Upper limit of normal for alanine aminotransferase: quo vadis?

Several studies suggest that a substantial number of patients with normal serum alanine aminotransferase (ALT) levels, defined by current thresholds, have ongoing hepatic necro-inflammation and fibrosis, and are at risk of liver disease progression. A major problem lies in the definition of normality. The current upper limit of normal (ULN) for ALT was established in the 1980s when reference populations were likely to include many persons with hepatitis C virus infection and nonalcoholic fatty liver disease. Because ALT may be influenced, not only by liver disease, but also by other medical conditions, changing lifestyle factors and demographic determinants, the current ALT ULN threshold has recently been challenged. This review not only highlights current evidence on why and how ALT ULN should be redefined, but also discusses the current concerns about updating the ULN threshold for ALT.

Arterial function and structure after a 1-year lifestyle intervention in children with nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Lifestyle modification has been the mainstay of controlling childhood obesity and has proved to be effective in reducing cardiovascular risk factors. However, it is currently unknown whether the subclinical atherosclerotic changes associated with nonalcoholic fatty liver disease (NAFLD) in such population are reversible. METHODS AND RESULTS: We analyzed changes of brachial flow-mediated dilation (FMD), carotid intima-media thickness (cIMT), clinical, laboratory, and imaging data in 120 obese children with NAFLD, at the end of a 1-year intervention program with diet and physical exercise. The lifestyle intervention led to a significant mean decrease of body mass index (BMI)-standard deviation score (SDS), waist circumference (WC) and fat mass, along with diastolic blood pressure, triglycerides, liver enzymes, insulin, insulin resistance (homeostasis model assessment of insulin resistance, HOMA-IR), and high-sensitivity C-reactive protein. At the end of the study, FMD improved (P < 0.0001), while cIMT did not change significantly (P = 0.20). A significant decrease in hepatic fat content as measured by magnetic resonance imaging was also observed. Changes in FMD were inversely associated with changes in BMI-SDS, WC, total cholesterol, non-HDL cholesterol, liver enzymes, HOMA-IR, physical activity, and hepatic fat content. After including in the model all the significant variables as well as age, gender, pubertal status, and baseline FMD values, changes in FMD were significantly and independently associated with changes in WC and total cholesterol. CONCLUSION: Also in obese children with NAFLD arterial function may be restored by improving metabolic risk factors and reducing visceral adiposity following a 1-year lifestyle intervention.

Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis.

OBJECTIVE: As atherosclerosis is increased in systemic lupus erythematosus (SLE) we compared dietary habits in patients with SLE with controls, and in the patients studied associations of diet components, especially fatty acids (FAs), with disease activity, serum lipids and carotid plaque presence. METHODS: In all 114 patients with SLE and 122 age- and sex-matched population-based controls answered a food frequency questionnaire (FFQ). Subcutaneous abdominal fat cell aspiration was analysed as to FA content and plaque occurrence was determined by B-mode ultrasound. RESULTS: The total diet energy intake did not differ between patients and controls. However, the patients with SLE reported a higher intake of carbohydrate, lower fibre intake and lower intake of omega-3 and omega-6, than controls (p < 0.05). In the patients, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in adipose tissue (AT) correlated negatively with disease activity (SLEDAI), r = -0.36, p = < 0.001 and r = -0.33, p = < 0.001, respectively. AT omega-3 was further positively associated with serum apoA1, r = 0.29, p = 0.004, whereas AT omega-6 showed a negative association, r = -0.21, p = 0.040. These FAs also had opposite associations with plaque presence, EPA and were DHA negative, r = -0.32, p = 0.002 and r = -0.33, p = 0.001, respectively, and omega-6 positive, r = 0.22, p = 0.027. The carbohydrate intake was positively correlated to AT omega-6, r = 0.38, p < 0.001, and negatively with serum apoA1, r = -0.27, p = 0.005. CONCLUSION: The macronutrient dietary pattern is different in SLE as compared with controls. The low intake of omega-3 and high intake of carbohydrate among patients with SLE appear to be associated with worse disease activity, adverse serum lipids and plaque presence.

Microcirculation as determined by iontophoresis in SLE-patients and controls.

BACKGROUND: The risk of cardiovascular disease (CVD), microangiopathy and prevalence of atherosclerotic plaques are increased in Systemic Lupus Erythematosus (SLE). As systemic endothelial dysfunction is one of the earliest signs of these vascular outcomes in the general population we assessed skin microvascular endothelial function in SLE patients. METHODS: Endothelial function in skin was tested with local application of acetylcholine (inducing endothelium-dependent vasodilatation) and any concomitant increase in skin perfusion was measured with Laser Doppler Fluxmetry (LDF) in 84 SLE-patients (83% women, mean age 47 years) and 81 age and sex matched controls. Common carotid intima-media thickness (cIMT) and plaque occurrence were also determined using B-mode ultrasound. RESULTS: There were no significant differences in skin microvascular endothelial function between SLE-patients and controls. In the SLE group, endothelial function did not vary in relation to skin manifestations, Raynaud's phenomenon, nephritis or plaque occurrence. In SLE patients with CVD, however, endothelial function was impaired. CONCLUSION: Skin microvascular endothelial function is associated with CVD but not with early signs of atherosclerosis in SLE-patients. The endothelial function is not different in SLE-patients as compared to controls.

Review article: bismuth-based therapy for Helicobacter pylori eradication in children.

BACKGROUND: Because of the decrease in the Helicobacter pylori eradication rate after standard triple therapy with a proton pump inhibitor and two antibiotics, bismuth-based therapy has recently been recommended as alternate first-line regimen in children. AIM: To comprehensively review the clinical, pharmacologic and microbiologic properties of bismuth salts, and to summarise the evidence for the therapeutic efficacy of bismuth-based therapy for H. pylori eradication in children. METHODS: Bibliographical searches were performed in MEDLINE. Results on the efficacy of bismuth-containing regimens on H. pylori eradication were combined using the inverse variance method. RESULTS: Bismuth monotherapy showed a very low efficacy. Overall, the mean eradication rate with bismuth-based dual therapy was 68% (95% CI, 60-76%) (intention-to-treat analysis-ITT) and 73% (95% CI, 64-81%) (per protocol-PP). In case series, the overall percentages of children with successful eradication for triple therapy containing bismuth were 82% (95% CI, 76-88%) and 86% (95% CI, 80-92%) according to ITT and PP respectively. In comparative studies, H. pylori eradication rates ranged between 69% and 85% according to ITT and between 74% and 96% PP. Side effects included dark stools, urine discoloration, black tongue, burning tongue, and marked darkness of the gums. CONCLUSIONS: The evidence in favour of bismuth compounds for treating infected children is still not clear. Well-designed, randomised, multi-centre studies of H. pylori eradication trials in children comparing bismuth-based triple therapy with the best available recommended first-line therapies are needed. The evidence obtained from audited case series that produce an eradication rate of >95% on PP analysis should also be considered.

Low 25(OH)D3 levels are associated with total adiposity, metabolic syndrome, and hypertension in Caucasian children and adolescents.

OBJECTIVES: Evidence of the association between vitamin D and cardiovascular risk factors in the young is limited. We therefore assessed the relationships between circulating 25-hydroxyvitamin D(3) (25(OH)D(3)) and metabolic syndrome (MetS), its components, and early atherosclerotic changes in 452 (304 overweight/obese and 148 healthy, normal weight) Caucasian children. METHODS: We determined serum 25(OH)D(3) concentrations in relation to MetS, its components (central obesity, hypertension, low high-density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, glucose impairment, and/or insulin resistance (IR)), and impairment of flow-mediated vasodilatation (FMD) and increased carotid intima-media thickness (cIMT) - two markers of subclinical atherosclerosis. RESULTS: Higher 25(OH)D(3) was significantly associated with a reduced presence of MetS. Obesity, central obesity, hypertension, hypertriglyceridemia, low HDL-cholesterol, IR, and MetS were all associated with increased odds of having low 25(OH)D(3) levels, after adjustment for age, sex, and Tanner stage. After additional adjustment for SDS-body mass index, elevated blood pressure (BP) and MetS remained significantly associated with low vitamin D status. The adjusted odds ratio (95% confidence interval) for those in the lowest (<17 ng/ml) compared with the highest tertile (>27 ng/ml) of 25(OH)D(3) for hypertension was 1.72 (1.02-2.92), and for MetS, it was 2.30 (1.20-4.40). A similar pattern of association between 25(OH)D(3), high BP, and MetS was observed when models were adjusted for waist circumference. No correlation was found between 25(OH)D(3) concentrations and either FMD or cIMT. CONCLUSIONS: Low 25(OH)D(3) levels in Caucasian children are inversely related to total adiposity, MetS, and hypertension.

Management of metabolic syndrome in children and adolescents.

Concomitantly with the increasing prevalence of childhood obesity, the prevalence of metabolic syndrome (MS) is rising among children and adolescents, leading to fears for future epidemics of type 2 diabetes mellitus and cardiovascular disease in the young. This makes the accurate identification and the appropriate treatment of children and adolescents with MS an important priority for health care systems. This review will focus on the management of each component of MS, including the nonalcoholic fatty liver disease (NAFLD), which is currently considered as the hepatic component of the syndrome. The most relevant target of treatment of MS in children and adolescents is the abdominal obesity. To this end, we will discuss the efficacy of dietary approaches, possibly coupled with regular physical activity, on eliciting visceral fat reduction. We will also highlight several aspects of the treatment of the high triglyceride/low high-density lipoprotein cholesterol phenotype, including the use of non-pharmacological measures, and indications for instituting drug therapies. Part of this review will address treatment of glucose abnormalities, including the benefits of lifestyle modification alone, and the potential adjunctive role of hypoglycemic drugs. The treatment of hypertension in children with MS also requires a multifaceted approach and the available data of this topic will be examined. The remainder of this review will address treatment to reverse NAFLD and prevent progression to end-stage disease.

[Pediatric non-alcoholic fatty liver disease: recent advances and challenges]. / Steatosi epatica non alcolica nel bambino: progressi recenti e nuove prospettive.

Non-alcoholic fatty liver disease (NAFLD) encompasses a range of liver histology severity and outcomes in the absence of chronic alcohol use. The mildest form is simple steatosis in which triglycerides accumulate within hepatocytes. A more advanced form of NAFLD, non-alcoholic steatohepatitis (NASH), includes inflammation and liver cell injury, progressive to cryptogenic cirrhosis. Although prevalence in children is very difficult to establish, NAFLD is probably the most common cause of liver disease in preadolescent and adolescent groups. Over the last two decades the rise in the prevalence rates of overweight and obesity likely explains the NAFLD epidemic worldwide. NAFLD is strongly associated with abdominal obesity, type 2 diabetes, and dyslipidemia, and most patients have evidence of insulin resistance. Thus, NAFLD shares many features of the metabolic syndrome, a highly atherogenic condition, and its presence could signify a substantial cardiovascular risk. Accurate diagnosis and staging of NAFLD requires liver biopsy. The development of non-invasive surrogate markers and the advancement in imaging technology will aid in the screening of large populations at risk for NAFLD. While the optimal treatment has yet to be determined, lifestyle modification through diet and exercise should be attempted in children diagnosed with NAFLD. This review outlines current understanding, recent advances and challenges on pediatric NAFLD for both clinicians and researchers. Key words: Fatty liver.

Helicobacter pylori therapy in children: overview and challenges.

Helicobacter pylori is one of the most common infections found in humans. It was first identified in 1982 and by 1989 had been associated with gastric inflammation and ulcers in adults and children. During the 1990's evidence emerged of its etiologic role in stomach cancers in adults. That the infection is common and may have serious consequences, has led to an avalanche of research during the last twenty years. During this time, there have been many studies on children which have sought an effective and safe treatment to eradicate the infection, but as yet, no therapy regimen has been found which is always effective and safe. This article provides information, from a pediatric point of view, on the major developments in the therapeutics and therapy of H. pylori infection. It examines first-line treatment regimens, evaluates the efficacy of the main drugs used in the management of (primary) H. pylori infection in children, assesses the potential for the use of probiotics and sequential therapy, examines therapeutic options after failure of initial treatment, and discusses factors affecting eradication rate, including antibiotic resistance, adherence to therapy, and bacterial factors.

Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference.

BACKGROUND: Breath tests represent a valid and non-invasive diagnostic tool in many gastroenterological conditions. The rationale of hydrogen-breath tests is based on the concept that part of the gas produced by colonic bacterial fermentation diffuses into the blood and is excreted by breath, where it can be quantified easily. There are many differences in the methodology, and the tests are increasingly popular. AIM: The Rome Consensus Conference was convened to offer recommendations for clinical practice about the indications and methods of H2-breath testing in gastrointestinal diseases. METHODS: Experts were selected on the basis of a proven knowledge/expertise in H2-breath testing and divided into Working Groups (methodology; sugar malabsorption; small intestine bacterial overgrowth; oro-coecal transit time and other gas-related syndromes). They performed a systematic review of the literature, and then formulated statements on the basis of the scientific evidence, which were debated and voted by a multidisciplinary Jury. Recommendations were then modified on the basis of the decisions of the Jury by the members of the Expert Group. RESULTS AND CONCLUSIONS: The final statements, graded according to the level of evidence and strength of recommendation, are presented in this document; they identify the indications for the use of H2-breath testing in the clinical practice and methods to be used for performing the tests.

Once-daily tacrolimus extended-release formulation: 1-year post-conversion in stable pediatric liver transplant recipients.

The pharmacokinetics, safety and tolerability of a once-daily formulation of tacrolimus (tacrolimus extended-release formulation; XL formerly referred to as MR or MR4) were assessed in 18 stable pediatric liver transplant recipients who were converted from the twice-a-day formulation of tacrolimus (TAC) to XL. Patients received their twice-a-day dose of TAC on study days 1 through 7. Beginning on the morning of study day 8, patients were converted to XL on a 1:1 (mg:mg) basis for their total daily dose, and were maintained on a once-daily AM dosing regimen using the same therapeutic monitoring and patient care techniques employed with TAC. Based on pharmacokinetic profiles obtained on study days 7 (TAC) and 14 (XL), steady state exposure (AUC(0-24)) was equivalent between XL and TAC; the mean XL/TAC ratio for lnAUC(0-24) was 100.9% (90% CI: 90.8%, 112.1%). AUC(0-24) and C(min) were strongly correlated at steady state (correlation coefficient: XL 0.90, TAC 0.94). During the first year post-conversion, there were no cases of acute rejection, discontinuation of XL, graft loss or death. The safety profile of XL was consistent with that known for TAC. These results support the safe and convenient conversion of pediatric liver transplant recipients from twice-a-day TAC to once-daily XL.

Chronic intestinal inflammation and seronegative spondyloarthropathy in children.

BACKGROUND: Spondyloarthropathy in adults has been shown to be associated with either clinical or subclinical intestinal inflammation, however this association has rarely been described in children. AIM: To report paediatric patients primarily referred to a paediatric gastroenterology centre for suspected inflammatory bowel disease and found to be affected by a seronegative spondyloarthropathy. Intestinal inflammatory lesions and rheumatological features have been described in them. SUBJECTS: During a 18-month period, 129 children were referred because of symptoms and signs suggesting an inflammatory bowel disease; 31 of them (range age: 5-17 years) were selected because they also had signs of axial and/or peripheral arthropathy and form the basis of our study. METHODS: The investigated patients underwent ileo-colonoscopy with biopsy and rheumatological assessment that also included X-ray and magnetic resonance imaging of the sacroiliac joints. RESULTS: Only seven children had a classical inflammatory bowel disease (four had ulcerative colitis, three had Crohn's disease), 12 had an indeterminate colitis, 12 a lymphoid nodular hyperplasia of the distal ileum as main feature. In the latter two groups, endoscopy and histology revealed an intestinal inflammation of chronic type distinct from the classical pattern found in inflammatory bowel disease. All were HLA B27 negative and fulfilled the European Spondyloarthropathy Study Group criteria for spondyloarthropathy (except five children classified as undifferentiated spondyloarthropathy). CONCLUSIONS: In a group of children primarily investigated for suspected inflammatory bowel disease and also presenting a seronegative spondyloarthropathy we have described both intestinal and rheumatological features. The majority of them exhibited either an indeterminate colitis or a lymphoid nodular hyperplasia of the distal ileum as main feature. These patients may be a population at risk of developing a full inflammatory bowel disease phenotype.

Migraine with visual aura in developing age: visual disorders.

Visual disorders are an important symptom in the migraine of developing age. Different kinds of visual disturbances can precede, accompany or follow a migraine attack. These visual disturbances can be grouped into negative (hemianopsia, quadrantopsia, scotoma) and positive (phosphene, teicopsia, metamorphopsia, macropsia, micropsia, teleopsia, diplopia, dischromatopsia, hallucination disturbances) disorders. The pathogenetic mechanism of the visual phenomena of migraine has not yet been clarified. Various hypotheses have been proposed: vasospasm with consequent ischemia of some cerebral areas, the opening of arteriovenous shunts between the intra and extra cerebral circulation, the formation of microthrombi in arterioles and dopaminergic hypersensitivity of some nervous centers. We have studied 1787 children, affected by migraine with (13%) or without (87%) aura. Among the patients, 211 (12%) referred visual disorders, especially scotoma and phosphene. These data let us hypothesize that a relationship between migraine and visual disorders is present also in pediatric age. However this relationship is less important than in adults.

Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding.

Basic fibroblast growth factor (bFGF) is a regulator of angiogenesis which is overexpressed in leiomyomas compared with matched myometrium. To understand the physiological significance of this finding we characterized the expression of the type 1 receptor for this ligand (FGFR1). Utilizing reverse transcription-polymerase chain reaction (RT-PCR) we identified the complete and alternatively spliced transmembrane forms and two secreted forms of the FGFR1 in endometrium, myometrium and leiomyomas from all patients. This is the first report of secreted forms in uterine tissue. Proteins consistent with each of these isoforms were identified by Western blot analysis in all three tissues. Immunohistochemistry revealed menstrual cycle-specific regulation of FGFR1 protein in the endometrial stroma of normal women but not in women with leiomyomas and abnormal uterine bleeding. Stromal FGFR1 expression is suppressed in the early luteal phase in normal women, but not in women with leiomyoma-related bleeding. These findings support the role of the bFGF ligand-receptor system in the pathogenesis of leiomyoma-related bleeding and may have implications for fertility and contraception since the differential FGFR1 expression occurs in the peri-implantation period of the early luteal phase.

Quality control study of H2 breath testing for the diagnosis of carbohydrate malabsorption in Italy. The "Tenue Club" Group.

BACKGROUND AND AIMS: H2 breath testing is increasingly used in Italy. The aim of this multicenter study was to assess the accuracy of this technique in the diagnosis of carbohydrate malabsorption. METHODS: An anonymous questionnaire was used to collect information about H2 breath testing methods and to design the quality control study. Fifteen out of 23 laboratories responded to the questionnaire and 12/23 completed the entire study. RESULTS: The survey revealed that a large variety of H2 testing methods are employed in Italy, but none have been previously tested for accuracy. This prospective study showed that these tests fail to identify > 20% of patients with malabsorption. In contrast, a new method based on single H2 breath measurement at 6 hours after lactulose ingestion and a cutoff value of greater than 5 ppm, had a sensitivity of 92% +/- 4% and a specificity of 94% +/- 0.5%. Increasing the cut-off to 10 ppm resulted in a sensitivity of 88% +/- 9% and a specificity of 100%. This improved accuracy was obtained with a much simpler testing procedure in which only one breath sample is analyzed, in contrast to the baseline and multiple subsequent samples that are analyzed using the currently employed techniques. CONCLUSIONS: A great improvement in the accuracy of the H2 breath test, as well as a considerable saving in terms of time and costs, may be possible through the use of a new, simplified H2 breath test followed by careful H2 analysis.

Polychlorinated biphenyls and dichlorodiphenyl trichloroethane in human milk. A review.

Polychlorinated biphenyls (PCBs) and dichlorodiphenyl trichloroethane (DDT) are the most frequent chemical contaminants present in human milk. Factors involving the levels of PCBs and DDT in human milk are revised. Allowable daily intake of both contaminants is indicated as well as their effect on human exposure are discussed. Since available data suggest that these contaminants are available for redistribution to the lactating mammary gland, we stress the importance of a dietary regimen to breast fed mothers in order to prevent the mobilization of body fat stores for milk fat synthesis.

Oral contraceptive therapy for polycystic ovary disease after chronic gonadotropin-releasing agonist administration. Predictors of continued ovarian suppression.

OBJECTIVE: To study the beneficial effects of oral contraceptive (OC) therapy following gonadotropin-releasing hormone agonist (GnRH-a) administration in women with polycystic ovary disease (PCOD). STUDY DESIGN: Twenty-three hyperandrogenic women (aged 15-39) were randomized into two groups; GnRH-a (depot every 28 days) for six months or combination therapy (GnRH-a plus OC "addback") for six months. Following six months of treatment with either therapy, all patients received OC therapy for at least six months. The hormonal state was evaluated at three-month intervals. RESULTS: Hormone levels of luteinizing hormone (LH), testosterone (T) and free T remained suppressed within the normal range in 11 of 17 patients (65%) during the six months of OC only therapy, while the other six patients showed "escape" from suppression, with the LH, T and free T concentrations rising to pre-GnRH-a treatment levels. Use of OC addback therapy did not potentiate the long-acting therapeutic effect of GnRH-a pretreatment; three of six patients in the escape group were pretreated with combination therapy and three with GnRH-a only. CONCLUSION: In the majority of women with PCOD, OC therapy following GnRH-a administration was effective in maintaining ovarian androgen suppression. Failure to maintain ovarian suppression in this patient population was associated with higher elevations of baseline free T concentrations.

PIP: Clinical investigators randomly allocated 24 hirsute women aged 15-39 years with polycystic ovary disease (PCOD) to either the treatment program offering an injection of leuprolide acetate (a highly potent gonadotropin-releasing hormone agonist [GnRH-a]) for depot suspension (3.75 mg) at 28-day intervals for six months or the treatment program offering both the same injection and a combined oral contraceptive (OC) as add-back for six months. At three months, one woman moved out of state and withdrew from the study. After six months of either GnRH-a treatment regimen, all remaining 23 women received only OCs for six more months. Six women did not successfully complete the OC therapy and were excluded from the statistical analyses. The investigators aimed to examine the benefits of OC use in the management of women with PCOD after six months of pretreatment with the GnRH-a. During the OC-only treatment period, 11 (65%) of 17 patients still had suppressed levels of luteinizing hormone (LH), testosterone (T), and free T within the normal range. These levels increased to pre-GnRH-a treatment levels in the remaining six women, indicating escape from ovarian suppression. Three of six women in the escape group received combination therapy for pretreatment, while the other three received only GnRH-a. The women in the escape group had a higher baseline free T concentration than the suppressed group (5.1 vs. 3.3 ng/dl; p = 0.02). The findings revealed that OC therapy following GnRH-a administration effectively maintained ovarian androgen suppression in most women with PCOD. They also indicated that failure to maintain this suppression had a significant association with higher baseline free T concentrations.

Combination gonadotropin-releasing hormone agonist and oral contraceptive therapy improves treatment of hirsute women with ovarian hyperandrogenism.

OBJECTIVE: To determine if combination GnRH agonist (GnRH-a) and oral contraceptive (OC) therapy was more effective than GnRH-a or OC alone in the treatment of hirsute women with ovarian hyperandrogenism. DESIGN: Thirty-three hirsute women (ages 15 to 39 years) were randomized into three groups: 3.75 mg IM leuprolide acetate (LA) depot every 28 days for 6 months, combination monophasic oral contraceptive for 6 months (OC), or GnRH-a plus OC for 6 months (LA + OC). MAIN OUTCOME MEASURES: Comparative studies of changes in hormonal and hair parameters were performed at baseline, 3, and 6 months after starting therapy. RESULTS: After 6 months, serum T and LH levels were decreased significantly in all groups although reduction was greater in GnRH-a groups than OC alone. The reduction of free T was significantly greater with LA + OC compared with LA or OC alone. This could be a consequence of the significant rise in sex hormone-binding globulin (SHBG) in LA + OC and OC groups compared with LA in which there was no change in SHBG. Reduced facila hair density and decrease in hirsutism score was observed in both GnRH-a groups after 6 months. CONCLUSION: "Add-back" OC therapy used in combination with a GnRH-a increases SHBG and more effectively lowers free T levels in women with ovarian hyperandrogenism. Enhanced suppression of "bioavailable" androgens with combined GnRH-a and OC therapy failed to improve significantly the therapeutic effect of GnRH-a treatment alone on hirsutism.

Perinatal consequences of maternal hypothyroidism in early pregnancy and inadequate replacement.

UNLABELLED: Maternal hypothyroidism may be associated with a variety of pregnancy complications. OBJECTIVE: We have evaluated the perinatal consequences of maternal hypothyroidism in early and late gestation. DESIGN: Retrospective study of pregnant women, with quasi-experimental design comparing different subjects. SUBJECTS: Forty-three pregnancies in 42 women with hypothyroidism--either biochemically hypothyroid or with a history of hypothyroidism on adequate replacement--and no other preexisting medical conditions. MEASUREMENT: Free thyroxine index (FTI), TSH, and haematocrit at initial antepartum presentation and near term gestation. Pregnancy outcome variables including: rate of Caesarean section performed for fetal distress in labour, neonatal weight percentile, and gestational age at birth. RESULTS: Of 42 hypothyroid pregnancies, six were complicated by fetal distress in labour leading to Caesarean section. Five of these six were severely hypothyroid (defined as FTI < or = 0.6 (normal range 1.1-4.4)) on initial antepartum presentation. In contrast, of the 36 pregnancies without fetal distress, only four initially presented severely hypothyroid (P < 0.001). Conversely, 56% (5/9) of pregnancies which initially presented severely hypothyroid were subsequently complicated by Caesarean section for fetal distress in labour. This compared to 3% (1/33) among those who presented either mildly hypothyroid or euthyroid on replacement (P < 0.0001). Fetal distress correlated with low FTI (P < 0.001) and high TSH at initial presentation. However, it was independent of FTI near term. A relation between fetal distress and TSH near term did not reach statistical significance. Fetal distress also correlated with low maternal haematocrit on admission to labour and delivery (P < 0.05), but was independent of haematocrit and gestational age at initial presentation, neonatal weight percentile, and gestational age at birth. CONCLUSIONS: Severe maternal hypothyroidism early in gestation is strongly associated with fetal distress in labour. This suggests that (1) inadequate maternal replacement leads to fetal distress and (2) maternal thyroid status in early gestation may exert irreversible effects on the fetus, the placenta, and/or on subsequent maternal adaptations to pregnancy. Early adequate replacement therapy is especially prudent in pregnant women presenting with severe hypothyroidism.

Alternated approach with local irradiation and combination chemotherapy including cisplatin or carboplatin plus epirubicin and etoposide in intermediate stage non-small cell lung cancer.

BACKGROUND: Prognosis of unresectable non-small cell lung cancer (NSCLC) patients is disappointing; their median survival time does not exceed 8-12 months. Recently, some authors reported an increased response rate and sometimes a prolonged survival for patients with intrathoracic disease treated with local irradiation combined with cytotoxic drugs. METHODS: Fifty-eight consecutive patients with Stage IIIA or IIIB NSCLC were enrolled in a randomized Phase II trial of alternated treatment composed of four courses of combination chemotherapy and three cycles of local irradiation. Chemotherapy consisted of a randomly selected platinum compound (cisplatin [60 mg/m2] or carboplatin [300 mg/m2]) intravenously (i.v.) on Day 1, epirubicin (50 mg/m2) i.v. on Day 1, and etoposide (100 mg/m2) i.v. on Days 1-3. A course of radiotherapy consisted of 5 consecutive fractions (3 Gy per fraction, 1 fraction per day) for a total dosage of 15 Gy per course. Each course of chemotherapy was alternated every 2 weeks with a course of irradiation so that the entire treatment was performed in 13 weeks. RESULTS: Of the 58 patients, 53 were evaluable for response: 7 showed a complete clinical remission, and 25 reached a partial response, giving an overall response rate of 60% (95% confidence interval, 46%-74%). The tumors of four patients who showed a complete or partial response subsequently were surgically resected, and the complete disappearance of any residual tumor cells was documented histologically in two of them. No difference in response was observed between cisplatin- (16 of 26 [62%]) and carboplatin-treated patients (16 of 27 [59%]), and no correlation was found between response and either stage or histology. Patients enrolled in the carboplatin arm experienced less severe leukopenia and vomiting than did those in the cisplatin arm. Median freedom from progression and overall survival time were 28 and 39 weeks, respectively. Patients who responded had a significantly longer median duration of survival (49 weeks) as compared to non-responders (15 weeks). CONCLUSIONS: The alternated chemoradiotherapy treatment obtained a high response rate with substantial toxicity. This approach did not seem to improve the prognosis of patients significantly. In this setting, the administration of carboplatin instead of cisplatin appeared to be tolerated better by the patients.