Estrogen in severe mental illness: a potential new treatment approach.

Kulkarni J et al

Context: Accumulating evidence suggests that estrogens may have therapeutic effects in severe mental illnesses, including schizophrenia, via neuromodulatory and neuroprotective activity. Objective: To compare the efficacy of adjunctive transdermal estradiol with that of adjunctive placebo in the treatment of acute psychotic symptoms. Design: Randomized, double-blind study. Setting: Patients were recruited from inpatient acute hospital wards and outpatient clinics of 2 metropolitan Melbourne general hospitals. Participants: One hundred two women of childbearing age with schizophrenia. All participants were in an acute or chronic phase of their illness; 73 participants were outpatients and the rest were inpatients. Intervention Patients were randomized to receive 100 microg of transdermal estradiol (n = 56) or transdermal placebo (n = 46) for 28 days. Main Outcome Measures: Psychopathological symptoms were assessed weekly with the Positive and Negative Syndrome Scale. Results: The addition of 100 microg of transdermal estradiol significantly reduced positive (P < .05) and general psychopathological (P < .05) symptoms during the 28-day trial period compared with women receiving antipsychotic medication alone. Conclusion: Estradiol appears to be a useful treatment for women with schizophrenia and may provide a new adjunctive therapeutic option for severe mental illness.

Arch Gen Psychiatry. 2008 Aug;65(8):955-60


An approach to using recombinant erythropoietin for neuroprotection in very preterm infants.

FauchŔre JC et al.

OBJECTIVE: Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome. METHODS: This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth. RESULTS: The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count. CONCLUSIONS: No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.

Pediatrics. 2008 Aug;122(2):375-82


Usefulness of the serum carcinoembryonic antigen kinetic for chemotherapy monitoring in patients with unresectable metastasis of colorectal cancer.

Iwanicki-Caron I et al

PURPOSE: The aim of the study was to evaluate the relationship between serum carcinoembryonic antigen (CEA) kinetic and response to chemotherapy in patients with unresectable metastasis of colorectal cancer. PATIENTS AND METHODS: The kinetic was calculated using the slope of an exponential-regressive curve connecting the semi-logarithmic values of CEA. Receiver operating characteristic (ROC) curves were drawn to select the CEA slope thresholds to define patients with progressive or responsive disease with the highest sensitivity, specificity, and diagnosis accuracy odds ratio (DOR). The correlation between the CEA slopes and progression-free survival (PFS) was evaluated by the Cox model and Kaplan-Meier methods. RESULTS: A total of 122 patients were included. Progression defined by CEA slope greater than +0.05 resulted in sensitivity of 85.7%, specificity of 85.1%, and DOR of 34. The area under the ROC (AUROC) curve was 0.885 (95% CI, 0.815 to 0.936; P = .0001). Response defined by CEA slope less than -0.2 resulted in sensitivity of 74.7%, specificity of 82.5%, and DOR of 16. The AUROC curve was 0.847 (95% CI, 0.770 to 0.906; P = .0001). The difference between AUROC curves calculated with six or four CEA values was not significant. PFS was correlated with CEA slopes (hazard ratio, 4.6; 95% CI, 2.48 to 8.57). The median PFS was 10 months for patients with CEA slope values less than -0.2 months versus 6 months for patients with CEA slope values greater than -0.2 (P < .0001). CONCLUSION: These results suggest that the CEA kinetic is an accurate, simple, and noninvasive method to identify the disease progression in patients with unresectable metastasis of colorectal cancer

J Clin Oncol. 2008 Aug 1;26(22):3681-6


Sildenafil treatment of women with antidepressant-associated sexual dysfunction: a randomized controlled trial.

Nurnberg HG et al

CONTEXT: Antidepressant-associated sexual dysfunction is a common adverse effect that frequently results in premature medication treatment discontinuation and for which no treatment has demonstrated efficacy in women. OBJECTIVE: To evaluate the efficacy of sildenafil for sexual dysfunction associated with selective and nonselective serotonin reuptake inhibitors (SRIs) in women. DESIGN, SETTING, AND PARTICIPANTS: An 8-week prospective, parallel-group, randomized, double-blind, placebo-controlled clinical trial conducted between September 1, 2003, and January 1, 2007, at 7 US research centers that included 98 previously sexually functioning, premenopausal women (mean [SD] age 37.1 [6] years) whose major depression was remitted by SRIs but who were also experiencing sexual dysfunction. INTERVENTION: Forty-nine patients were randomly assigned to take sildenafil or placebo at a flexible dose starting at 50 mg adjustable to 100 mg before sexual activity. MAIN OUTCOME MEASURES: The primary outcome measure was the mean difference in change from baseline to study end (ie, lower ordinal score) on the Clinical Global Impression sexual function scale. Secondary measures included the Female Sexual Function Questionnaire, the Arizona Sexual Experience scale-female version, the University of New Mexico Sexual Function Inventory-female version, a sexual activity event log, and the Hamilton Depression Rating scale. Hormone levels were also assessed. RESULTS: In an intention-to-treat analysis, women treated with sildenafil had a mean Clinical Global Impression-sexual function score of 1.9 (95% confidence interval [CI], 1.6-2.3) compared with those taking placebo (1.1; 95% CI, 0.8-1.5), with a mean end point difference of 0.8 (95% CI, 0.6-1.0; P = .001). Assigning baseline values carried forward to the 22% of patients who prematurely discontinued resulted in a mean end point in the sexual function score of 1.5 (95% CI, 1.1-1.9) among women taking sildenafil compared with 0.9 (95% CI, 0.6-1.3) among women taking placebo with a mean end point difference of 0.6 (95% CI, 0.3-0.8; P = .03). Baseline endocrine levels were within normal limits and did not differ between groups. The mean (SD) Hamilton scores for depression remained consistent with remission in both groups (4.0 [3.6]; P = .90). Headache, flushing, and dyspepsia were reported frequently during treatment, but no patients withdrew because of serious adverse effects. CONCLUSION: In this study population, sildenafil treatment of sexual dysfunction in women taking SRIs was associated with a reduction in adverse sexual effects.

JAMA. 2008 Jul 23;300(4):395-404.


Impact of immediate versus delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes.

Olson JA Jr et al

PURPOSE: Patients with breast cancer metastasis to the sentinel lymph nodes (SLNs) generally undergo completion axillary lymph node dissection (cALND), either concurrently with SLN biopsy or at a second procedure. The impact of the timing of cALND on pathologic results and complications in these patients has not been examined. PATIENTS AND METHODS: We examined outcomes from SLN-positive patients in American College of Surgeons Oncology Group (ACOSOG) trials Z0010 and Z0011. Pathologic data examined included primary tumor characteristics, total number of SLNs recovered, positive SLN(s) and non-SLN(s) identified. Complications assessed included axillary seroma, paresthesia, arm morbidity and range of motion, and lymphedema. RESULTS: A total of 1,003 assessable patients with SLN metastasis had immediate (n = 425) or delayed (n = 578) cALND. The median number of SLNs and axillary LNs removed were the same between groups. Patients who had immediate cALND more often had larger tumors, SLN metastasis identified intraoperatively, two or more positive SLNs, and higher pathologic N stage. Axillary paresthesia, seroma, and impaired extremity range of motion were more common in the immediate group during the early postoperative period, but not at later time points. There was no difference in lymphedema at any time point. CONCLUSION: In ACOSOG trials Z0010 and Z0011, LN recovery and long-term complications were similar after either delayed or immediate cALND for patients with metastasis to SLNs. Patients who undergo immediate cALND experience more short-term morbidity. With respect to staging and complications, there is no clear detriment for patients with a positive SLN who undergo a second procedure for cALND.

J Clin Oncol. 2008 Jul 20;26(21):3530-5.


Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study.

McQueen MJ et al

BACKGROUND: Whether lipoproteins are better markers than lipids and lipoproteins for coronary heart disease is widely debated. Our aim was to compare the apolipoproteins and cholesterol as indices for risk of acute myocardial infarction. METHODS: We did a large, standardised case-control study of acute myocardial infarction in 12,461 cases and 14,637 age-matched (plus or minus 5 years) and sex-matched controls in 52 countries. Non-fasting blood samples were available from 9345 cases and 12,120 controls. Concentrations of plasma lipids, lipoproteins, and apolipoproteins were measured, and cholesterol and apolipoprotein ratios were calculated. Odds ratios (OR) and 95% CI, and population-attributable risks (PARs) were calculated for each measure overall and for each ethnic group by comparison of the top four quintiles with the lowest quintile. FINDINGS: The apolipoprotein B100 (ApoB)/apolipoprotein A1 (ApoA1) ratio had the highest PAR (54%) and the highest OR with each 1 SD difference (1.59, 95% CI 1.53-1.64). The PAR for ratio of LDL cholesterol/HDL cholesterol was 37%. PAR for total cholesterol/HDL cholesterol was 32%, which was substantially lower than that of the ApoB/ApoA1 ratio (p<0.0001). These results were consistent in all ethnic groups, men and women, and for all ages. INTERPRETATION: The non-fasting ApoB/ApoA1 ratio was superior to any of the cholesterol ratios for estimation of the risk of acute myocardial infarction in all ethnic groups, in both sexes, and at all ages, and it should be introduced into worldwide clinical practice.

Lancet. 2008 Jul 19;372(9634):224-33.


Cost-effectiveness analysis of introduction of rapid, alternative methods to identify multidrug-resistant tuberculosis in middle-income countries.

Acuna-Villaorduna C et al

BACKGROUND: Resistance to commonly used antituberculosis drugs is emerging worldwide. Conventional drug-susceptibility testing (DST) methods are slow and demanding. Alternative, rapid DST methods would permit the early detection of drug resistance and, in turn, arrest tuberculosis transmission. METHODS: A cost-effectiveness analysis of 5 DST methods was performed in the context of a clinical trial that compared rapid with conventional DST methods. The methods under investigation were direct phage-replication assay (FASTPlaque-Response; Biotech), direct amplification and reverse hybridization of the rpoB gene (INNO-LiPA; Innogenetics), indirect colorimetric minimum inhibitory concentration assay (MTT; ICN Biomedicals), and direct proportion method on L÷wenstein-Jensen medium. These were compared with the widely used indirect proportion method on L÷wenstein-Jensen medium. RESULTS: All alternative DST methods were found to be cost-effective, compared with other health care interventions. DST methods also generate substantial cost savings in settings of high prevalence of multidrug-resistant tuberculosis. Excluding the effects of transmission, the direct proportion method on L÷wenstein-Jensen medium was the most cost-effective alternative DST method for patient groups with prevalences of multidrug-resistant tuberculosis of 2%, 5%, 20%, and 50% (cost in US$2004, $94, $36, $8, and $2 per disability-adjusted life year, respectively). CONCLUSION: Alternative, rapid methods for DST are cost-effective and should be considered for use by national tuberculosis programs in middle-income countries.

Clin Infect Dis. 2008 Aug 15;47(4):487-95.


Relation of iron and red meat intake to blood pressure: cross sectional epidemiological study.

Tzoulaki I et al

OBJECTIVE: To investigate associations of dietary iron (total, haem, and non-haem), supplemental iron, and red meat with blood pressure. DESIGN: Cross sectional epidemiological study. SETTING: 17 population samples from Japan, China, the United Kingdom, and the United States participating in the international collaborative study on macro-/micronutrients and blood pressure (INTERMAP). PARTICIPANTS: 4680 adults aged 40-59. MAIN OUTCOME MEASURE: Average of eight blood pressure readings. RESULTS: In multiple linear regression analyses dietary total iron and non-haem iron were consistently inversely associated with blood pressure. With adjustment for potential non-dietary and dietary confounders, dietary total iron intake higher by 4.20 mg/4.2 MJ (2 SD) was associated with -1.39 mm Hg (P<0.01) lower systolic blood pressure. Dietary non-haem iron intake higher by 4.13 mg/4.2 MJ (2 SD) was associated with -1.45 mm Hg (P<0.001) lower systolic blood pressure. Differences were smaller for diastolic blood pressure. In most models haem iron intake from food was positively, non-significantly associated with blood pressure. Iron intake from combined diet and supplements yielded smaller associations than dietary iron alone. Red meat intake was directly associated with blood pressure; 102.6 g/24 h (2 SD) higher intake was associated with 1.25 mm Hg higher systolic blood pressure. Associations between red meat and blood pressure persisted after adjustment for multiple confounders. CONCLUSION: Non-haem iron has a possible role in the prevention and control of adverse blood pressure levels. An unfavourable effect of red meat on blood pressure was observed. These results need confirmation including in prospective studies, clinical trials, and from experimental evidence on possible mechanisms.

BMJ. 2008 Jul 15;337:a258. doi: 10.1136/bmj.a258.



Drug-prescribing patterns during pregnancy in the tertiary care hospitals of Pakistan: a cross sectional study.

Rohra DK et al

BACKGROUND: The rationale for use of drugs during pregnancy requires a careful assessment as in addition to the mother, the health and life of her unborn child is also at stake. Information on the use of drugs during pregnancy is not available in Pakistan. The aim of this study was to evaluate the patterns of drug prescriptions to pregnant women in tertiary care hospitals of Pakistan. METHODS: This was a cross-sectional study conducted at five tertiary care hospitals of Pakistan. Copies of outpatient medicinal prescriptions given to pregnant patients attending the antenatal clinics were collected. The drugs were classified according to the pharmacological class and their teratogenic potential. RESULTS: All the pregnant women attending the antenatal clinics received a prescription containing at least one drug. A total of 3769 distinct prescriptions given to different women were collected. Majority of the women who received the prescriptions belonged to third trimester (55.4%) followed by second (33.6%) and first trimester (11.0%). On an average, each prescription contained 1.66 +/- 0.14 drugs. The obstetricians at Civil Hospital, Karachi and Chandka Medical College Hospital, Larkana showed a tendency of prescribing lesser number of drugs compared to those in other hospitals. Anti-anemic drugs including iron preparations and vitamin and mineral supplements (79.4%) were the most frequently prescribed drugs followed by analgesics (6.2%) and anti-bacterials (2.2%). 739 women (19.6%) received prescriptions containing drugs other than vitamin or mineral supplements. Only 1275 (21.6%) of all the prescribed drugs (n = 6100) were outside this vitamin/mineral supplement class. Out of these 1275 drugs, 29 (2.3%) drugs were prescribed which are considered to be teratogenic. Misoprostol was the most frequently prescribed (n = 6) among the teratogenic drugs followed by carbimazole (n = 5) and methotrexate (n = 5). Twenty nine pregnant women (0.8% of all the women studied) were prescribed these teratogenic drugs. CONCLUSION: Less than one percent of the pregnant women attending tertiary care hospitals in Pakistan are prescribed teratogenic drugs. The prescribing practices of Pakistani physicians are similar to those in western countries.

BMC Pregnancy Childbirth. 2008 Jul 15;8:24


Effect of intermittent preventive treatment of malaria on health and education in schoolchildren: a cluster-randomised, double-blind, placebo-controlled trial.

Clarke SE et al

BACKGROUND: Malaria is a major cause of morbidity and mortality in early childhood, yet its consequences for health and education during the school-age years remain poorly understood. We examined the effect of intermittent preventive treatment (IPT) in reducing anaemia and improving classroom attention and educational achievement in semi-immune schoolchildren in an area of high perennial transmission. METHODS: A stratified, cluster-randomised, double-blind, placebo-controlled trial of IPT was done in 30 primary schools in western Kenya. Schools were randomly assigned to treatment (sulfadoxine-pyrimethamine in combination with amodiaquine or dual placebo) by use of a computer-generated list. Children aged 5-18 years received three treatments at 4-month intervals (IPT n=3535, placebo n=3223). The primary endpoint was the prevalence of anaemia, defined as a haemoglobin concentration below 110 g/L. This outcome was assessed through cross-sectional surveys 12 months post-intervention. Analysis was by both intention to treat, excluding children with missing data, and per protocol. This study is registered with, number NCT00142246. FINDINGS: 2604 children in the IPT group and 2302 in the placebo group were included in the intention-to-treat analysis of the primary outcome; the main reason for exclusion was loss to follow-up. Prevalence of anaemia at 12 months averaged 6.3% in the IPT group and 12.6% in the placebo group (adjusted risk ratio 0.52, 95% CI 0.29-0.93; p=0.028). Significant improvements were also seen in two of the class-based tests of sustained attention, with a mean increase in code transmission test score of 6.05 (95% CI 2.83-9.27; p=0.0007) and counting sounds test score of 1.80 (0.19-3.41; p=0.03), compared with controls. No effect was shown for inattentive or hyperactive-compulsive behaviours or on educational achievement. The per-protocol analysis yielded similar results. 23 serious adverse events were reported within 28 days of any treatment (19 in the IPT group and four in the placebo group); the main side-effects were problems of balance, dizziness, feeling faint, nausea, and/or vomiting shortly after treatment. INTERPRETATION: IPT of malaria improves the health and cognitive ability of semi-immune schoolchildren. Effective malaria interventions could be a valuable addition to school health programs.

Lancet. 2008 Jul 12;372(9633):127-38.