Species Used for Drug Testing Reveal Different Inhibition Susceptibility for 17beta-Hydroxysteroid Dehydrogenase Type 1

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17beta-hydroxysteroid dehydrogenase type 1 (17β-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution

Traumatic avulsion of kidney and spleen into the chest through a ruptured diaphragm in a young worker: a case report

<p>Abstract</p> <p>Introduction</p> <p>Rupture of the diaphragm is almost always due to major trauma. Diaphragmatic injuries are rare (5–7%), usually secondary to blunt, or more rarely to penetrating, thoracic or abdominal trauma. No single investigation provides a reliable diagnosis of diaphragmatic rupture when a patient first arrives at hospital. Almost 33% are suspected on initial chest x-ray, but the percentage is lower in patients who are immediately intubated. Mortality in patients with diaphragmatic rupture following blunt abdominal trauma is generally associated with coexistent vascular and visceral injuries that could be rapidly fatal. It's mandatory that the right diagnosis is reached as soon as possible given that mortality is influenced by the time elapsing between trauma and diagnosis.</p> <p>Case presentation</p> <p>A 35-year-old worker was hit by a heavy object while working in the factory. He was transferred immediately to our emergency room. Chest x-ray showed massive left hemothorax without any additional signs to suggest diaphragmatic injury. It was decided to perform immediate surgical exploration before further radiological examination. During surgery, the right kidney and liver appeared normal, but the left kidney and spleen were not found in their anatomical position. The left hemidiaphragm had a10-cm oblique posterior tear. The left kidney was found lacerated in the left side of the chest, separated completely from its vascular pedicle and ureter, along with the entire spleen which was also separated from its vascular tree.</p> <p>Conclusion</p> <p>The avulsion of both kidney and spleen following abdominal trauma is uncommon and survival depends on prompt diagnosis and treatment.</p

Hérnia diafragmática traumática

Traumatic diaphragmatic hernia is an uncommon but important problem in the patient with multiple injuries. Since diaphragmatic injuries are difficult to diagnose, those that are missed may present with latent symptoms of bowel obstruction and strangulation. The same may occur in the patients with stab wounds to the lower chest. Traumatic diaphragmatic hernia should be suspected on the basis of an abnormal chest radiograph in the trauma victim with multiple injuries. This article discuss about history, epidemiology, clinical signs and symptoms, diagnostic modalities, treatment and complications