Prescription of therapeutic exercise in migraine, an evidence-based clinical practice guideline.

The main objective of this clinical practice guideline is to provide a series of recommendations for healthcare and exercise professionals, such as neurologists, physical therapists, and exercise physiologists, regarding exercise prescription for patients with migraine.This guideline was developed following the methodology and procedures recommended in the Appraisal of Guidelines for Research and Evaluation (AGREE). The quality of evidence and strength of recommendations were evaluated with the Scottish Intercollegiate Guidelines Network (SIGN). A systematic literature review was performed and an established appraisal process was employed to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology).The evaluation of the current evidence, the elaboration of the grades of recommendation, and their validation show a B grade of recommendation for aerobic exercise, moderate-continuous aerobic exercise, yoga, and exercise and lifestyle recommendations for the improvement of symptoms, disability, and quality of life in patients with migraine. Relaxation techniques, high-intensity interval training, low-intensity continuous aerobic exercise, exercise and relaxation techniques, Tai Chi, and resistance exercise obtained a C grade of recommendation for the improvement of migraine symptoms and disability.

Physiotherapy Based on a Biobehavioral Approach with or Without Orthopedic Manual Physical Therapy in the Treatment of Nonspecific Chronic Low Back Pain: A Randomized Controlled Trial.

OBJECTIVE: To compare the effectiveness of a biobehavioral approach with and without orthopedic manual physical therapy on the intensity and frequency of pain in patients diagnosed with nonspecific chronic low back pain. METHODS: A single-blind randomized controlled trial. Fifty patients were randomly allocated into two groups: one group received biobehavioral therapy with orthopedic manual physical therapy, and the other group received only biobehavioral therapy. Both groups completed a total of eight sessions, with a frequency of two sessions per week. The somatosensory, physical, and psychological variables were recorded at baseline and during the first and third month after initiation of treatment. RESULTS: In both groups, the treatment was effective, presenting significant differences for all the variables in the time factor. There were no significant differences between groups in intensity or frequency of pain, with a large effect size (>0.80), but there were intragroup differences for both intervention groups at one- and three-month follow-up. There were also no significant differences between groups in the secondary variables during the same follow-up period. CONCLUSIONS: The results of this study suggest that orthopedic manual physical therapy does not increase the effects of a treatment based on biobehavioral therapy in the short or medium term, but these results should be interpreted with caution.

Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases.

BACKGROUND & AIMS: Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. METHODS: Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. RESULTS: From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CONCLUSIONS: CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient.

A Systematic Review and Meta-Analysis on the Effectiveness of Graded Activity and Graded Exposure for Chronic Nonspecific Low Back Pain.

OBJECTIVE: Our aim was to systematically review and meta-analyze the effectiveness of graded activity (GA) or graded exposure (GEXP) for chronic nonspecific low back pain (CNSLBP). METHODS: A literature search of multiple databases (MEDLINE, EMBASE, PEDro, CINAHL, and PsychINFO) was conducted to identify randomized control trials (RCTs). Standardized mean difference (SMD) and 95% confidence intervals (CI) were calculated for relevant outcome measures (pain intensity, disability, quality of life, and catastrophizing). RESULTS: Thirteen RCTs met the inclusion criteria. Only nine studies were included in the meta-analysis. GA was significantly more effective than the control group (CG) for improvements in disability in the short term (three studies: n = 254, SMD = -0.3, 95% CI -0.55 to -0.05, P = 0.02) and long term (two studies: n = 238, SMD = -0.53, 95% CI -0.79 to -0.27, P < 0.0001). GA was significantly less effective than GEXP for the improvement of disability in the short term (two studies: n = 105, SMD = 0.39, 95% CI 0.003-0.78, P = 0.048). GA was also significantly less effective than GEXP at improving catastrophizing in the short term (two studies: n = 105, SMD = 0.48, 95% CI 0.09-0.87, P = 0.02). CONCLUSION: Limited evidence has been found to show that GA significantly reduces disability in the short and long term when compared with the CG in CNSLBP. There is moderate evidence that GEXP more effectively decreases catastrophizing than GA in the short term. No difference was found between GA and other exercise for any variable.

[Effects of incorporating additional blood pressure measurements during The National Health Survey in Chile]. / Efecto de la incorporación de registros adicionales a la presión arterial en la Encuesta Nacional de Salud, Chile 2010.

BACKGROUND: It is of utmost importance to identify hypertensive subjects in a country, in order to use efficiently public resources. The National Health Survey 2009-10 in Chile incorporated a third measurement of blood pressure (BP) during the home visit performed by a nurse, and a second day of measurement in a representative sub-sample. AIM: To study the effect of these two additional actions over both the average value of BP and the national prevalence of hypertension. MATERIAL AND METHODS: A third blood pressure measurement was carried out in 5,058 subjects, and it was measured in a second day in 930 individuals. The effect of these additional measurements on absolute blood pressure values and the prevalence of hypertension were assessed. RESULTS: A small but statistically significant reduction in mean systolic pressure (0.52 mmHg) and the prevalence of hypertension (1%) was observed after the incorporation of the third blood pressure measurement. No effects in these figures were observed after the measurement performed on a second day. CONCLUSIONS: These findings should be considered when designing the new National Health Survey in Chile.

Masticatory sensory-motor changes after an experimental chewing test influenced by pain catastrophizing and neck-pain-related disability in patients with headache attributed to temporomandibular disorders.

BACKGROUND: Recent research has shown a relationship of craniomandibular disability with neck-pain-related disability has been shown. However, there is still insufficient information demonstrating the influence of neck pain and disability in the sensory-motor activity in patients with headache attributed to temporomandibular disorders (TMD). The purpose of this study was to investigate the influence of neck-pain-related disability on masticatory sensory-motor variables. METHODS: An experimental case-control study investigated 83 patients with headache attributed to TMD and 39 healthy controls. Patients were grouped according to their scores on the neck disability index (NDI) (mild and moderate neck disability). Initial assessment included the pain catastrophizing scale and the Headache Impact Test-6. The protocol consisted of baseline measurements of pressure pain thresholds (PPT) and pain-free maximum mouth opening (MMO). Individuals were asked to perform the provocation chewing test, and measurements were taken immediately after and 24 hours later. During the test, patients were assessed for subjective feelings of fatigue (VAFS) and pain intensity. RESULTS: VAFS was higher at 6 minutes (mean 51.7; 95% CI: 50.15-53.26) and 24 hours after (21.08; 95% CI: 18.6-23.5) for the group showing moderate neck disability compared with the mild neck disability group (6 minutes, 44.16; 95% CI 42.65-45.67/ 24 hours after, 14.3; 95% CI: 11.9-16.7) and the control group. The analysis shows a decrease in the pain-free MMO only in the group of moderate disability 24 hours after the test. PPTs of the trigeminal region decreased immediately in all groups, whereas at 24 hours, a decrease was observed in only the groups of patients. PPTs of the cervical region decreased in only the group with moderate neck disability 24 hours after the test. The strongest negative correlation was found between pain-free MMO immediately after the test and NDI in both the mild (r = -0.49) and moderate (r = -0.54) neck disability groups. VAFS was predicted by catastrophizing, explaining 17% of the variance in the moderate neck disability group and 12% in the mild neck disability group. CONCLUSION: Neck-pain-related disability and pain catastrophizing have an influence on the sensory-motor variables evaluated in patients with headache attributed to TMD.

Effectiveness of therapeutic patient education for adults with migraine. A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Our aim was to systematically review and meta-analyze the effectiveness of therapeutic patient education for migraine. METHODS: A literature search of multiple electronic databases (MEDLINE, EMBASE, PEDro, CINAHL, and PsychINFO) was conducted to identify randomized control trials (RCTs) published in the English and Spanish languages up to and including May 2013. Two reviewers independently selected the studies, conducted the quality assessment (Delphi list), and extracted the results. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses method was used throughout the systematic review and meta-analysis. Standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated for relevant outcome measures (headache frequency, headache disability, self-efficacy, depressive symptoms, and quality of life) and pooled in a meta-analysis using the random effects model. RESULTS: Fourteen RCTs were included in the systematic review. Only nine studies were included in the meta-analysis. The median quality score was 6.14 ± 1.29 (range: 5-9). There was strong-moderate evidence for intermediate-term effectiveness of therapeutic patient education on headache frequency (five studies: N = 940, SMD = -0.24, 95% CI of -0.48 to -0.01, P = 0.03), headache disability (four studies: N = 799, SMD = -1.02, 95% CI of -1.95 to -0.08, P = 0.03), and quality of life (three studies: N = 674, SMD = 0.36, 95% CI of 0.05-0.67, P = 0.02). There was no evidence for either short-term or intermediate-term effectiveness of therapeutic patient education on self-efficacy or depressive symptoms. CONCLUSION: This systematic review revealed strong-moderate evidence for intermediate-term effectiveness of therapeutic patient education for migraine. Further high-quality RCTs are required for conclusive determination of its effectiveness.

The biobehavioural pain and movement questionnaire (BioPMovQ): development and psychometric validation of a new questionnaire.

Objective: The purpose of this research was to design and psychometrically validate a new instrument (the Biobehavioural Pain and Movement Questionnaire/BioPMovQ), which assesses the relationship between pain and various factors related to motor behaviour from a biobehavioural perspective. Methods: A mixed-method design combining a qualitative study with an observational and cross-sectional study was employed to develop (content validity) and psychometrically validate (construct validity, reliability and concurrent/discriminant validity) a new instrument. A total of 200 patients with chronic musculoskeletal pain were recruited. Results: According to the exploratory factor analysis, the final version of the BioPMovQ consists of 16 items distributed across 4 subscales (1, disability, 2, self-efficacy for physical activity; 3, movement avoidance behaviours; and 4, self-perceived functional ability), all with an eigen value greater than 1, explaining 55.79% of the variance. The BioPMovQ showed high internal consistency (Cronbach's α = 0.82; McDonald's ω = 0.83). The intraclass correlation coefficient was 0.86 (95% confidence interval 0.76 to 0.91), which was considered to demonstrate excellent test-retest reliability. The standard error of measurement and minimal detectable change were 3.43 and 8.04 points, respectively. No floor or ceiling effects were identified. There was a positive, significant and moderate magnitude correlation with the Graded Chronic Pain Scale (r = 0.54), kinesiophobia (r = 0.60), pain catastrophising (r = 0.44) and chronic pain self-efficacy (r = -0.31). Conclusion: The BioPMovQ showed good psychometric properties. Based on the findings of this study, the BioPMovQ can be used in research and clinical practice to assess patients with chronic musculoskeletal pain.

Psychological, Pain, and Disability Factors Influencing the Perception of Improvement/Recovery from Physiotherapy in Patients with Chronic Musculoskeletal Pain: A Cross-Sectional Study.

OBJECTIVES: The aim of this study was to identify the possible relationships between psychological, pain, and disability variables with respect to the perception of change/recovery from physiotherapy in patients with chronic musculoskeletal pain (CMP). METHODS: A cross-sectional observational study was performed with 150 patients. All patients completed a series of self-administered questionnaires and a series of self-reports to quantify the perception of change with respect to the physiotherapy they underwent, the level of disability and pain intensity, the level of fear of movement, the level of catastrophism, the degree of self-efficacy, the level of therapeutic alliance and their adherence to the physiotherapy. RESULTS: The strongest correlations were between the subjective perception of change and the number of sessions, treatment beliefs, self-efficacy, pain intensity, collaboration, and bonding. The linear regression model showed that the number of sessions, treatment beliefs, self-efficacy, compliance, pain intensity, and bonding were predictors of subjective perception of improvement, with 50% of the variance. CONCLUSIONS: Treatment beliefs, therapeutic alliance, degree of self-efficacy, and pain intensity have been shown to be predictors of a subjective perception of improvement in patients with CMP. In turn, multimodal treatments had the greatest positive impact on the subjective perception of improvement.

Development and validation of the dizziness fear-avoidance behaviours and beliefs inventory for patients with vestibular disorders.

The purpose of this study is to present the development and analysis of the factorial structure and psychometric properties of a new self-administered questionnaire (Dizziness Fear-Avoidance Behaviours and Beliefs Inventory (D-FABBI)) designed to measure fear-avoidance behaviors and cognitions related to dizziness disability. A mixed-method design combining a qualitative study with an observational and cross-sectional study was employed to develop (content validity) and psychometrically validate (construct validity, reliability, and convergent/discriminant validity) a new instrument. A total of 198 patients with vestibular disorders (acute vestibular syndrome (AVS), 23.2%; chronic vestibular syndrome (CVS), 35.4%; and episodic vestibular syndrome (EVS) 41.4%) were recruited. Sociodemographic characteristics, the Dizziness Handicap Inventory (DHI) and the Hospital Anxiety and Depression Scale (HADS) and D-FABBI were evaluated. The final version of the D-FABBI consists of 17 items distributed across two subscales: activities of daily living fear-avoidance and movement fear-avoidance. The D-FABBI showed high internal consistency (Cronbach α = 0.932; 95% CI [0.91-0.94]) and so did the subscales (Cronbach α > 0.8). The exploratory structural equation model and confirmatory factor analysis provided better fit results, with a comparative fit index and root mean square error of approximation values of 0.907 to 0.081. No floor or ceiling effects were identified. There was a positive, significant, and moderate-strong magnitude correlation with the total DHI (r = 0.62) and low-moderate with respect to the HADS depression (r = 0.35) and HADS anxiety subscales (r = 0.26). The patients with CVS had a higher D-FABBI score than those with AVS or EVS. The D-FABBI appears to be a valid and reliable instrument for measuring the fear-avoidance behaviors and cognition related to dizziness disability of patients with vestibular disorders.

Development and validation of the therapeutic alliance in physiotherapy questionnaire for patients with chronic musculoskeletal pain.

OBJECTIVE: The purpose of this study is to present the development and analysis of the factorial structure and psychometric properties of a new self-administered questionnaire (Therapeutic Alliance in Physiotherapy Questionnaire-Patients [CAF-P]) designed to measure therapeutic alliance in physiotherapy. METHODS: The sample included 204 patients with chronic pain attending nine primary care centres. The CAF-P was developed and validated using standard methodology, which included developing items, cognitive debriefing and psychometric validation. RESULTS: CAF-P has excellent internal consistency, with Cronbach's α of 0.91 and an intraclass correlation coefficient (ICC) of 0.87. We propose a structure of two factors that explain 55.80 % of the variance. The convergent validity showed a moderate positive correlation with the probability of recommending treatment and with the level of satisfaction. CONCLUSIONS: The CAF-P appears to be a valid and reliable instrument for measuring the therapeutic alliance perceived by patients in physiotherapy. PRACTICE IMPLICATIONS: The results of the present study leads to further research to identify the differences in the therapeutic alliance construct between different settings or professions.

Clinical and serological profile of asymptomatic and non-severe symptomatic COVID-19 cases: Lessons from a longitudinal study in primary care in Latin America.

BACKGROUND: Chile has one of the highest incidences of COVID-19 infection in the world. Primary care can play a key role in early detection and containment of the disease. There is a lack of information on the clinical profile of patients with suspected COVID-19 in primary care, and controversy on the effectiveness of rapid serologic tests in the diagnosis and surveillance of the disease. AIM: To assess the effectiveness of rapid serologic testing in detection and surveillance of COVID-19 cases in primary care. DESIGN & SETTING: A longitudinal study was undertaken, which was based on a non-random sample of 522 participants, including 304 symptomatic patients and 218 high-risk asymptomatic individuals. They were receiving care at four primary health clinics in an underserved area in Santiago, Chile. METHOD: The participants were systematically assessed and tested for COVID-19 with reverse transcriptase-polymerase chain reaction (RT-PCR) and serology at baseline, and were followed clinically and serologically for 3 weeks. RESULTS: The prevalence rate of RT-PCR confirmed COVID-19 cases were 3.5 times higher in symptomatic patients (27.5%; 95% confidence interval [CI] = 22.1 to 32.8) compared with asymptomatic participants (7.9%; 95% CI = 4.3 to 11.6). Similarly, the immune response was significantly different between both groups. Sensitivity of serologic testing was 57.8% (95% CI = 44.8 to 70.1) during the third week of follow-up and specificity was 98.4% (95% CI = 95.5 to 99.7). CONCLUSION: Rapid serologic testing is ineffective for detecting asymptomatic or non-severe cases of COVID-19 at early stages of the disease, but can be of value for surveillance of immunity response in primary care. The clinical profile and immune response of patients with COVID-19 in primary care differs from those in hospital-based populations.

[Methodology for evaluating cost-effectiveness in primary health care centers in Chile]. / Metodología para la evaluación de la relación costo-efectividad en centros de atención primaria de Chile.

OBJECTIVE: Present a methodology for evaluating cost-effectiveness in primary health care centers (PHCs) in Chile based on the family health care model promoted in Chile and evaluate the results of the first two years of operation of the first pilot center to work under this new primary-care model. METHODS: A cost-effectiveness study with a social perspective and a one-year time frame was conducted. In order to compare the university health center in question with the control (a municipal health center), a Family Health Center Composite Quality Index (FHCCQI) was devised. It combines technical indicators and user perceptions of the health centers in six areas: access, continuity of medical care, a preventive and promotional clinical approach, problem-solving capability, participation, and a biopsychosocial and family approach. In order to calculate the costs, the centers' expenses, the savings realized in the rest of the health system, and patients' out-of-pocket expenditures were considered. The incremental cost-effectiveness ratio (ICR) was estimated and a sensitivity analysis was performed. RESULTS: The university health center was 13.4% more expensive (an additional US$8.93 per annum per enrollee) and was more effective (FHCCQI 13.3% greater) than the municipal one. Accordingly, the ICR is US$0.67 for each additional percentage point of FHCCQI increase. CONCLUSIONS: According to the PHC evaluation model that was implemented, the centers that follow the Chilean family health care model are more effective than traditional PHC centers, as measured by both technical indicators and user ratings.

Cross-Cultural Adaptation and Psychometric Properties of the Spanish Version of the Tampa Scale for Kinesiophobia for Temporomandibular Disorders.

The aim was to perform a translation, cross-cultural adaptation, and psychometric evaluation of the Spanish version of the Tampa Scale of Kinesiophobia for Temporomandibular Disorders (TSK-TMD-S). The study sample included 110 patients with TMD. We translated and cross-culturally adapted the TSK-TMD-S using standard methodology and analysed its internal consistency, test-retest reliability, construct validity, floor and ceiling effects, and discriminant validity. Confirmatory factor analysis extracted two factors and 10 items deemed essential for the scale. The TSK-TMD-S demonstrated good internal consistency (Cronbach's α of 0.843, 0.938, and 0.885 for the entire scale, activity avoidance subscale, and somatic focus subscale, respectively; intraclass correlation coefficient, 0.81-0.9). No floor or ceiling effects were identified for this final version of the scale. The TSK-TMD-S total score showed moderate positive correlation with the craniofacial pain and disability inventory, visual analogue scale, general TSK and pain catastrophizing scale, and a moderate negative correlation with maximal mouth-opening. The receiver operating characteristic curve analysis showed that the subclassification employed for the TSK-TMD-S discriminates different kinesiophobia levels with a diagnostic accuracy between sufficient and good. The optimal cut-off point for considering kinesiophobia is 23 points. TSK-TMD-S appears to be a valid and reliable instrument for measuring kinesiophobia in patients with TMD.

Craniocervical and Cervical Spine Features of Patients with Temporomandibular Disorders: A Systematic Review and Meta-Analysis of Observational Studies.

To assess neck disability with respect to jaw disability, craniocervical position, cervical alignment, and sensorimotor impairments in patients with temporomandibular disorders (TMD), a systematic review and meta-analysis of observational studies trials were conducted. The meta-analysis showed statistically significant differences in the association between neck disability and jaw disability (standardized mean difference (SMD), 0.72 (0.56-0.82)). However, results showed no significant differences for cervical alignment (SMD, 0.02 (-0.31-0.36)) or for the craniocervical position (SMD, -0.09 (-0.27-0.09)). There was moderate evidence for lower pressure pain thresholds (PPT) and for limited cervical range of motion (ROM). There was limited evidence for equal values for maximal strength between the patients with TMD and controls. There was also limited evidence for reduced cervical endurance and conflicting evidence for abnormal electromyographic (EMG) activity and motor control in TMD patients. Results showed a clinically relevant association between cervical and mandibular disability in patients with TMD. Regarding sensory-motor alterations, the most conclusive findings were observed in the reduction of PPT and cervical ROM, with moderate evidence of their presence in the patients with TMD. Lastly, the evidence on impaired motor control and cervical EMG activity in patients with TMD was conflicting.

Adaptation and validation of the Spanish version of the graded chronic pain scale. / Adaptación y validación de la Escala de gradación del dolor crónico al español.

OBJECTIVE: To adapt the Graded Chronic Pain Scale for use in Primary care patients in Spain, and to assess its psychometric properties. METHODS: Clinical measures observational study investigating the severity of chronic pain. The methodology included a process of translation and back-translation following the international guidelines. Study participants were 75 patients who experienced lower back pain for more than six months and were sent to Primary Care physiotherapy units. Internal consistency, construct validity, test-retest reliability, floor and ceiling effects, and answering capacity were analysed. RESULTS: The Spanish version of the Graded Chronic Pain Scale had a high internal consistency, with a Cronbach's alpha of 0.87 and intraclass correlation coefficient of 0.81. Regarding construct validity, it was identified that two factors explained 72.37% of the variance. Convergent validity showed a moderate positive correlation with the Visual Analogue Scale, the activity avoidance subscale of the Tampa Scale of Kinesophobia, the Pain Catastrophizing Scale, the Roland-Morris Low Back Pain and Disability Questionnaire, and the FearAvoidance Beliefs Questionnaire. A moderate negative correlation was identified with the Chronic Pain Self-Efficacy Scale. The mean time of questionnaire administration was 2minutes and 28seconds. CONCLUSIONS: The Spanish version of the Graded Chronic Pain Scale appears to be a valid, reliable, and useful tool for measuring chronic pain at an early stage in Primary Care settings in Spain.

Biochemical and genetic characterization of 11 beta-hydroxysteroid dehydrogenase type 2 in low-renin essential hypertensives.

BACKGROUND: The 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) catalyzes the conversion of cortisol (F) to cortisone (E), avoiding the interaction of cortisol with the mineralocorticoid receptor. If it fails, cortisol will stimulate sodium and water reabsorption, increasing the intravascular volume that suppresses renin and secondarily increase the blood pressure. OBJECTIVE: To look for the possible contribution of a decreased ability of 11betaHSD2 to convert cortisol to its inactive metabolite cortisone in the pathogenesis of low renin hypertension (LREH). PATIENTS AND METHODS: We studied 64 LREH patients (plasma renin activity, PRA < 1 ng/ml per h), eighty normo-renin essential hypertensives (NREH) (PRA: 1-2.5 ng/ml per h) and 74 normotensives. Serum aldosterone (SA), F, E and serum F/E ratio was determined in all patients. A serum F/E ratio was considered high when it was higher than X + 2SD from the normotensive value. Cytosine-adenine (CA)-repeat microsatellite region in intron 1 of HSD11B2 gene was genotyped in all patients and normotensives volunteers. In 13 LREH with high F/E ratio we performed HSD11B2 gene sequencing. RESULTS: LREH had serum F/E ratio higher than NREH and normotensive controls (3.6 (2.9-4.3) versus 2.9 (2.2-4.3) versus 3.0 (2.4-3.7) (P = 0.004), respectively). We observed an inverse relation between F/E ratio and SA and PRA. In NREH and normotensives we did not find correlation between these variables. In the LREH subset the longer 155 bp CA-allele showed the highest serum F/E ratio. No mutations in coding region or short introns were found in LREH patients. CONCLUSION: In this study we show that low-renin essential hypertensives had increased serum cortisol/cortisone ratios as compared with normotensive subjects. This suggest that some essential hypertensives, with suppressed renin activity, may have an impairment in the cortisol inactivation catalyzed by the enzyme 11betaHSD2, whose low activity in LREH patients could be associated with the length of CA-repeat microsatellite in intron 1 of the HSD11B2 gene.

Two homozygous mutations in the 11 beta-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess.

The human microsomal 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) metabolizes active cortisol into cortisone and protects the mineralocorticoid receptor from glucocorticoid occupancy. In a congenital deficiency of 11 beta-HSD2, the protective mechanism fails and cortisol gains inappropriate access to mineralocorticoid receptor, resulting in low-renin hypertension and hypokalemia. In the present study, we describe the clinical and molecular genetic characterization of a patient with a new mutation in the HSD11B2 gene. This is a 4-yr-old male with arterial hypertension. The plasma renin activity and serum aldosterone were undetectable in the presence of a high cortisol to cortisone ratio. PCR amplification and sequence analysis of HSD11B2 gene showed the homozygous mutation in exon 4 Asp223Asn (GAC-->AAC) and a single nucleotide substitution C-->T in intron 3. Using site-directed mutagenesis, we generated a mutant 11 beta HSD2 cDNA containing the Asp223Asn mutation. Wild-type and mutant cDNA was transfected into Chinese hamster ovary cells and enzymatic activities were measured using radiolabeled cortisol and thin-layer chromatography. The mRNA and 11 beta HSD2 protein were detected by RT-PCR and Western blot, respectively. Wild-type and mutant 11 beta HSD2 protein was expressed in Chinese hamster ovary cells, but the mutant enzyme had only 6% of wild-type activity. In silico 3D modeling showed that Asp223Asn changed the enzyme's surface electrostatic potential affecting the cofactor and substrate enzyme-binding capacity. The single substitution C-->T in intron 3 (IVS3 + 14 C-->T) have been previously reported that alters the normal splicing of pre-mRNA, given a nonfunctional protein. These findings may determine the full inactivation of this enzyme, explaining the biochemical profile and the early onset of hypertension seen in this patient.