Day: 02/12/2012

Neuroprotective and neurorestorative effects of thymosin β4 treatment initiated 6 hours after traumatic brain injury in rats.

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Thymosin β4 (Tβ4) is a regenerative multifunctional peptide. The aim of this study was to test the hypothesis that Tβ4 treatment initiated 6 hours postinjury reduces brain damage and improves functional recovery in rats subjected to traumatic brain injury (TBI).

Methods

Traumatic brain injury was induced by controlled cortical impact over the left parietal cortex in young adult male Wistar rats. The rats were randomly divided into the following groups: 1) saline group (n = 7); 2) 6 mg/kg Tβ4 group (n = 8); and 3) 30 mg/kg Tβ4 group (n = 8). Thymosin β4 or saline was administered intraperitoneally starting at 6 hours postinjury and again at 24 and 48 hours. An additional group of 6 animals underwent surgery without TBI (sham-injury group). Sensorimotor function and spatial learning were assessed using the modified Neurological Severity Score and the Morris water maze test, respectively. Animals were euthanized 35 days after injury, and brain sections were processed to assess lesion volume, hippocampal cell loss, cell proliferation, and neurogenesis after Tβ4 treatment.

Results

Compared with saline administration, Tβ4 treatment initiated 6 hours postinjury significantly improved sensorimotor functional recovery and spatial learning, reduced cortical lesion volume and hippocampal cell loss, and enhanced cell proliferation and neurogenesis in the injured hippocampus. The high dose of Tβ4 showed better beneficial effects compared with the low-dose treatment.

Conclusions

Thymosin β4 treatment initiated 6 hours postinjury provides both neuroprotection and neurorestoration after TBI, indicating that Tβ4 has promising therapeutic potential in patients with TBI. These data warrant further investigation of the optimal dose and therapeutic window of Tβ4 treatment for TBI and the associated underlying mechanisms.

Source: Journal of Neurosurgery.

 

 

 

 

 

A meta-analysis of predictors of seizure freedom in the surgical management of focal cortical dysplasia.

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Focal cortical dysplasia (FCD) is one of the most common causes of medically refractory epilepsy leading to surgery. However, seizure control outcomes reported in isolated surgical series are highly variable. As a result, it is not clear which variables are most crucial in predicting seizure freedom following surgery for FCD. The authors’ aim was to determine the prognostic factors for seizure control in FCD by performing a meta-analysis of the published literature.

Methods

A MEDLINE search of the published literature yielded 37 studies that met inclusion and exclusion criteria. Seven potential prognostic variables were determined from these studies and were dichotomized for analysis. For each variable, individual studies were weighted by inverse variance and combined to generate an odds ratio favoring seizure freedom. The methods complied with a standardized meta-analysis reporting protocol.

Results

Two thousand fourteen patients were included in the analysis. The overall rate of seizure freedom (Engel Class I) among patients undergoing surgery for FCD in the cohort of studies was 55.8% ± 16.2%. Partial seizures, a temporal location, detection with MRI, and a Type II Palmini histological classification were associated with higher rates of postoperative seizure control. As a treatment-related factor, complete resection of the anatomical or electrographic abnormality was the most important predictor overall of seizure freedom. Neither age nor electroencephalographic localization of the ictal onset significantly affected seizure freedom after surgery.

Conclusions

Using a large population cohort pooled from the published literature, an analysis identified important factors that are prognostic in patients with epilepsy due to FCD. The most important of these factors—diagnostic imaging and resection—provide modalities through which improvements in the impact of FCD can be effected.

Source: Journal of Neurosurgery.

 

 

 

Tai Chi and Postural Stability in Patients with Parkinson’s Disease.

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Patients with Parkinson’s disease have substantially impaired balance, leading to diminished functional ability and an increased risk of falling. Although exercise is routinely encouraged by health care providers, few programs have been proven effective.

METHODS

We conducted a randomized, controlled trial to determine whether a tailored tai chi program could improve postural control in patients with idiopathic Parkinson’s disease. We randomly assigned 195 patients with stage 1 to 4 disease on the Hoehn and Yahr staging scale (which ranges from 1 to 5, with higher stages indicating more severe disease) to one of three groups: tai chi, resistance training, or stretching. The patients participated in 60-minute exercise sessions twice weekly for 24 weeks. The primary outcomes were changes from baseline in the limits-of-stability test (maximum excursion and directional control; range, 0 to 100%). Secondary outcomes included measures of gait and strength, scores on functional-reach and timed up-and-go tests, motor scores on the Unified Parkinson’s Disease Rating Scale, and number of falls.

RESULTS

The tai chi group performed consistently better than the resistance-training and stretching groups in maximum excursion (between-group difference in the change from baseline, 5.55 percentage points; 95% confidence interval [CI], 1.12 to 9.97; and 11.98 percentage points; 95% CI, 7.21 to 16.74, respectively) and in directional control (10.45 percentage points; 95% CI, 3.89 to 17.00; and 11.38 percentage points; 95% CI, 5.50 to 17.27, respectively). The tai chi group also performed better than the stretching group in all secondary outcomes and outperformed the resistance-training group in stride length and functional reach. Tai chi lowered the incidence of falls as compared with stretching but not as compared with resistance training. The effects of tai chi training were maintained at 3 months after the intervention. No serious adverse events were observed.

CONCLUSIONS

Tai chi training appears to reduce balance impairments in patients with mild-to-moderate Parkinson’s disease, with additional benefits of improved functional capacity and reduced falls.

Source:NEJM.

 

Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area.

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The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.

METHODS

We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).

RESULTS

Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.

CONCLUSIONS

Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning.

 

Source:NEJM.

 

Antenatal Thyroid Screening and Childhood Cognitive Function.

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Children born to women with low thyroid hormone levels have been reported to have decreased cognitive function.

METHODS

We conducted a randomized trial in which pregnant women at a gestation of 15 weeks 6 days or less provided blood samples for measurement of thyrotropin and free thyroxine (T4). Women were assigned to a screening group (in which measurements were obtained immediately) or a control group (in which serum was stored and measurements were obtained shortly after delivery). Thyrotropin levels above the 97.5th percentile, free T4 levels below the 2.5th percentile, or both were considered a positive screening result. Women with positive findings in the screening group were assigned to 150 μg of levothyroxine per day. The primary outcome was IQ at 3 years of age in children of women with positive results, as measured by psychologists who were unaware of the group assignments.

RESULTS

Of 21,846 women who provided blood samples (at a median gestational age of 12 weeks 3 days), 390 women in the screening group and 404 in the control group tested positive. The median gestational age at the start of levothyroxine treatment was 13 weeks 3 days; treatment was adjusted as needed to achieve a target thyrotropin level of 0.1 to 1.0 mIU per liter. Among the children of women with positive results, the mean IQ scores were 99.2 and 100.0 in the screening and control groups, respectively (difference, 0.8; 95% confidence interval [CI], −1.1 to 2.6; P=0.40 by intention-to-treat analysis); the proportions of children with an IQ of less than 85 were 12.1% in the screening group and 14.1% in the control group (difference, 2.1 percentage points; 95% CI, −2.6 to 6.7; P=0.39). An on-treatment analysis showed similar results.

CONCLUSIONS

Antenatal screening (at a median gestational age of 12 weeks 3 days) and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age.

 

Source:NEJM.

A 37-year observation of mortality in Chinese chrysotile asbestos workers.

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This 37-year prospective cohort study was undertaken to provide additional evidence for mortality risks associated with exposure to chrysotile asbestos.

Methods 577 asbestos workers and 435 control workers in original cohorts were followed from 1972 to 2008, achieving a follow-up rate of 99% and 73%, respectively. Morality rates were determined based on person-years of observation. Cox proportional hazard models were constructed to estimate HRs of cause-specific mortality, while taking into account age, smoking and asbestos exposure level.

Results There were 259 (45%) deaths identified in the asbestos cohort, and 96 died of all cancers. Lung cancer (n=53) and non-malignant respiratory diseases (n=81) were major cause-specific deaths, in contrast to nine lung cancers and 11 respiratory diseases in the controls. Age and smoking-adjusted HRs for mortality by all causes and all cancers in asbestos workers were 2.05 (95% CI 1.56 to 2.68) and 1.89 (1.25 to 2.87), respectively. The risks for lung cancer and respiratory disease deaths in asbestos workers were over threefold that in the controls (HR 3.31(95% CI 1.60 to 6.87); HR 3.23 (95% CI 1.68 to 6.22), respectively). There was a clear exposure–response trend with asbestos exposure level and lung cancer mortality in both smokers and non-smokers.

Conclusion Data from this prospective cohort provide strong evidence for increased mortality risks, particularly from lung cancer and non-malignant respiratory diseases, associated with exposure to chrysotile asbestos, while taking into account of the smoking effect.

Key messages

What is the key question?

  • What is the major cause-specific mortality in the cohort of workers who were exposed to chrysotile asbestos, and how strong are the associations between the cause-specific mortality and asbestos exposure?
  • This 37-year prospective cohort study observed significantly greater mortality of all causes, and all cancers in the asbestos workers, in comparison with the controls. However, the strongest association with asbestos exposure was seen in lung cancer and non-malignant respiratory disease, which showed a clear exposure–response trend.
  • Chrysotile asbestos continues to be mined and used heavily in China, largely because a controversy remains on carcinogenic potency of chrysotile asbestos. This prospective cohort study with the longest observation time to date, and high follow-up rate delivers a strong message that exposure to chrysotile asbestos can cause substantially high mortality risk for lung cancer as well as non-malignant respiratory disease.

 

Source:Thorax

 

Plasma uric acid remains a marker of poor outcome in hypertensive pregnancy: a retrospective cohort study.

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Objective  To examine the relationship between hyperuricaemia, haemoconcentration and maternal and fetal outcomes in hypertensive pregnancies.

Design  Retrospective analysis of a database of hypertensive pregnancies.

Setting  St George Hospital, a major obstetric unit in Australia.

Population  A cohort of 1880 pregnant women without underlying hypertension or renal disease, referred for management of pre-eclampsia or gestational hypertension.

Methods  Demographic, clinical and biochemical data at time of referral and delivery were collected for each pregnancy. Women were grouped according to diagnosis (pre-eclampsia or gestational hypertension) and logistic regression analysis was used to determine the relationship between uric acid, haemoglobin, haematocrit and adverse outcomes; an α level of P < 0.01 was used for statistical significance.

Main outcome measures  Composites of adverse maternal and fetal outcomes.

Results  In women with ‘benign’ GH (without proteinuria or any other maternal clinical feature of pre-eclampsia) gestation-corrected hyperuricaemia was associated with increased risk of a small-for-gestational-age infant (OR 2.5; 95% CI 1.3–4.8) and prematurity (OR 3.2; 95% CI 1.4–7.2), but not with adverse maternal outcome. In the whole cohort of hypertensive pregnant women (those with pre-eclampsia or gestational hypertension) the risk of adverse maternal outcome (OR 2.0; 95% CI 1.6–2.4) and adverse fetal outcome (OR 1.8; 95% CI 1.5–2.1) increased with increasing concentration of uric acid. Hyperuricaemia corrected for gestation provided additional strength to these associations. Haemoglobin and haematocrit were not associated with adverse pregnancy outcome.

Conclusions  Hyperuricaemia in hypertensive pregnancy remains an important finding because it identifies women at increased risk of adverse maternal and particularly fetal outcome; the latter, even in women with gestational hypertension without any other feature of pre-eclampsia.

Source:BJOG.

 

First trimester maternal serum free β-human chorionic gonadotropin and pregnancy-associated plasma protein A in pregnancies complicated by diabetes mellitus.

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Objective  To investigate whether markers of first trimester screening for aneuploidies, including fetal nuchal translucency (NT), maternal serum free β-human chorionic gonadotropin (β-hCG) and pregnancy-associated plasma protein A (PAPP-A), are altered in women with pre-existing type-1 and type-2 diabetes mellitus, and in women that subsequently develop gestational diabetes mellitus (GDM).

Design  Retrospective analysis of prospective combined screening for aneuploidies in singleton pregnancies at 11+0–13+6 weeks of gestation.

Setting  Antenatal clinic.

Population  Singleton pregnancies at 11+0–13+6 weeks of gestation resulting in the delivery of phenotypically normal neonates. The study included 194 women with type-1 diabetes, 122 women with type-2 diabetes, 779 women who developed GDM and 41 007 non-diabetic controls.

Methods  Maternal free β-hCG and PAPP-A levels were expressed as multiples of the respective normal median (MoM), and fetal NT was expressed as a difference from the expected median (Δ).

Main outcome measures  Comparison of median MoM maternal free β-hCG and PAPP-A, and fetal NT, in the four outcome groups.

Results  There were no significant differences between the groups in median ΔNT and maternal free β-hCG MoM. Maternal median PAPP-A in type-2 diabetes, compared with the non-diabetic group, was reduced (0.75 MoM, IQR 0.50–1.09 MoM versus 1.00 MoM, IQR 0.68–1.42 MoM; P < 0.001), which resulted in doubling in the false-positive rate in the combined screening in this population. There were no significant differences in maternal PAPP-A between the other groups.

Conclusions  In women with type-2 diabetes, the estimation of accurate patient-specific risk in the first trimester combined screening for aneuploidies necessitates an adjustment of maternal serum PAPP-A.

Source:BJOG.

Impending macrosomia: will induction of labour modify the risk of caesarean delivery?

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Objective  To compare the annual incidence rates of caesarean delivery between induction of labour and expectant management in the setting of macrosomia.

Design  This is a retrospective cohort study.

Setting  Deliveries in the USA in 2003.

Population  Singleton births of macrosomic neonates to low-risk nulliparous women at 39 weeks of gestation and beyond.

Methods  Women who had induction of labour at 39 weeks of gestation with a neonatal birthweight of 4000 ± 125 g (3875–4125 g) were compared with women who delivered (either induced or spontaneous labour) at 40, 41 or 42 weeks (i.e. expectant management), assuming an intrauterine fetal weight gain of 200 g per additional week of gestation. Similar comparisons were made at 40 and 41 weeks of gestation. Chi-square test and multivariable logistic regression analysis were used for statistical comparison.

Main outcome measures  Method of delivery, 5-minute Apgar scores, neonatal injury.

Results  There were 132 112 women meeting the study criteria. In women whose labours were induced at 39 weeks and who delivered a neonate with a birthweight of 4000 ± 125 g, the frequency of caesarean was lower compared with women who delivered at a later gestational age (35.2% versus 40.9%; adjusted OR 1.25, 95% CI 1.17–1.33). This trend was maintained at both 40 weeks (36.1% versus 42.6%; adjusted OR 1.31, 95% CI 1.23–1.40) and 41 weeks (38.9% versus 41.8%; adjusted OR 1.16, 95% CI 1.06–1.28) of gestation.

Conclusions  In the setting of known birthweight, it appears that induction of labour may reduce the risk of caesarean delivery. Future research should concentrate on clinical and radiological methods to better estimate birthweight to facilitate improved clinical care. These findings deserve examination in a large, prospective, randomised trial.

Source:BJOG.

 

Glucose challenge test for detecting gestational diabetes mellitus: a systematic review.

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Background  The best strategy to identify women with gestational diabetes mellitus (GDM) is unclear.

Objectives  To perform a systematic review to calculate summary estimates of the sensitivity and specificity of the 50-g glucose challenge test for GDM.

Search strategy  Systematic search of MEDLINE, EMBASE and Web of Science.

Selection criteria  Articles that compared the 50-g glucose challenge test with the oral glucose tolerance test (OGTT, with a 75- or 100-g reference standard) before 32 weeks of gestation.

Data collection and analysis  Summary estimates of sensitivity and specificity, with 95% confidence intervals and summary receiver operating characteristic curves, were calculated using bivariate random-effects models. Two reviewers independently selected articles that compared the 50 g glucose challenge test to the oral glucose tolerance test (OGTT, 75 or 100 gram, reference standard) before 32 weeks of gestation.

Main results  Twenty-six studies were included (13 564 women). Studies that included women with risk factors showed a pooled sensitivity of the 50-g glucose challenge test of 0.74 (95% CI 0.62–0.87), a pooled specificity of 0.77 (95% CI 0.66–0.89) (threshold value of 7.8 mmol/l), a derived positive likelihood ratio (LR) of 3.2 (95% CI 2.0–5.2) and a negative LR of 0.34 (95% CI 0.22–0.53). In studies with consecutive recruitment, the pooled sensitivity was 0.74 (95% CI 0.62–0.87) for a specificity of 0.85 (95% CI 0.80–0.91), with a derived positive LR of 4.9 (95% CI 3.5–7.0) and negative LR of 0.31 (95% CI 0.20–0.47). Increasing the threshold for disease (OGTT result) increased the sensitivity of the challenge test, and decreased the specificity.

Author’s conclusions  The 50-g glucose challenge test is acceptable to screen for GDM, but cannot replace the OGTT. Further possibilities of combining the 50-g glucose challenge test with other screening strategies should be explored.

Source:BJOG.