Cryoablation as standard treatment of atrial flutter: a prospective, 2-center study (CASTAF).

BACKGROUND: Cryoablation (CRYO) of cavotricuspid isthmus (CTI)-dependent atrial flutter (AFL) has been shown to be non-inferior to radiofrequency ablation (RF) in terms of ablation success and is associated with less pain. However, procedural time has been significantly longer with CRYO compared to RF. A possible explanation for this could be that operators had less experience with CRYO than with RF. The purpose of this study was to test the hypothesis that in the hands of experienced operators, cryoablation of CTI-dependent AFL is effective with procedure-time similar to what is reported for RF. METHODS: This prospective 2-center study included 184 patients with CTI-dependent AFL - median age 66 years (range 28-83), 159 men (86%). Cryoablation was performed using a 9 F, 8 mm tip catheter (Freezor MAX, Medtronic, Inc, MN, USA). Ablation endpoint was bidirectional CTI-block. Pain was evaluated with a visual analogue scale (VAS 0-10). All operators had experience of at least 25 previous CTI-ablations with CRYO. RESULTS: The acute success rate was 89%. Procedural time including an observation period of 30 min, was 115 ± 36 min which is similar to procedural times for RF in previous studies. Fluoroscopy time was 11 ± 9 min. Cryoablation was perceived as almost pain- free by the patients, VAS (mean) 1.8 ± 1.2. Success rate at 12-month follow-up (FU) was 88% in patients with primary success. No major adverse events occurred. CONCLUSIONS: Cryoablation of CTI-dependent AFL is effective, with a low level of procedure-related pain. In experienced hands, the procedure time in this prospective non-randomised trial seems to be in the level of reported procedure times for RF. The long-term relapse rate appears to be higher than for RF.

Runx1 repression by histone deacetylation is critical for Setbp1-induced mouse myeloid leukemia development.

Abnormal activation of SETBP1 through overexpression or missense mutations is highly recurrent in various myeloid malignancies; however, it is unclear whether such activation alone is able to induce leukemia development. Here we show that Setbp1 overexpression in mouse bone marrow progenitors through retroviral transduction is capable of initiating leukemia development in irradiated recipient mice. Before leukemic transformation, Setbp1 overexpression significantly enhances the self-renewal of hematopoietic stem cells (HSCs) and expands granulocyte macrophage progenitors (GMPs). Interestingly, Setbp1 overexpression also causes transcriptional repression of critical hematopoiesis regulator gene Runx1 and this effect is crucial for Setbp1-induced transformation. Runx1 repression is induced by Setbp1-mediated recruitment of a nucleosome remodeling deacetylase (NuRD) complex to Runx1 promoters and can be reversed by treatment with histone deacetylase (HDAC) inhibitors Entinostat and Vorinostat. Moreover, treatment with these inhibitors caused efficient differentiation of Setbp1 activation-induced leukemia cells in vitro, and significantly extended the survival of mice transplanted with such leukemias, suggesting that HDAC inhibition could be an effective strategy for treating myeloid malignancies with SETBP1 activation.

Association of HLA-DRB1*01 with Dupuytren's disease.

OBJECTIVES: To explore the human leucocyte antigen (HLA)-DRB1 allele frequency in Dupuytren's disease (DD). METHOD: HLA-DRB1 genotypes were analysed by sequence-specific primers (SSPs) in samples collected from 172 men participating in a nested case-control study on the clinical manifestations and progression of DD. Of those, 121 had signs of DD while 51 did not. Of the 121 men with DD, 49 had contracted fingers or had been operated on, while 72 had nodules or fibrous cords in the palms. Odds ratios (ORs) and 95% confidence interval (CIs) were used to evaluate the results. RESULTS: The HLA-DRB1*01 allele was observed in 26 of the 121 affected men (23.7%) but in only four of the controls (7.8%) (OR 3.22, 95% CI 1.06-9.75). The HLA-DRB1*01 allele frequency in those affected was 11%, while in the control group it was 4% (OR 3.07, 95% CI 1.05-9.03). CONCLUSIONS: This observation indicates a possible association of HLA-DRB1*01 with DD, but further studies are needed for confirmation.

Gastric reflux is a significant causative factor of tooth erosion.

Dental erosion is caused by dietary or gastric acid. This study aimed to examine the location and severity of tooth erosion with respect to causative factors, and to determine whether the clinical pattern of erosion reflected the dominant etiological factor. The study involved 249 Icelandic individuals and included: a detailed medical history; clinical oral examination; salivary sampling, and analysis for flow rate, pH, and buffering capacity. Reflux was assessed in 91 individuals by gastroscopy, esophageal manometry, and 24-hour esophageal-pH monitoring. Reflux symptoms were reported by 36.5% individuals. Manometry results were abnormal in 8% of study participants, abnormal esophageal pH in 17.7%, and a pathological 24-hour pH recording in 21.3%. 3.6% were positive for Helicobacter pylori. Normal salivary flow was found in 92%, but low salivary buffering (10.4%) was associated with erosion into dentin (P < 0.05). Significant associations were found between erosion and diagnosed reflux disease (OR 2.772; P < 0.005) and daily consumption of acidic drinks (OR 2.232; P < 0.005).

Inflammatory cytokines in relation to adrenal response following total hip replacement.

Our objective was to investigate the initiation and course of pro- and anti-inflammatory cytokines in early inflammatory response and to elucidate the cytokine system in relation to the adrenal response caused by stress. Seven blood samples were collected, pre- and postoperatively (0-72 h) after total hip replacement (THR) due to osteoarthritis. The following cytokines were measured using Cytometric Bead Array: interleukin-1beta (IL-1beta), IL-6, tumour necrosis factor-alpha, IL-8, IL-12 and IL-10 (B&D). Thirteen patients took part in the study (67 +/- 9 years). C-reactive protein increased from <6 to over 200 mg/l on the second post-op day. The concentration of IL-6 increased 10-fold just 3 h post-op (4-47 pg/ml) and reached its maximum value 6 h post-op (77 pg/ml; Wilcoxon test P < 0.01) Repeated measurements were also significant (Friedman P < 0.05). The concentration of IL-8 doubled the day of surgery but did not reach a significant level (Friedman test =0.069). None of the other cytokines showed any significant changes. The diurnal cortisol rhythm was interrupted after the surgery and there was a significant correlation between the cortisol secretion and IL-6 response. This study demonstrates an isolated elevation in IL-6 levels with only a minor elevation in IL-8 following THR. This pro-inflammatory response seemed to decline without activation of anti-inflammatory cytokines (IL-10), but cortisol seemed to play a complicated role in halting the acute inflammatory response.

20 years follow-up after the first microsurgical lumbar discectomies in Iceland.

BACKGROUND: Microsurgical discectomies are an established procedure in spinal surgery. This operating technique was first used in the Department of Neurosurgery in Iceland in 1981 and has become standard operative treatment for herniated lumbar discs. There is a great variability in outcome reports regarding recurrence rate and re-operation rate. Few articles are based on follow-up of more than 10 years. This article presents the results of a 20 years follow-up study. METHODS: A retrospective study of all patients undergoing microsurgical discectomy for herniated lumbar disc, from June 1, 1981 to December 31, 1984. Outcome, based on recurrence rate, return to work and patient satisfaction was determined by a self-evaluation questionnaire, phone interviews and patient medical records. FINDINGS: Of the 170 patients, 134 (78.8%) were included in the study (M:F, 58:42%). Preoperative symptoms: back pain with sciatica 108 (80.6%), sciatica 20 (14.9%), back pain 2 (1.5%). Mean follow-up time was 20.7 years (19.5-22.8). Recurrence rate was 12.7%. 19 patients (14.2%) underwent a subsequent lumbar operation at a different level or side. A majority of patients 108 (80.6%) returned to previous level of work, 26 (19.4%) lost some or all working capabilities. Patient satisfaction was high, 91.1% reporting excellent (68.7%) or good (22.4%) results. 5.2% of patients rated the outcome fair and 3.7% poor. Women reported worse outcome than men, excellent M:F 74.7:60.7%, and poor 7.1:1.3%. There was no significant difference in patient satisfaction in patients undergoing additional operations or those with recurrence of the herniated disc. CONCLUSIONS: Outcome was very good with 92.0% return to work and 91.1% patient satisfaction. The recurrence rate was 12.7% with a substantial number of cases occurring 10-20 years after operation. To conclude, microsurgical discectomies maintain a high success rate in the long-term.

Relationship between dental erosion, soft drink consumption, and gastroesophageal reflux among Icelanders.

The aim of this study was to determine the prevalence of dental erosion in young Icelandic adults (19-22 years old) and patients with gastroesophageal reflux disease (GERD), in relation to their soft drink consumption and gastroesophageal reflux. Eighty subjects (40 males and 40 females), comprising 57 young adults (mean age 21 +/- 2 years) and 23 GERD patients (mean age 35 +/- 10 years), were enrolled in this study. All subjects answered a detailed frequency questionnaire of soft drink consumption and participated in a clinical examination. Erosion was scored for incisor and molar teeth separately. No significant difference was observed in the prevalence of dental erosion between young adults and GERD patients. However, by combining the two study groups a three-fold higher risk of having erosion in molars or incisors was found for subjects drinking Coca-Cola three times a week or more often ( p < 0.05). Additionally, significantly higher erosion scores were found in molars among subjects drinking more than 1 litre of carbonated drinks (all brands) per week ( p < 0.05). It is concluded that the frequency of soft drink consumption is a strong risk factor in the development of dental erosion.

Increased expression of interleukin-13 but not interleukin-4 in CD4+ cells from patients with the hyper-IgE syndrome.

Hyper IgE syndrome (HIES) is a rare immunodeficiency disorder characterized mainly by high levels of polyclonal IgE in serum and recurrent staphylococcal abscesses of the skin and lungs. The raised IgE levels have led researchers to study the synthesis of cytokines that regulate switching of immunoglobulin production towards IgE such as interleukin-4 (IL-4), IL-12 and interferon-gamma (IFN)-gamma. However, the role of IL-13 in the disease pathogenesis has not been investigated extensively. In this study, we investigated intracellular expression of IL-4 and IL-13 in mononuclear cells and CD4+ cells isolated from patients with HIES and healthy controls. Cells were stained intracellularly with antibodies directed against IL-4 and IL-13 and analysed by flow cytometry before and after activation with PMA and calcium ionophore. The mean proportion of resting or activated IL-4 and IL-13 expressing mononuclear cells were comparable in the two groups as well as the proportion of IL-4 expressing CD4+ cells. In contrast, the mean proportion of IL-13 expressing CD4+ cells was increased significantly in patients with HIES in both the resting and the activated state compared to healthy controls. We conclude that increased expression of IL-13 in CD4+ cells from patients with HIES could account, at least partly, for raised IgE levels in those individuals.

Dupuytren's disease, alcohol consumption and alcoholism.

OBJECTIVE: To assess the relation between alcohol consumption and Dupuytren's disease. DESIGN: The participants were recruited from a previous study on Dupuytren's disease carried out in 1981-82 as part of a cohort study. Men with Dupuytren's disease in the former study and a control group were invited. The groups were matched for age and smoking habits. SETTINGS: The study took place at the Heart Preventive Clinic in Reykjavik. PATIENTS: Of 244 invited participants, 193 (79.1%) responded to the invitation; 137 had Dupuytren's disease and 56 were disease-free. Participants were examined for the presence of Dupuytren's disease and answered a questionnaire about alcohol habits. MAIN OUTCOME MEASURES: Alcoholism, alcohol consumption and signs of Dupuytren's disease. RESULTS: Of the Dupuytren's group, 19 (13.9%) had been treated for alcoholism or were heavy drinkers compared to 8 (14.3%) of those without Dupuytren's disease (NS). Little or moderate alcohol consumption was reported in 78.1% of the Dupuytren's patients compared to 73.2% of the controls (NS). Total abstainers from alcohol were 11 (8.0%) in the Dupuytren's group compared to 7 (12.5%) in the control group (NS). CONCLUSION: Our findings do not support a positive association between the use of alcohol and Dupuytren's disease.

Synthesis of carbocyclic analogs of 2',3'-dideoxysangivamycin, 2',3'-dideoxytoyocamycin, and 2',3'-dideoxytriciribine.

Syntheses and antiviral activity of new carbocyclic analogs of 2', 3'-dideoxysangivamycin, 2',3'-dideoxytoyocamycin and 2',3'-dideoxytriciribine is described. The key intermediate, carbocyclic 4-chloro-5-iodopyrrolopyrimidine. was synthesized in good yield via a novel iodination method using I2 and CF3COOAg. This carbocyclic 4-chloro-5-iodopyrrolopyrimidine then allowed for a concise synthesis of the desired 4,5-disubstituted carbocyclic nucleosides.

The relationship between educational level and mortality. The Reykjavík Study.

OBJECTIVE: Epidemiological studies have indicated an association between socioeconomic factors and health. It has not been clearly established whether this association is wholly or partly independent of classical risk factors. Our objective was to estimate the relationship between educational level and coronary artery disease (CAD), mortality and all-cause mortality. The Reykjavík Study involving 18 912 participants followed-up 4-30 years provides an ideal opportunity to address this question. DESIGN AND SUBJECTS: The participants were aged 33-81 years and living in the Reykjavík area. They were divided into four groups according to education. The standard risk factors were assessed on entry and mortality, and cause of death registered during follow-up. Multiple Cox regression analysis was applied to assess the relationship between age at examination, year of examination, educational level and mortality. RESULTS: The all-cause mortality and CAD mortality was significantly related to education, even after adjustment for classical risk factors. For men, 14% (95% CI: 2-24) reduction was found in CAD mortality for those having high school education relative to elementary school. The figures for junior college and university education were 17% (95% CI: 1-31) and 38% (95% CI: 21-32), respectively. These figures were only slightly lower when major CAD risk factors were controlled for and still significant. Similar figures were found for all-cause mortality. For women 34% (95% CI: 18-48) reduction was found in CAD mortality for high school education and 55% (95% CI: 22-74) for junior college, but too few had university education for reliable results. The figures were lower for all-cause mortality, but significant. The figures were reduced when major CAD risk factors were controlled for, but still significant. CONCLUSION: Education is a strong protective factor both for all-cause and CAD mortality. Only a small part of this effect can be explained through conventional risk factors.

Eighteen years follow-up study of the clinical manifestations and progression of Dupuytren's disease.

OBJECTIVE: To evaluate the clinical manifestations and progression of Dupuytren's disease. METHODS: In 1981-82 a total of 1297 men were examined for Dupuytren's disease, and of these 19.2% had the disease. In 1999 those with signs of the disease in 1981-82 were invited for a follow-up study. As controls symptom free individuals from the study in 1981-82 were invited. RESULTS: A total of 53 individuals from the control group had developed Dupuytren's disease in 1999. Men with palmar nodules/fibrous cord in 1981-82 were more likely to develop contracted fingers than those without Dupuytren's disease. Patients with young age at disease onset more often required operations than those with later onset. Of the men who had been operated 70% still had finger contractures in 1999. CONCLUSION: The incidence of Dupuytren's disease is high in elderly men. Dupuytren's disease is progressive in nature and most operated patients have recurrent finger contractures.

[Mesenchymal stem cells. A review.].

The bone marrow contains various types of stem cells. Among them are hematopoietic stem cells, which are the precursors of all blood cells, and mesenchymal stem cells. Mesenchymal stem cells have recently received a lot of attention in biological research because of their capability to self renewal, to expand and transdifferentiate into many different cell types; bone cells, adipocytes, chondrocytes, tendocytes, neural cells and stromal cells of the bone marrow. Mesenchymal stem cells can be cultured in vitro although their differentiation potential is not yet fully understood. Several experiments have been conducted in animal models where mesenchymal stem cells have been transplanted in order to enhance hematopoiesis or to facilitate the repair of mesenchymal tissue. Similar experiments are being conducted in humans. Mesenchymal stem cells are believed to be able to enhance hematopoietic stem cells transplantation by rebuilding the bone marrow microenvironment which is damaged after radiation- and/or chemotherapy. Mesenchymal stem cells are promising as vehicles for gene transfer and therapy. It may prove possible to tranduce them with a gene coding for a defective protein i.e. collagen I in osteogenesis imperfecta. The cells could then be expanded ex vivo and transplanted to the patients where they home to the bone marrow, differentiate and produce the intact protein. Future medicine will probably involve mesenchymal stem cells in various treatment settings.

Exercise-induced laryngochalasia: an imitator of exercise-induced bronchospasm.

BACKGROUND: Patients with exercise-induced laryngochalasia present with dyspnea and stridor during exercise. Symptoms are due to a subtotal occlusion of the larynx resulting from mucosal edema from the aryepiglottic folds being drawn into the endolarynx. METHODS: We report on three patients with exercise-induced bronchospasm, refractory to standard therapy. RESULTS: Spirometry with flow-volume loops revealed truncation of the inspiratory limb. Abnormal movement of the arytenoid region was visualized on laryngoscopy. A diagnosis of exercise-induced laryngochalasia was made. CONCLUSIONS: Evaluation of laryngeal motion in patients with refractory exercise-induced bronchospasm is important. Surgical correction with laser laryngoplasty is effective in carefully selected cases.

Synthesis and antiviral evaluation of halogenated beta-D- and -L-erythrofuranosylbenzimidazoles.

A series of 2-substituted benzimidazole D- and L-erythrofuranosyl nucleosides were synthesized and tested for activity against herpesviruses and for cytotoxicity. The D-nucleosides 2,5, 6-trichloro-1-(beta-D-erythrofuranosyl)benzimidazole (8a) and 2-bromo-5,6-dichloro-1-(beta-D-erythrofuranosyl)benzimidazole (8b) were prepared by coupling 1,2,3-tri-O-acetyl-beta-D-erythrofuranose (D-6) with the appropriate benzimidazole, followed by removal of the acetyl protecting groups. The 2-isopropylamino (9), 2-cyclopropylamino (10), and 2-mercaptobenzyl (11) derivatives were synthesized by nucleophilic displacements of the C-2 chlorine in the benzimidazole moiety of 8a. The D-nucleoside 4-bromo-5, 6-dichloro-2-isopropylamino-1-(beta-D-erythrofuranosyl)benzimid azo le (17) was prepared by coupling D-6 with the appropriate benzimidazole. The L-erythrofuranosyl derivatives, 5, 6-dichloro-2-isopropylamino-1-(beta-L-erythrofuranosyl)benzimid azo le (21a), its 2-cyclopropylamino analogue (21b), and the 2-isopropylamino analogue (25), were prepared by coupling L-6 with the appropriate benzimidazole. Several of these new derivatives had very good activity against HCMV in plaque and yield reduction assays (IC(50) = 0.05-19 microM against the Towne strain of HCMV) and DNA hybridization assays. Very little activity was observed against other herpesviruses. This pattern is similar to the antiviral activity profile observed for the corresponding ribofuranosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (4a), its 2-bromo analogue (4b), and the 2-cyclopropylamino analogue (4c). In comparison, 8a was 15-fold more active against HCMV than 4a, and 8b was 4-fold more active against HCMV than 4b. The 5, 6-dichloro-2-isopropylamino-1-(beta-L-erythrofuranosyl)benzimid azo le (21a) was less active than 4c, which is now in clinical trials for HCMV infection. Both 8a,b had comparable HCMV activity to 4c. Mode of action studies with the D-erythrose analogues established that 8b acted by inhibition of viral DNA processing whereas 9 and 10 may act via a different mechanism. The lack of a 5'-hydroxymethyl group in all members of this series established that antiviral activity occurred without 5'-phosphorylation, a feature required for the activity of most nucleoside analogues.

Synthesis of fluorosugar analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole as antivirals with potentially increased glycosidic bond stability.

The metabolic instability in vivo of the glycosidic bond of 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole , 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole, and 2-bromo-5, 6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3',5'-ditrityl derivatives, which were fluorinated with DAST and deprotected to yield 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole and 2,5, 6-trichloro-1-(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low overall yield (5%) of 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5, 6-trichlorobenzimidazole was condensed with 1-bromo-3, 5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5, 6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.

Assessment of aluminium in human deciduous teeth.

The possible role of environmental aluminium exposure in the pathogenesis of various diseases has highlighted the need for methods by which the long-term exposure to aluminium can be assessed. Therefore, we have further developed a method to determine aluminium in human deciduous teeth and applied this method for studying populations in Sweden, Crete and Iceland.

Epidemiology of Dupuytren's disease: clinical, serological, and social assessment. The Reykjavik Study.

Dupuytren's disease or palmar fibromatosis is a common disabling hand disorder, mainly confined to Caucasians of northwestern European origin. The prevalence of Dupuytren's disease and possible risk factors related to the disease were evaluated in a random sample of 1297 males and 868 females, aged 46 to 74 years. Blood samples were collected and biochemical parameters were evaluated. The possible relation between the disease and clinical, social, and biochemical parameters were estimated with age-adjusted univariate logistic regression analysis. Altogether 19.2% of the males and 4.4% of the female participants had clinical signs of Dupuytren's disease. The prevalence increased with age, from 7.2% among males in the age group 45-49 years up to 39.5% in those 70-74 years old. The more severe form of the disease, finger contractures, was found in 5.0% of the men and 1.4% had required operation, while this was rarely seen among women. In men elevated fasting blood glucose (P < 0.04), low body weight, and body mass index were significantly correlated with the presence of the disease (P < 0.001). Dupuytren's disease was common among heavy smokers (P = 0.02) and those having manual labor as occupation (P = 0.018). These results show that Dupuytren's disease is common in the Icelandic population and occupation and lifestyle seem to be related to the disease.

[The surgical microscope and its use in neurological surgery.].

This is a short history of glasses, telescopes and microscopes and how the surgical microscope developed from these optical instruments and became one of the most necessary and most widely used surgical instruments in the world for the past 30 years. It has been of great importance to modern surgery, especially ear, nose and throat surgery, eye surgery and last but not least neurological surgery. The role of the surgical microscope in Iceland, and especially in neurological surgery, is discussed.

Virilising 21-hydroxylase deficiency: timing of newborn screening and confirmatory tests can be crucial.

Early diagnosis of congenital adrenal hyperplasia (CAH) can be lifesaving. With the advent of newborn screening programs employing blood 17-hydroxyprogesterone, fewer cases are missed. Because false positive results occur, especially in premature and low birth weight babies, infants with borderline elevations, although requiring follow-up, are often considered normal. We describe a newborn female that, despite severe virilization, only had a borderline elevation in 17-hydroxyprogesterone (17OHP) on newborn screening, as well as on initial confirmatory testing in our clinical laboratory. Our confirmatory method, which employs high performance liquid chromatography (HPLC) separation, because of its high specificity, yields steroid values from both normal children and those with CAH that are lower than found with older, less specific methods. Given the heterogeneity of phenotypes of CAH, less severe forms, especially in males, could result in marginally abnormal laboratory results early in life, with possible adverse effects later. Although in retrospect the diagnosis of the described patient was clear and not a novel entity, we consider it an important example for several reasons. It emphasizes the broad range of 17OHP levels in CAH, the lack of correlation of these levels with clinical phenotype and the importance of the timing of both screening and confirmatory tests. Due to the complexity of interpreting these tests, any screening program for CAH should be controlled by an experienced pediatric endocrinologist.