Gentamicin alters membrane structure as shown by freeze-fracture of liposomes

Freeze-fracture has been used to examine the effects of gentamicin on membrane structure in liposomes of different anionic phospholipids combined with a neutral phospholipid, phosphatidylcholine. The molar ratios of neutral: anionic lipid were 1:1 (high anionic lipid ratio) and 4:1 (low anionic lipid) and the liposomes were incubated with 0.1 mM (low) and 1 mM (high) gentamicin. With the anionic phospholipid phosphatidylinositol bisphosphate, an identifiable disruption of the membrane bilayer was observed as well as aggregation of liposomes leading to membrane fusion. These effects occurred both at low gentamicin concentration and low anionic lipid content of the liposomes; these responses were not inhibited by 1 mM Ca2+. With the other anionic lipids tested (phosphatidylserine, phosphatidylinositol and phosphatidylinositol monophosphate), only aggregation and fusion of liposomes was observed and this effect only occurred at high gentamicin concentration and high anionic lipid content. Further, 1 mM Ca2+ inhibited the responses of these other anionic lipids to gentamicin. The results demonstrate the unique character of the interaction between gentamicin and phosphatidylinositol bisphosphate and provide further support for the hypothesis that a specific binding to this lipid is a key step in the ototoxic action of aminoglycoside antibiotics. They also suggest that such an interaction in vivo might cause alterations to the structure and properties of cell membranes in the inner ear.     

The first report of a patient with interrupted inferior vena cava,multiple post-renal veins and azygos-hemiazygos continuation

The first case of a patient with interrupted inferior vena cava, four post-renal veins and an azygoshemiazygos continuation is presented. The complicated anomalies were omphalocele and atrial septal defect. Cine-magnetic resonance imaging and cardiac catheterization showed an anomalous retroaortic left innominate vein, azygos-hemiazygos continuation in the prerenal portion, arch formed renal vein in the renal portion and four embryonic vessels in the post-renal portion. Combination of these anomalies in the major venous system suggested that the inferior vena cava had failed to form and that the bilateral embryonic venous system, postcardinal and supracardinal veins persisted to be the systemic venous channels.     

An energy-dependent step in aminoglycoside ototoxicity: prevention of gentamicin ototoxicity during reduced endolymphatic potential

Guinea pigs received a bolus of gentamicin (10 mM for 5 min) by perilymphatic perfusion which normally led to an irreversible loss of the cochlear microphonic potential (CM). Various experimental conditions that reduced the endolymphatic potential (EP) were then superimposed on the gentamicin application. Reversible reductions in EP (and, concomitantly, in CM) were induced by asphyxia (3 min), intravenous furosemide (50 mg/kg), and perilymphatic perfusion of aminooxyacetic acid (10 mM). When the administration of gentamicin was initiated at the time of maximal EP reduction the usual irreversible gentamicin-induced decline of CM was prevented. The results indicate that a metabolic process is essential in the expression of gentamicin toxicity. The data are consistent with the inhibition of an energy-dependent transport of the aminoglycoside. Alternatively, the data are also compatible with the hypothesis that entry of gentamicin into hair cells is prevented by a reduction in their transmembrane electrical potential.     

Gamma-carboxyglutamate in normal and pathological human middle ear bones

Summary The presence of the amino acid -carboxyglutamate (GLA) was established in human middle ear bones. Proteins containing GLA have been described as being associated with normal as well as pathological calcifications. The GLA content of human incus, malleus, and stapes with 1–2 nmol/mg bone is in the range previously reported for a variety of bone. A limited number of samples with middle ear pathology, including otosclerosis, did not show altered GLA levels.     

A heroin epidemic at the intersection of histories: the 1960s epidemic among African Americans in Baltimore

In the drug field the fundamental epidemiological question-why illicit drug use, here, now, among these people-has still not been adequately answered. Drawing on the work of colleagues in medical anthropology, we attempt to move closer to an answer by developing a "trend theory." In this article we analyze a single case: the increase in heroin use and addiction among African Americans in the City of Baltimore in the 1960s. We found that the two most important historical processes behind the epidemic were (1) a changing distribution/supply system and (2) the mix of hope and despair that was part of the early civil rights movement.     

Contraception and treatment in the perimenopause with a novel "frameless" intrauterine levonorgestrel-releasing drug delivery system: an extended pilot study

The objective of the study was to evaluate the contraceptive performance, acceptability, side effects, and adverse events of a novel "frameless" intrauterine drug delivery system (IUS), FibroPlant-levonorgestrel (LNG) releasing 14 microg of LNG/day, in perimenopausal women. An ancillary objective was to evaluate the effect of the new IUS on menstrual blood loss in women with or without fibroids.The study, consisting of 109 women, suggests that FibroPlant-LNG IUS is an effective contraceptive. No pregnancies occurred with the FibroPlant-LNG IUS. The total use-related discontinuation rate at 1 year is low (1.9) and results in a high rate of continuation of use (98.1). In addition, the FibroPlant-LNG IUS demonstrated a high level of effectiveness in reducing bleeding in women with excessive menstrual flow even when medium or large fibroids were present. However, an effect on the size of the fibroids could not be demonstrated.Patient satisfaction with the method is high, which is a prerequisite for continuance of the method, and may be linked with the advantageous design characteristics of the FibroPlant-LNG IUS, the virtual absence of hormonal side effects, and the low incidence of irregular bleeding and spotting even during the first 3 months after insertion of the FibroPlant IUS. Counseling remains important though to explain to women about the possible occurrence of changes in their menstrual pattern that may sometimes be annoying but harmless.It is concluded that many women over age 40 years could substantially benefit from the advantages of this intrauterine drug delivery technology which provides contraception and treatment of a possible associated condition such as menorrhagia. The treatment also creates the opportunity to pass through the transitional perimenopausal period smoothly and to benefit fully from the advantages hormone replacement therapy offers in terms of treatment of short-term symptoms and long-term prevention by gradually replacing the waning estrogens.     

Intrauterine levonorgestrel delivered by a frameless system, combined with systemic estrogen: acceptability and endometrial safety after 3 years of use in peri- and postmenopausal women.

OBJECTIVE: To evaluate the acceptability and endometrial safety of a novel intrauterine drug delivery system, FibroPlant-levonorgestrel (LNG), combined with estrogen therapy (ET) in 150 peri- and postmenopausal women, followed-up for at least 3 years. DESIGN: This was a prospective, non-comparative study in peri- and postmenopausal women. In the majority of women, treatment with the FibroPlant-LNG intrauterine system (IUS), combined with ET, was initiated during the perimenopausal transitional phase to establish a smooth transition to menopause and suppress the endometrium to prevent endometrial proliferation and bleeding. A 3.5-cm long coaxial fibrous delivery system, delivering approximately 14 microg LNG/day, was used. The calculated duration of release of the system is at least 3 years. The majority of women received percutaneous 17beta-estradiol (Oestrogel), 1.5 mg daily on a continuous basis, which provides sufficient blood levels of estrogen in most women to suppress climacteric symptoms and protect against bone loss. OUTCOME MEASURES: To measure acceptability, women were asked, after they had the IUS in place for a minimum of 3 years, if they would like to continue the combined regimen and if they would accept renewal of the IUS. Endometrial safety was evaluated by transvaginal ultrasound examination and endometrial biopsy in a subset of 101 women prior to replacement of the IUS. RESULTS: Ninety-four insertions were done in perimenopausal and 56 in postmenopausal women aged between 33 and 78 years. Of the total group of 150 women, 132 women (88.0%) accepted replacement of the IUS and ten are waiting for replacement. This group includes nine women who will receive a second replacement. The number of women continuing the method is 142 (94.6%). Histological examinations conducted on endometrial biopsies from 101 postmenopausal women prior to replacement, after an average period of use of the regimen of 40 months (range 25-50 months), showed predominantly inactive endometrium characterized by pseudodecidual reaction of the endometrial stroma with endometrial atrophia, which is in keeping with the effects seen with a progestogenic compound. There were no specimens showing signs of proliferation. CONCLUSIONS: Results suggest that the frameless FibroPlant-LNG IUS is safe, well tolerated, well accepted and effective in suppressing the endometrium during ET. Intrauterine progestogen administration in postmenopausal women can be regarded as fundamentally advantageous compared with systemically applied progestogens, which may have potentially inherent ill side-effects, especially on the breast and cardiovascular system, as reported in the recent literature.     

Mycobacterial infection in an inner city children's hospital

Childhood tuberculosis is perceived by many as a disease of the past. Experience in a children's hospital serving a deprived population suggested that tuberculosis and other mycobacterial infections were not declining in clinical practice. Fifty three tuberculous and 11 atypical mycobacterial infections were identified between 1978 and 1992. There was no decline in tuberculosis and nine of the 11 atypical infections occurred in the last five years. Altogether 40% of cases of tuberculosis were in non-Asian children; 32% had arrived in the UK or visited family overseas in the previous year; and 38% had a history of tuberculosis contact, usually a close adult relative. Nationally, the previous decline in tuberculosis in all ages has reversed. In the local health districts in London's east end, childhood tuberculosis has also stopped declining and seems to be increasing. It is regrettable that BCG vaccination has been abolished by some districts in the UK, against current recommendations. Childhood tuberculosis is still common in the practice described here, including among children who do not fall into conventionally recognised high risk groups. Inner city dwellers and junior doctors are both highly mobile populations, adding to the risk that paediatricians, particularly those in training, may encounter tuberculosis with little or no previous experience of the condition.