Combined effects of diflunisal and nifedipine on uterine contractility in dysmenorrhoeic patients

In eight nulliparous women with severe primary dysmenorrhoea, intrauterine pressure was recorded on the first day of menstruation before and after administration of diflunisal 1000 mg. Uterine activity was significantly decreased in all patients but abolished in none. Seven women experienced almost complete relief of pain. To four of the patients, including the one who did not become pain-free after diflunisal, nifedipine 30 mg was also given. Uterine activity was abolished in all, but the patient not responding to diflunisal had persistent pains. It is suggested that diflunisal may be used for treatment of pain in primary dysmenorrhoea. Addition of nifedipine can produce a further decrease in uterine activity, but whether combined therapy may offer therapeutic advantages remains to be established.     

Accumulation of cocaine in maternal and fetal hair; the dose response curve.

Cocaine and its major metabolites are incorporated into hair during the growth of the shaft and stay there for the whole life of the hair. Cocaine crosses the placenta and its metabolites for example Benzoylecgonine (BZ), have been found in neonatal urine, meconium and hair. In order to utilize hair measurements of cocaine as a biological marker of systemic exposure, we conducted both animal and human investigations on the dose response characteristics of this phenomenon. Our data suggest that both maternal and fetal accumulation of cocaine and its metabolite follow a linear pattern within the clinically used doses. Similarly, a good correlation was observed in animals between maternal dose and fetal hair accumulation.     

Vanadate inhibits saltatory organelle movement in a permeabilized cell model

A method has been developed for sustaining saltatory organelle movement in permeabilized cells. Fibroblasts are permeabilized using the nonionic detergent, Brij 58, with a 2-step procedure modified from the methods of Cande [1–4]. Saltatory movement continues for 20–40 min in the permeabilized cells, provided that ATP is present in the lysis medium, although the saltations are less frequent and slower than those seen before detergent treatment. Vanadate rapidly and reversibly inhibits saltatory movement in the permeabilized cells. Inhibition by vanadate suggests that a dynein-like molecule may be involved in the mechanism of saltatory movement.     

Dihydroorotate-dependent superoxide production in rat brain and liver. A function of the primary dehydrogenase.

Dihydroorotate dehydrogenase in rat brain mitochondria is capable of producing superoxide. The presence of a superoxide dismutase activity in brain mitochondria, similar to that found in mitochondria from chicken liver, suggests that production of superoxide may occur in vivo. Formation of superoxide is not dependent upon reduction of cytochrome b, rather, superoxide production is competitive with cytochrome b reduction. Phenazine methosulfate apparently competes with both oxygen (superoxide production) and cytochrome b as an electron carrier but does not enhance reduction of dichlorophenolindophenol or cytochrome c.     

Naturally Occurring Mutations Alter the Stability of Polycystin-1 Polycystic Kidney Disease (PKD) Domains

Mutations in polycystin-1 (PC1) can cause autosomal dominant polycystic kidney disease, which is a leading cause of renal failure. The available evidence suggests that PC1 acts as a mechanosensor, receiving signals from the primary cilia, neighboring cells, and extracellular matrix. PC1 is a large membrane protein that has a long N-terminal extracellular region (about 3000 amino acids) with a multimodular structure including 16 Ig-like polycystic kidney disease (PKD) domains, which are targeted by many naturally occurring missense mutations. Nothing is known about the effects of these mutations on the biophysical properties of PKD domains. Here we investigate the effects of several naturally occurring mutations on the mechanical stability of the first PKD domain of human PC1 (HuPKDd1). We found that several missense mutations alter the mechanical unfolding pathways of HuPKDd1, resulting in distinct mechanical phenotypes. Moreover, we found that these mutations also alter the thermodynamic stability of a structurally homologous archaeal PKD domain. Based on these findings, we hypothesize that missense mutations may cause autosomal dominant polycystic kidney disease by altering the stability of the PC1 ectodomain, thereby perturbing its ability to sense mechanical signals.