Azepanone-based inhibitors of human and rat cathepsin K.

The synthesis, in vitro activities, and pharmacokinetics of a series of azepanone-based inhibitors of the cysteine protease cathepsin K (EC 3.4.22.

Thermocoagulation for selective reduction of conjoined twins at 12 weeks of gestation.

Conjoined twins occur rarely. Most of the prenatally diagnosed cases are terminated either because of extensive organ sharing or because of the presence of major structural abnormalities. We present a case of omphalopagus conjoined twins diagnosed at 10 weeks of gestation with selective reduction performed at 12 weeks.

Improvement in mitochondrial dysfunction as a new surrogate efficiency measure for preclinical trials: dose-response and time-window profiles for administration of the calcium channel blocker Ziconotide in experimental brain injury.

Object: Determining the efficacy of a drug used in experimental traumatic brain injury (TBI) requires the use of one or more outcome measures such as decreased mortality or fewer neurological and neuropsychological deficits. Unfortunately, outcomes in these test batteries have a fairly large variability, requiring relatively large sample sizes, and administration of the tests themselves is also very time consuming. The authors previously demonstrated that experimental TBI and human TBI induce mitochondrial dysfunction.

Impaired cerebral mitochondrial function after traumatic brain injury in humans.

Object: Oxygen supply to the brain is often insufficient after traumatic brain injury (TBI), and this results in decreased energy production (adenosine triphosphate [ATP]) with consequent neuronal cell death. It is obviously important to restore oxygen delivery after TBI; however, increasing oxygen delivery alone may not improve ATP production if the patient's mitochondria (the source of ATP) are impaired. Traumatic brain injury has been shown to impair mitochondrial function in animals; however, no human studies have been previously reported.

Coexistent insulin dependent diabetes mellitus and hyperthyroidism in a patient with Down's syndrome.

The prevalence of thyroid disease is increased in Down's syndrome. Compared with adults, thyroid dysfunction in children with Down's syndrome is less frequently reported. Insulin dependent diabetes mellitus is also uncommon in Down's syndrome children.

Acceptability of serum screening as an alternative to cytogenetic diagnosis of down syndrome among women 35 years or older in Hong Kong.

The addition of second trimester serum markers to maternal age increases the efficacy of screening for Down syndrome by maternal age alone. Among women aged 35 years or older, serum screening makes a large proportion of amniocentesis unnecessary. However, there are ethical and medicolegal concerns about serum screening in 'old' women, largely because some of the pregnancies affected by Down syndrome and other chromosomal abnormalities may not be detected.

Prediction of the intestinal absorption of endothelin receptor antagonists using three theoretical methods of increasing complexity.

Purpose: Three new computational strategies have been evaluated for their ability to predict intestinal membrane permeability to a series of endothelin receptor antagonists.

Methods: The three methods were evaluated using a set of ten nonpeptide endothelin receptor antagonists. The simplest method, "the rule of five", is based on 2D parameters such as the number of potential hydrogen bonds, molecular weight and calculated lipophilicity.

Effect of N-acetylcysteine on mitochondrial function following traumatic brain injury in rats.

Efficacy of N-acetylcysteine (NAC) in traumatic brain injury (TBI)-induced mitochondrial dysfunction was evaluated following controlled cortical impact injury in rats. Respiratory function and calcium transport of rat forebrain mitochondria from injured and uninjured hemispheres were examined. NAC significantly restored mitochondrial electron transfer, energy coupling capacity, calcium uptake activity and reduced calcium content absorbed to brain mitochondrial membranes when examined 12 h post-TBI if NAC was administered i.

Echogenic bowel in fetuses with homozygous alpha-thalassemia-1 in the first and second trimesters.

Objective: Fetal echogenic bowel has been observed in fetuses with meconium peritonitis, cystic fibrosis, aneuploidy, congenital viral infection and intrauterine growth restriction. The pathogenesis of echogenic bowel is unknown, but it may be attributed to bowel ischemia. Fetuses affected by homozygous alpha-thalassemia-1 are severely anemic and hypoxic.

Detection and identification of Mycobacterium tuberculosis by nested PCR assays in cerebrospinal fluid samples from patients with suspected tuberculous meningitis.

We used the nested polymerase chain reaction (PCR) assays developed previously to detect and identify Mycobacterium tuberculosis (M. tuberculosis) in the cerebrospinal fluid (CSF) samples from patients with suspected tuberculous meningitis and non-tuberculous patients. Our nested PCR assays target the multi-copy IS6110 insertion element and the single-copy mtp40 genomic DNA of M.

Comparison of the sensitivity and specificity of an automatic ligase chain reaction assay system with a one-step polymerase chain reaction assay in the diagnosis of Mycobacterium tuberculosis complex.

Background: Polymerase chain reaction (PCR) and ligase chain reaction (LCR) are two nucleic acid amplification-based molecular methods. The former has been used widely in the identification of Mycobacterium tuberculosis (M. tuberculosis).

Determination of the sensitivity and specificity of PCR assays using different target dnas for the detection of Mycobacterium tuberculosis.

To establish a sensitive, specific and reproducible PCR assay for the detection of Mycobacterium tuberculosis, we evaluated three target DNAs: IS6110, 65 kDa heat shock protein gene; and mtp40 genomic fragment. We purified genomic DNA from 15 mycobacterial strains including four M. tuberculosis isolates, four M.

Nuchal translucency in fetuses affected by homozygous alpha-thalassemia-1 at 12-13 weeks of gestation.

Objective: Fetuses affected by homozygous alpha-thalassemia-1 are anemic in the first trimester. We studied their nuchal translucency (NT) measurements at 12-13 weeks of gestation.

Methods: Nuchal translucency was measured prospectively in fetuses at risk of homozygous alpha-thalassemia-1.

Prenatal sonographic features of spondylocostal dysostosis and diaphragmatic hernia in the first trimester.

Spondylocostal dysostosis is a congenital disorder characterized by multiple malformations of the vertebrae and ribs. We describe the sonographic features of an affected fetus at 12 and 14 weeks of gestation. The fetus had thoracic scoliosis, multiple vertebral and rib malformations and a grossly dilated stomach that had herniated into the chest through a left-sided diaphragmatic hernia.

Cardiac blood flow studies in fetuses with homozygous alpha-thalassemia-1 at 12-13 weeks of gestation.

Objective: Fetuses affected by homozygous alpha-thalassemia-1 develop anemia as early as the first trimester. Our objective was to study hemodynamic indices in affected fetuses at 12-13 weeks of gestation to determine whether these would be useful in the prediction of anemia.

Design: Prospective observational study.

Critical appraisal of exercise variables: a treadmill study.

Background: New criteria for diagnosing ischemic response to treadmill exercise testing (TET) have continuously been proposed. Simultaneous comparison of test performances according to these criteria is likely contributory to interpreting TET and needs to be updated time after time. This study was conducted to accomplish this end.

Prenatal ultrasonographic prediction of homozygous type 1 alpha-thalassemia at 12 to 13 weeks of gestation.

We determined the feasibility of prenatal prediction of type 1 homozygous alpha-thalassemia at 12 to 13 weeks of gestation by either abdominal or vaginal (or both) ultrasonographic examination to measure the fetal cardiothoracic ratio in 135 at-risk pregnancies. Forty-three fetuses were affected by homozygous type 1 alpha-thalassemia. The mean cardiothoracic ratio was significantly larger than that of the unaffected fetuses (0.

Structure-affinity relationships of Val-Val and Val-Val-Val stereoisomers with the apical oligopeptide transporter in human intestinal Caco-2 cells.

The objective of this study was to elucidate the structural features of the stereoisomers of Val-Val and Val-Val-Val that afford optimal binding affinity for the apical oligopeptide transporter in human intestinal Caco-2 cells. Three-dimensional conformations of cephalexin and Val stereoisomers were optimized using Chem-X molecular modeling software. Molecular features associated with the optimized conformations of the Val stereoisomers were analyzed to identify potential relationships with their binding affinities for the apical oligopeptide transporter.

Transport of L-valine-acyclovir via the oligopeptide transporter in the human intestinal cell line, Caco-2.

It has been reported that conjugating acyclovir, a potent antiviral with low oral bioavailability, to L-valine increases its urinary excretion in rats. However, it was also reported that this increase is not found for the D-valine ester, suggesting that a carrier-mediated mechanism is involved in its intestinal absorption. Therefore, mechanisms involved in the transepithelial transport of L-valine-acyclovir were investigated using the intestinal cell line, Caco-2, as a model system for the intestinal epithelium.

5'-Amino acid esters of antiviral nucleosides, acyclovir, and AZT are absorbed by the intestinal PEPT1 peptide transporter.

Purpose: General use of nucleoside analogues in the treatment of viral infections and cancer is often limited by poor oral absorption. Valacyclovir, a water soluble amino acid ester prodrug of acyclovir has been reported to increase the oral bioavailability of acyclovir but its absorption mechanism is unknown. This study characterized the intestinal absorption mechanism of 5' -amino acid ester prodrugs of the antiviral drugs and examined the potential of amino acid esters as an effective strategy for improving oral drug absorption.

Mitochondrial dysfunction after experimental traumatic brain injury: combined efficacy of SNX-111 and U-101033E.

We recently demonstrated that posttraumatic administration of the N-type calcium channel blocker SNX-111 (S) and a novel blood-brain barrier penetrating antioxidant U-101033E (U), significantly alleviated mitochondrial dysfunction induced by traumatic brain injury (TBI) in rats. The present study was designed to determine whether a combination of S and U, which act on different biochemical mechanisms of secondary brain injury, would be more efficacious than either drug alone. Brain mitochondria from injured and uninjured hemispheres were isolated and examined at 12 h post TBI induced by a severe controlled cortical impact injury.