A prospective and randomized study, "SVEA," comparing effects of three methods for delayed breast reconstruction on quality of life, patient-defined problem areas of life, and cosmetic result

During the last 30 years, many methods for delayed breast reconstruction have been described. There is a lack of prospective randomized trials comparing reconstruction methods. The present study (SVEA), conducted 1995 to 1996, describes the impacts of three methods: the lateral thoracodorsal flap, the latissimus dorsi flap, and the pedicled transverse rectus abdominis muscle flap (TRAM), on important areas of life, patients' perception of cosmetic result, and quality of life. Questionnaires were completed before randomization and at 6 and 12 months postoperatively. The preoperative questionnaire concerned the impact of breast loss and expectations on reconstruction. Follow-up questionnaires dealt with satisfaction with cosmetic result and impact on important areas of life. A health-related quality-of-life questionnaire (SF-36) was completed at all points of assessment. A total of 75 of 87 randomized patients underwent breast reconstruction: 16 patients with the lateral thoracodorsal flap, 30 with the latissimus dorsi flap, and 29 with the TRAM flap. The majority were very satisfied with the cosmetic result. Most women reported improvements in important areas of life, and quality of life in terms of "social functioning" and "mental health" increased significantly after the reconstruction. The latissimus dorsi flap and TRAM flap scored significantly higher as compared with the lateral thoracodorsal flap for similarity with the contralateral breast and reduced problems in social situations. No differences between irradiated and nonirradiated patients were found. All methods were considered to produce good cosmetic results and improvements in patient-defined problem areas of life and quality of life. No negative effects were recorded. Thus, irrespective of method, breast reconstruction is a valuable tool for the mastectomized woman to cope with problems in everyday life.     

In vitro inhibitory activity of EDTA against planktonic and adherent cells ofCandida sp.

Candida sp. can cause infections of indwelling medical devices associated with biofilm formation, which are difficult to treat due to insensitivity of adherent microorganisms to host defence mechanisms and standard antimicrobial therapy. The aim of this paper was to determine the effect of EDTA (disodium salt) on the adhesion ofCandida sp. to some catheters and also on biofilm formation by the yeasts and its eradication in relation to cytotoxicity of this chelating agent to the cell cultures. The adhesion process and biofilm formation, and also EDTA cytotoxicity to green monkey kidney (GMK) cell culture were determined using MTT tetrazolium salt [3-(4,5-dimethylthiazol-2-yl) ?2,5-diphenyltetrazolium bromide)] reduction assay. EDTA inhibited the growth of free-floating forms ofCandida sp. strains with minimal inhibitory concentration (MIC) from 0.06 to 0.25 mM; the minimal fungicidal concentration (MFC) values ranged from 64 to 128 mM. The prevention ofCandida sp. adhesion on the catheters used or eradication of the adherent cells was achieved at 0.5 to 4.0 mM EDTA. Also biofilm formation was prevented by 0.5 to 4.0 mM EDTA. Much higher concentration of EDTA (32 to 128 mM) was needed to eradicate the mature biofilm. EDTA at concentration up to 1 mM was not toxic for GMK cells. At higher concentration, toxicity of EDTA to GMK cells was correlated with the concentration of this agent and the time of exposure. Summing up, EDTA may be regarded as a useful agent rather in prophylaxis of candidal infections of medical devices.     

Synthesis and in Vitro Antimicrobial Activity Screening of New 3‐Acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline Derivatives

Thirteen new 3‐acetyl‐2,5‐disubstituted‐1,3,4‐oxadiazoline derivatives were synthesized from corresponding hydrazide‐hydrazones of isonicotinic acid in the reaction with acetic anhydride. The obtained compounds were identified with the use of spectral methods (IR, ¹H‐NMR, ¹³C‐NMR, MS). In vitro antimicrobial activity screening of synthesized compounds against a panel of bacteria and fungi revealed interesting antibacterial and antifungal activity of tested 1,3,4‐oxadiazoline derivatives, which is comparable to that of commonly used antimicrobial agents.     

Thyroid receptor ligands. Part 7: Indirect antagonists of the thyroid hormone receptor with improved affinity

Based on the concept of 'indirect antagonism' of nuclear receptors, a series of thyroid hormone receptor (TR) antagonists were prepared with improved affinity compared with what was previously described. The results of a binding assay for the human TR and reporter cell assay revealed, within this series, that an m-bromobenzoyl substituent (11f) was optimal in terms of affinity and antagonist activity. Compared with already reported TR antagonists, their affinities are within the same range, thus potentially representing useful approach to novel and high-affinity TR-antagonists.     

Skeletal muscle morphology in power-lifters with and without anabolic steroids

The morphological appearance of the vastus lateralis (VL) muscle from high-level power-lifters on long-term anabolic steroid supplementation (PAS) and power-lifters never taking anabolic steroids (P) was compared. The effects of long- and short-term supplementation were compared. Enzyme-immunohistochemical investigations were performed to assess muscle fiber type composition, fiber area, number of myonuclei per fiber, internal myonuclei, myonuclear domains and proportion of satellite cells. The PAS group had larger type I, IIA, IIAB and IIC fiber areas (p<0.05). The number of myonuclei/fiber and the proportion of central nuclei were significantly higher in the PAS group (p<0.05). Similar results were seen in the trapezius muscle (T) but additionally, in T the proportion of fibers expressing developmental myosin isoforms was higher in the PAS group compared to the P group. Further, in VL, the PAS group had significantly larger nuclear domains in fibers containing ≥5 myonuclei. The results of AS on VL morphology in this study were similar to previously reported short-term effects of AS on VL. The initial effects from AS appear to be maintained for several years.     

Development and stability of a heat‐stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle‐income countries

Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat‐stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat‐stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25–5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat‐stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle‐income countries, where maintaining cold chain distribution is difficult. Ferring Pharmaceuticals, the World Health Organization, and MSD # for Mothers have established a collaboration to develop this heat‐stable formulation of carbetocin for the prevention of post‐partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality.     

Energetic basis of cadmium toxicity in Staphylococcus aureus

In washed cells of cadmium-sensitive Staphylococcus aureus 17810S oxidizing glutamate, initial Cd²⁺⁺⁺ influx via the Mn²⁺ porter down membrane potential () was fast due to involvement of energy generated by two proton pumps—the respiratory chain and the ATP synthetase complex working in the hydrolytic direction. Such an unusual energy drain for rapid initial Cd²⁺ influx is suggested to be due to a series of toxic events elicited by Cd²⁺ accumulation down generated via the redox proton pump: (i) strong inhibition of glutamate oxidation accompanied by a decrease of electrochemical proton gradient ( _H ⁺) formation via the respiratory chain, (ii) automatic reversal of ATP synthetase from biosynthetic to hydrolytic mode, which was monitored by a decrease of _H ⁺-dependent ATP synthesis, (iii) acceleration of the initial Cd²⁺ influx down generated the reversed ATP synthetase, the alternative proton pump hydrolyzing endogenous ATP. The primary, cadmium-sensitive targets in strain 17810S seem to be dithiols located in the cytoplasmic glutamate oxidizing system, prior to the membrane-embedded NADH oxidation system. Inhibition by Cd²⁺ of _H ⁺-dependent ATP synthesis and of pH gradient (pH)-linked [¹⁴C]glutamate transport is a secondary effect due to cadmium-mediated inhibition of _H ⁺ generation at the cytoplasmic level. In washed cells of cadmium-resistant S. aureus 17810R oxidizing glutamate, Cd²⁺ accumulation was prevented due to activity of the plasmid-coded Cd²⁺ efflux system. Consequently, _H ⁺-producing and -requiring processes were not affected by Cd²⁺.     

The use of aqueous two-phase systems to concentrate and purify bovine leukemia virus outer envelope protein gp51

Enzootic bovine leucosis is a chronic lymphoproliferative disease of cattle. The causative agent, bovine leukemia virus (BLV), is related to the human retroviruses HTLV-I and -II. The external env-protein of BLV, a glycoprotein of 51 kDa, carries neutralizing epitopes and should be an essential component in a vaccine against the virus. Problems have been encountered with the concentration and purification of intact virions of BLV and other retroviruses. During centrifugation procedures the external env-proteins are to a great extent detached and consequently poorly recovered with the virion particles. Therefore, other methods are sought to obtain a high yield of the external glycoproteins. The use of two-phase systems based on water soluble polymers is described for the extraction of BLV-gp51 from culture medium. Several polymer systems were tested and the results showed that some were attractive for large scale application. The classical combination dextran-polyethylene glycol gave promising results; a partition coefficient of about 0.02 was obtained for the distribution of the gp51 between the top and combined inter- and bottom phases. In a single extraction step it was possible to obtain 45% of the glycoprotein in a small volume bottom phase and at the same time about 15-fold purified. That should be compared with a recovery of less than 20% with the conventional centrifugation procedures. It is concluded that extraction in phase systems based on water soluble polymers is a methodology well suited for the concentration and purification of BLV-gp51.     

Arsenite-Induced Pseudo-Hypoxia Results in Loss of Anchorage-Dependent Growth in BEAS-2B Pulmonary Epithelial Cells

Epidemiology studies have established a strong link between lung cancer and arsenic exposure. Currently, the role of disturbed cellular energy metabolism in carcinogenesis is a focus of scientific interest. Hypoxia inducible factor-1 alpha (HIF-1A) is a key regulator of energy metabolism, and it has been found to accumulate during arsenite exposure under oxygen-replete conditions. We modeled arsenic-exposed human pulmonary epithelial cells in vitro with BEAS-2B, a non-malignant lung epithelial cell line. Constant exposure to 1 µM arsenite (As) resulted in the early loss of anchorage-dependent growth, measured by soft agar colony formation, beginning at 6 weeks of exposure. This arsenite exposure resulted in HIF-1A accumulation and increased glycolysis, similar to the physiologic response to hypoxia, but in this case under oxygen-replete conditions. This “pseudo-hypoxia” response was necessary for the maximal acquisition of anchorage-independent growth in arsenite-exposed BEAS-2B. The HIF-1A accumulation and induction in glycolysis was sustained throughout a 52 week course of arsenite exposure in BEAS-2B. There was a time-dependent increase in anchorage-independent growth during the exposure to arsenite. When HIF-1A expression was stably suppressed, arsenite-induced glycolysis was abrogated, and the anchorage-independent growth was reduced. These findings establish that arsenite exerts a hypoxia-mimetic effect, which plays an important role in the subsequent gain of malignancy-associated phenotypes.