissection were included into the study. The presence of STATs and HIFs in 24 breast cancer cases was evaluated immunohistochemically. We evaluated the differences in tumor grade, diameter, limits, intratumor desmoplasia, inflammatory infiltration, necrosis, axillary lymph node involvement, estrogen, progesterone and CerbB2 staining. RESULTS: In this study, the presence of STATs and HIFs expressions in breast tumors is shown. In our study, no statistically significant correlation was found between tumor grade, diameter, limits, intratumor desmoplasia, inflammatory infiltration, necrosis, axillary lymph node involvement, CerbB2 staining status and STATs and HIFs expressions. However, STAT5a and estrogen staining and HIF2α and progesterone staining were found statistically significant. In addition, STAT3 expression was found to have significantly higher correlation with luminal breast cancer. CONCLUSIONS: The findings suggest that STATs and HIFs may play a role in the development of invasive ductal carcinomas; concerning their future use as treatment options due to their association with hormone receptors, new studies are required (Tab. 6, Fig. 7, Ref. 65).

Constipation as an Atypical Sign of ARC Syndrome - Case Report.

BACKGROUND: Arthrogryposis- renal tubular dysfunction - cholestasis (ARC) syndrome is a rare multisystem disorder originally described in 1973 and recently ascribed to mutation in VPS33 B whose product acts in intracellular trafficking. It exhibits wide clinical variability but the constipation isn't a characteristic clinical sign. CASE: This girl presented after birth severe contractures of legs. She was admitted at 30 days of age with poor feeding, cholestatic jaundice with normal GGT and failure to thrive . Also we have noted a severe acidosis (pH=7.2) associated with aminoaciduria and glucosuria. At second month of age the girl presented a severe ichtyosis, recurrent fever and constipation. Apart from treatment the constipation has persisted. The baby died of sepsis at 12 weeks of age. CONCLUSION: ARC syndrome exhibits notable clinical variability. Constipation has not been reported previously on the contrary diarrhea is a frequent clinical sign. Knowledge of this rare condition can benefit the practitioner as well as the patient.

COX-2 gene polymorphisms and risk of chronic periodontitis: a case-control study and meta-analysis.

OBJECTIVE: Cyclooxygenase-2 (COX-2) enzyme is a major mediator of inflammation in periodontitis, leading to loss of gingival tissues and alveolar bone supporting the teeth. Previous studies have explored the role of COX-2 polymorphisms with the risk of periodontitis in different ethnic groups; however, findings are inconsistent. So, we aimed to investigate the association of COX-2 polymorphisms (rs20417, rs689466, and rs5275) in susceptibility to chronic periodontitis (CP) in northern Indian population. Meta-analysis was also carried out to precisely estimate the effect of COX-2 polymorphisms in CP. MATERIALS AND METHODS: Genotyping of COX-2 polymorphisms was carried out through PCR-RFLP in 200 CP cases and 200 controls. For risk estimation, binary logistic regression was applied using SPSS, version 15.0, while meta-analysis was carried using MIX 2.0 software. RESULTS: None of the COX-2 polymorphisms independently were associated with the risk of CP. Meta-analysis suggested a significant reduced risk of CP with rs5275+8473 C allele and rs20417 in Chinese population. CONCLUSIONS: No association was observed in any of the studied COX-2 polymorphisms with CP in North India. But, the study should be replicated in larger sample size to arrive at a definitive conclusion. Meta-analysis suggested a role of rs5275 COX-2 polymorphisms in susceptibility to overall CP, and on ethnic basis, rs20417 showed reduced risk of CP in Chinese population.

[Aesthetic reconstructive surgery of the lip]. / Chirurgie réparatrice et esthétique labiale.

Lip reconstruction can be performed with numerous surgical techniques. The aim was here to present these usual techniques and to focus on the details that can be used to obtain the most favourable results. The goal of this surgery, that represents a compromise between function and aesthetic, has to be kept in mind to prevent mistakes that decrease the quality of the result.

[Flaps in lower limb reconstruction: a 10-year retrospective review of 157 pedicled flaps]. / Cent cinquante-sept lambeaux pédiculés utilisés dans la reconstruction des membres inférieurs : étude rétrospective sur dix ans.

BACKGROUND: The aim of this study was to review and present our experience with pedicled flap reconstruction of lower limb defects with particular reference to choice of flap, complications and pre-existing health disorders. METHODS: A retrospective review of lower limb reconstructions by pedicled flaps was carried out by the plastic and reconstructive surgery unit at Marseille's hospitals from January 1st, 1997 to December 31st, 2007. This study evaluated patients satisfaction and complications rate. RESULTS: During 10 years, 152 patients had 157 local flap reconstructions of lower limb defects. General patients satisfaction was 94% with 80% good or very good results and 20% of medium results. There were 16 immediate complications with three total necrosis, four partial necrosis, six hematoma, and three infections. There were nine late complications including wound dehiscence and graft instability. There were 11 functional sequels and 40 aesthetic sequels secondary to flaps. CONCLUSIONS: The current study presented our experience with locoregional flap reconstruction of lower limb defects. Lower limb reconstruction used a lot of locoregional flaps which had their own advantages and disadvantages. Their indication depended on the fiability and quality of the donor site.

Prenatal diagnosis of Pompe disease: enzyme assay or molecular testing?

We report two cases which illustrate that enzyme assay results alone, may at times be equivocal and inconclusive in the prenatal diagnosis of storage disorders like Pompe disease and therefore, if the probands mutation is known, targeted mutation analysis of fetal DNA is the most reliable method for fetal evaluation.

Emerging therapies for glycogen storage disease type I.

Glycogen storage disease type I (GSD I) is caused by deficiency of the glucose-6-phosphatase catalytic subunit in type Ia or of glucose-6-phosphate transporter in type Ib. The cellular bases for disruptions of homeostasis have been increasingly understood in GSD I, including those for anemia, renal failure and neutropenia. Advances in the understanding of cellular abnormalities in GSD I have provided rationales for new therapy, and recent developments in gene therapy have led to potential curative treatments for GSD I. These advances will benefit patients with GSD I in the future, improving both quality of life and survival, as well as illuminating the molecular effects of altered metabolism upon multiple organ systems.

Methods for a prompt and reliable laboratory diagnosis of Pompe disease: report from an international consensus meeting.

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It presents at any age, with variable rates of progression ranging from a rapidly progressive course, often fatal by one-year of age, to a more slowly, but nevertheless relentlessly progressive course, resulting in significant morbidity and premature mortality. In infants, early initiation of enzyme replacement therapy is needed to gain the maximum therapeutic benefit, underscoring the need for early diagnosis. Several new methods for measuring GAA activity have been developed. The Pompe Disease Diagnostic Working Group met to review data generated using the new methods, and to establish a consensus regarding the application of the methods for the laboratory diagnosis of Pompe disease. Skin fibroblasts and muscle biopsy have traditionally been the samples of choice for measuring GAA activity. However, new methods using blood samples are rapidly becoming adopted because of their speed and convenience. Measuring GAA activity in blood samples should be performed under acidic conditions (pH 3.8-4.0), using up to 2 mM of the synthetic substrate 4-methylumbelliferyl-alpha-D-glucoside or glycogen (50 mg/mL), in the presence of acarbose (3-9 microM) to inhibit the isoenzyme maltase-glucoamylase. The activity of a reference enzyme should also be measured to confirm the quality of the sample. A second test should be done to support the diagnosis of Pompe disease until a program for external quality assurance and proficiency testing of the enzymatic diagnosis in blood is established.

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

We present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13-45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD = 11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). Alpha-fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence.

We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.

[Longitudinal melanic nail bands (melanonychia): report of 22 cases]. / Bandes mélaniques longitudinales unguéales (mélanonychies): conduite à tenir à propos de 22 cas.

INTRODUCTION: Longitudinal melanonychia is a diagnostic and treatment problem for the surgeon. Fear of melanoma most frequently leads to total excision of nail bed, matrix and plate. METHOD: Twenty two patients, aged from 7 to 77, were operated on from 89 to 98 in our department, using different techniques (total matrix biopsy, total excision of melanonichia with direct suture, Schernberg flap). RESULTS: Thumb and index are predominant locations (11 out of 16). No malignant lesions were found histologically. Aesthetic sequellae were frequent and directly linked to the width and location of the melanonychia. Limited matrix biopsy produce the best aesthetic result. DISCUSSION: Malignant lesions are rare and our series is short. Therefore an additional multicentric study is required. Our choice is to make a limited matrix biopsy in the first place with a minimal aesthetic prejudice. Histology determines the treatment choice: excision or follow up.

Tissue expansion of the lower limb: complications in a cohort of 103 cases.

Over 10 years we performed 103 skin-expansion procedures and placed 207 prostheses on lower limbs, using the same surgical protocol. In 83 cases (80.6%) the expansion was achieved without complications. We recorded 20 complications in all (19.4%). Major complications included sepsis, damage due to undermining, exposure of the prosthesis and necrosis of the flap in 16 cases (15.5%), resulting in complete failure of the method in five cases (4.9%). In all, nine patients had septic complications (8.7% of the patients and 45% of the complications), five had exposure of the prosthesis and two had skin necrosis after expansion. Infection and skin necrosis, which are the main causes of failure of this method, can be prevented by a strict surgical protocolcovering all stages of the procedure. Atraumatic undermining, remote and external valves, suction drains in the cavities, advancement flaps and plaster casts after surgery can help to prevent skin necrosis. A separate and remote approach for each prosthesis can prevent infection of all the prostheses and complete failure of the expansion procedure.

Familial antiphospholipid antibody syndrome: criteria for disease and evidence for autosomal dominant inheritance.

OBJECTIVE: To develop diagnostic criteria for a familial form of antiphospholipid antibody syndrome (APS), identify families with >1 affected member, examine possible modes of inheritance, and determine linkage to potential candidate genes. METHODS: Family members of probands with primary APS were analyzed for clinical and laboratory abnormalities associated with APS. Families with > or =2 affected members were analyzed by segregation analysis and typed for candidate genetic markers. RESULTS: Seven families were identified. Thirty of 101 family members met diagnostic criteria for APS. Segregation studies rejected both environmental and autosomal recessive models, and the data were best fit by either a dominant or codominant model. Linkage analysis showed independent segregation of APS and several candidate genes. CONCLUSION: Clinical and laboratory criteria are essential to identify the spectrum of disease associated with APS. We believe a set of criteria was developed that can precisely define affected family members with APS. Modeling studies utilizing these criteria strongly support a genetic basis for disease in families with APS and suggest that a susceptibility gene is inherited in an autosomal dominant pattern. However, in these families, APS was not linked with HLA, Fas, or other candidate genes, including beta2-glycoprotein 1, HLA, T cell receptor beta chain, Ig heavy chain, antithrombin III, Fas ligand, factor V, complement factor H, IgK, and Fas.

Discordant organ laterality in monozygotic twins with primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is a genetic disease characterized by abnormal ciliary structure and function, impaired mucociliary clearance, and chronic middle ear, sinus, and lung disease. PCD is associated with situs inversus in approximately 50% of the patients. One proposed explanation for this relationship is that normal ciliary function plays a role in normal organ orientation, whereas organ orientation in PCD is a random event because of dysfunctional cilia in early embryonic development. Another hypothesis for the association between PCD and situs inversus is that mutated genes in PCD not only cause defective cilia, but are also linked to the control of organ laterality, such that abnormalities in this molecular pathway result in random left-right asymmetry. We report on a set of monozygotic twin women with PCD. In both patients, deficiency of the inner dynein arms was noted on ciliary ultrastructural analysis, associated with a clinical syndrome of bronchiectasis, chronic sinusitis, and middle ear disease. One of the twins has situs solitus, the other has situs inversus totalis. DNA analysis confirmed that the twins are monozygotic. This is consistent with the hypothesis that situs inversus occurring in patients with primary ciliary dyskinesia is a random but "complete" event in the fetal development of patients with PCD.

Genetic analysis of multiplex rheumatoid arthritis families.

To examine the genetic contribution of HLA and non-HLA genes in the etiopathogenesis of rheumatoid arthritis (RA), 60 Caucasian multiplex families were identified and DNA analyzed for over 52 markers including DRB1, DQA1 and DQB1 alleles. Many of the markers were chosen because of close proximity to candidate genes suggested by previous studies or models of pathogenesis. Sibling pair analysis (SIBPAL), relative pair analysis (RELPAL) and linkage studies using two different models of inheritance suggested linkage for the MHC and two additional chromosomal regions: chromosome 2 (D2S443 near CD8 and IGk; 2p13-2p11.1), and chromosome 15 (CYP19-estrogen synthase; 15q15). No support was found for two chromosomal regions, 1p36 and 3q13, recently suggested by other studies. We used transmission disequilibrium testing (TDT), conditional logistic regression, and segregation analysis to study the contributions that the shared epitope and TNF-c have in contributing to risk for RA. These studies provide additional evidence that the association of HLA alleles in RA patients from multiplex families is similar to that observed in sporadic disease, suggest candidate regions for further analysis and find additional support for an association of TNF-c alleles with RA susceptibility.

Fine mapping of a genetic locus for Peutz-Jeghers syndrome on chromosome 19p.

Peutz-Jeghers syndrome (PJS) was recently mapped in a single report to the telomeric region of chromosome 19p (A. Hemminki et al., Nat. Genet., 15: 87-90, 1997). Our studies confirm this location and provide further localization of the PJS locus. In the five families examined, there were no recombinants with the marker D19S886. The multipoint log odds score at D19S886 is 7.52, and we found no evidence for genetic heterogeneity. We also found that all carriers expressed the PJS phenotype and no noncarriers displayed PJS sequellae, indicating complete penetrance with no sporadic cases.

Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene.

Glucokinase catalyzes a rate-limiting step in glucose metabolism in hepatocytes and pancreatic beta cells and is considered the "glucose sensor" for regulation of insulin secretion. Patients with maturity-onset diabetes of the young (MODY) have heterozygous point mutations in the glucokinase gene that result in reduced enzymatic activity and decreased insulin secretion. However, it remains unclear whether abnormal liver glucose metabolism contributes to the MODY disease. Here we show that disruption of the glucokinase gene results in a phenotype similar to MODY in heterozygous mice. Reduced islet glucokinase activity causes mildly elevated fasting blood glucose levels. Hyperglycemic clamp studies reveal decreased glucose tolerance and abnormal liver glucose metabolism. These findings demonstrate a key role for glucokinase in glucose homeostasis and implicate both islets and liver in the MODY disease.

In vitro and in vivo genotoxicity evaluation of hormonal drugs. II. Dexamethasone.

Genotoxicity evaluation of a widely used glucocorticoid medicine, dexamethasone, was undertaken using in vitro and in vivo assays. Analyses of chromosomal aberrations, sister-chromatid exchanges (SCEs) in human lymphocytes and micronuclei and SCEs in mouse bone marrow showed the drug to be capable of attacking the genetic material. However, the Ames/Salmonella assay, both with and without S9 mix, did not show any increase in His+ revertants.

Selective loss of a DNase I hypersensitive site upstream of the tyrosine aminotransferase gene in mice homozygous for lethal albino deletions.

Several overlapping chromosomal deletions spanning the albino locus in the mouse cause perinatal lethality when homozygous and a block in the transcriptional induction of various unlinked hepatocyte-specific genes. Studies of such lethal albino deletion homozygotes in perinatal stages revealed a deficiency in the transcriptional inducibility of the tyrosine aminotransferase (TAT) gene by glucocorticoids; yet, glucocorticoid receptor and hormone levels were shown to be unaffected. To identify a molecular defect underlying the failure of inducible expression, we examined the chromatin structure of the TAT gene. Whereas in wild-type animals the TAT promoter becomes DNase I hypersensitive at birth, such hypersensitivity fails to develop in lethal albino deletion homozygotes. By contrast, the deletions do not affect the appearance of three DNase I-hypersensitive sites upstream of the TAT promoter in the liver, nor do they affect two hypersensitive sites upstream of the expressed alpha-fetoprotein gene. These findings demonstrate that the abnormality of chromatin structure identified in lethal albino deletion homozygotes occurs on a highly selective basis. Specifically, normal differentiation of the TAT promoter chromatin appears to depend directly or indirectly on the action and product of a gene mapping within the deleted region.