Molecular physiology of renal potassium channels.

The application of patch-clamp technique to the study of ion channels showed the enormous diversity of K channels. In the kidney, K channels play an major role in transepithelial K transport, in the regulation of vascular tone, and in cellular proliferation. In the last 5 years, the use of powerful genetic and molecular biological techniques has provided an understanding of the molecular structure of some types of K channels. Although much work remains to be done in this area, the greater challenge will be to integrate the molecular information with the extensive physiological data already available. Finally, the rapidly accumulating knowledge of K channel structure, and the recent appreciation of their possible role in important disease states, such as hypertension, make the study of K channels very exciting.     

Effects of exercise in breast cancer patients: implications of the trials within cohorts (TwiCs) design in the UMBRELLA Fit trial

Breast Cancer Research and Treatment - The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of...     

Population screening and cascade testing for carriers of SMA

Spinal muscular atrophy (SMA) is one of the most common autosomal-recessive diseases, caused by absence of both copies of the survival motor neuron 1 (SMN1) gene. Identification of SMA carriers has important implications for individuals with a family history and the general population. SMA carriers are completely healthy and most are unaware of their carrier status until they have an affected child. A total of 422 individuals have been studied to identify SMA carriers. This cohort included 117 parents of children homozygously deleted for SMN1 (94% were carriers and 6% had two copies of SMN1; of these individuals, two in seven had the '2+0' genotype, two in seven were normal but had children carrying a de novo deletion and three in seven were unresolved), 158 individuals with a significant family history of SMA (47% had one copy, 49% had two copies and 4% had three copies of SMN1) and 146 individuals with no family history of SMA (90% had two copies, 2% had one copy and 8% had three copies of SMN1). The SMA carrier frequency in the Australian population appears to be 1/49 and the frequency of two-copy SMN1 alleles and de novo deletion mutations are both at least 1.7%. A multimodal approach involving quantitative analysis, linkage analysis and genetic risk assessment (GRA), facilitates the resolution of SMA carrier status in individuals with a family history as well as individuals of the general population, providing couples with better choices in their family planning.     

MR-Guided High-Intensity Focused Ultrasound Ablation of Breast Cancer with a Dedicated Breast Platform

Optimizing the treatment of breast cancer remains a major topic of interest. In current clinical practice, breast-conserving therapy is the standard of care for patients with localized breast cancer. Technological developments have fueled interest in less invasive breast cancer treatment. Magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) is a completely noninvasive ablation technique. Focused beams of ultrasound are used for ablation of the target lesion without disrupting the skin and subcutaneous tissues in the beam path. MRI is an excellent imaging method for tumor targeting, treatment monitoring, and evaluation of treatment results. The combination of HIFU and MR imaging offers an opportunity for image-guided ablation of breast cancer. Previous studies of MR-HIFU in breast cancer patients reported a limited efficacy, which hampered the clinical translation of this technique. These prior studies were performed without an MR-HIFU system specifically developed for breast cancer treatment. In this article, a novel and dedicated MR-HIFU breast platform is presented. This system has been designed for safe and effective MR-HIFU ablation of breast cancer. Furthermore, both clinical and technical challenges are discussed, which have to be solved before MR-HIFU ablation of breast cancer can be implemented in routine clinical practice.     

The radiodensity of cerebrospinal fluid and vitreous humor as indicator of the time since death

Purpose

After death, a series of changes occur naturally in the human body in a fairly regular pattern. These postmortem changes are detectable on postmortem CT scans (PMCT) and may be useful in estimating the postmortem interval (PMI). The purpose of our study is to correlate the PMCT radiodensities of the cerebrospinal fluid (CSF) and vitreous humor (VH) to the PMI.

Methods

Three patient groups were included: group A consisted of 5 donated cadavers, group B, 100 in-hospital deceased patients, and group C, 12 out-of-hospital forensic cadavers. Group A were scanned every hour for a maximum of 36 h postmortem, and the tympanic temperature was measured prior to each scan. Groups B and C were scanned once after death (PMI range 0.2–63.8 h). Radiodensities of the VH and CSF were measured in Hounsfield units. Correlation between density and PMI was determined using linear regression and the influence of temperature was assessed by a multivariate regression model. Results from group A were validated in groups B and C.

Results

Group A showed increasing radiodensity of the CSF and VH over time (r ² CSF, 0.65). PMI overruled the influence of temperature (r = 0.99 and p = 0.000). Groups B and C showed more diversity, with CSF and VH radiodensities below the mean regression line of Group A. The formula of this upper limit indicated the maximum PMI and was correct for >95 % of the cadavers.

Conclusion

The results of group A showed a significant correlation between CSF radiodensity and PMI. The radiodensities in groups B and C were higher than in group A, therefore the maximum PMI can be estimated with the upper 95 % confidence interval of the correlation line of group A.

     

Structure–activity relationship of a series of 1,2-dihydroquinoline analogues and binding mode with <Emphasis Type="Italic">Vibrio cholerae</Emphasis> dihydrofolate reductase

Cholera is a reemerging disease caused by Vibrio cholerae that can occasion severe dehydration and death if it is not appropriately treated. The irrational use of antibiotics has led to emergence and dissemination of resistant strains; thus, the development of new antibiotics is required. The aim of this study was to establish a structure–activity relationship analysis of a series of 1,2-dihydroquinoline analogues described in the literature as dihydrofolate reductase (DHFR) inhibitors and evaluate their binding mode. Herein, some stereoelectronic properties were found to be correlated with the antibacterial activity such as molecular weight, molecular area, volume, ovality, polar surface area and highest occupied molecular orbital (HOMO) energy, besides HOMO location and the electronic distribution profile. A three-dimensional model of V. cholerae DHFR was constructed using Swiss Model Server, and molecular docking of the most potent and less potent 1,2-dihydroquinoline analogues of the series was carried out using AutoDock 4.2 program. The results showed a similar binding mode of the most potent inhibitors with the antibiotic trimethoprim, and some interactions with the DHFR seemed to be important as hydrogen bonds with E28, van der Waals contacts with F32, M51 and hydrophobic interactions with the pocket comprised of residues Q29, G52, K53 and L54. Therefore, our study provides new insights into inhibition of V. cholerae DHFR which may be used to guide the rational design of new antibiotic agents.     

Idiopathic polyhydramnios and postnatal findings

Objective.?Our objective was to investigate the outcome of neonates with idiopathic polyhydramnios in the first year after birth.

Methods.?All patients diagnosed in the Erasmus Medical Centre Rotterdam and the University Medical Centre Utrecht between January 2000 and April 2005 with idiopathic polyhydramnios were studied. The outcome variables included mode of delivery, pre-term delivery, birth weight, macrosomia, large-for-gestational-age (weight > p90), neonatal or infant mortality and infant morbidity at 1 year after delivery. These were related to antenatal findings, including the onset of polyhydramnios and ultrasonographic evidence of macrosomia (estimated fetal weight > p90).

Results.?Polyhydramnios was diagnosed at a mean gestational age (± s.d.) of 31.0 ± 4.9 weeks. The mean gestational age at birth (± s.d.) was 37.9 ± 3.7 weeks. Macrosomia at birth was present in 25.3% (22/88). Sixty-three of 88 infants were in good health 1 year after birth; 20 infants had an abnormality and 5 children had died. Macrosomia and detection of polyhydramnios in the third trimester was associated significantly with a good outcome.

Conclusion.?In neonates with idiopathic polyhydramnios, abnormalities were detected during the first year of life in 28.4%. Detection of polyhydramnios in the second trimester and low or normal birth weight are risk factors for associated abnormalities.