Human natural killer cells mediate killing of intracellular Mycobacterium tuberculosis H37Rv via granule-independent mechanisms.

Despite the continued importance of tuberculosis as a world-wide threat to public health, little is known about the mechanisms used by human lymphocytes to contain and kill the intracellular pathogen Mycobacterium tuberculosis. We previously described an in vitro model of infection of human monocytes (MN) with virulent M. tuberculosis strain H37Rv in which the ability of peripheral blood lymphocytes to limit intracellular growth of the organism could be measured. In the current study, we determined that lymphocyte-mediated killing of intracellular M. tuberculosis occurs within the first 24 h of coculture with infected MN. Natural killer (NK) cells isolated from both purified protein derivative (PPD)-positive and PPD-negative subjects were capable of mediating this early killing of intracellular H37Rv. NK cell-mediated killing of intracellular M. tuberculosis was not associated with the production of gamma interferon. Transferred supernatants of cocultured NK cells and M. tuberculosis-infected MN could not mediate the killing of intracellular M. tuberculosis, and Transwell studies indicated that direct cell-to-cell contact was required for NK cells to mediate the killing of the organism. Killing was not dependent upon exocytosis of NK cell cytotoxic granules. NK cells induced apoptosis of mycobacterium-infected MN, but neither killing of intracellular M. tuberculosis by NK cells nor NK cell-induced apoptosis of infected MN was inhibited by blocking the interaction of FasL and Fas. Thus, human NK cells may mediate killing of intracellular M. tuberculosis via alternative apoptotic pathways.

Electroencephalographic changes induced by a noise generator in tinnitus patients and healthy controls.

The present study was conducted in an attempt to determine whether noise generators (NGs) induce changes of electroencephalographic activity in healthy control subjects and in subjects suffering from tinnitus. The results indicated that the application of an NG, irrespective of its placement, induced a significant increase of the average total power in both the female and male tinnitus groups. However, no significant changes were observed for the male control group. A weak increase of average total power was noted for the female control group with the NG placed either in the left or the right ear. The NG induced significant changes of average power in different frequency bands. In conclusion, the NG-induced electroencephalographic changes were dependent on gender, tinnitus location, and placement of the NG.

Occult breast cancer and axillary mass.

Occult breast cancer presenting with axillary metastases is an unusual presentation and can be a diagnostic and therapeutic challenge. A comprehensive work-up, including mammogram, sonogram, magnetic resonance imaging, and even pathologic examination of the mastectomy specimen may not disclose the primary tumor in up to one third of patients. Traditionally, occult breast cancer is treated with total mastectomy and axillary dissection, but accumulating data suggest that primary breast irradiation following axillary dissection may provide an equivalent survival with the advantage of breast conservation. Occult breast cancer patients are eligible for adjuvant chemotherapy and radiation as stage II/ III node-positive patients would be treated. Overall, the prognosis for occult breast cancer is equivalent to or slightly better than staged counterparts with detectable primary breast tumors.

Electroencephalography correlates in tinnitus.

This study was conducted in an attempt to determine whether the quantitative electroencephalograph activity differs between normal control subjects and subjects suffering from tinnitus. Results indicated that male tinnitus patients as a group had a significantly reduced average total power as compared to control subjects. This finding contrasted with female tinnitus patients, who as a group had a higher average total power as compared to normal female control subjects. Topographical maps (control value-tinnitus value) indicate that with male patients, the frontocentral regions of the brain show the greatest difference. For the female tinnitus patients, the brain regions most affected are the central, parietal, temporal, and occipital regions.

Quantitative electroencephalography and tinnitus: a case study.

We report changes in quantitative electroencephalography activity in a male tinnitus patient when his tinnitus suddenly disappeared. Topographical illustration of the quantitative electroencephalography data showed beta foci in T3 and C4 with tinnitus, which resolved on spontaneous remission of the tinnitus. Comparison of the power spectra in the presence and absence of tinnitus revealed significant changes of a 16-Hz band. Also, a significant increase in alpha power was observed after remission of the tinnitus.

Parenchymal cell proliferation in coronary arteries after percutaneous transluminal coronary angioplasty: a human tissue bank study.

PURPOSE: Restenosis after percutaneous transluminal coronary angioplasty (PTCA) remains a limitation of this technique. Arterial wall cell proliferation is a component of restenosis preventable with intravascular brachytherapy. This study attempts to locate the sites of cellular proliferation after PTCA so as to aid the optimization of this therapy. METHODS AND MATERIALS: Autopsy records from January 1, 1985 through December 31, 1995 were reviewed, and 27 patients who received PTCA prior to death were identified who also had evidence of PTCA on histologic examination of the arterial sections. The sections were subjected to immunohistochemical staining for proliferating cell nuclear antigen (PCNA) to detect the proliferating cells in the arterial sections, followed by image analysis to determine the proliferative index (PI) of all regions and layers of the section. RESULTS: The PI did not differ significantly according to vessel region (plaque, plaque shoulder, or portion of vessel wall with lowest plaque burden), vessel layer (intima, media, adventitia), or evidence of prior PTCA. There was a trend toward a higher PI in young lesions. CONCLUSION: Cell proliferation in the vascular wall after PTCA was found throughout the treated arterial section's axial plane, not only in the periluminal region.

[The effectiveness of oral cyproterone acetate in combination with ethinylestradiol in acne tarda of the facial type]. / Efficacité de l'acétate de cyprotérone oral associé à l'éthinylestradiol dans le traitement de l'acné tardive de type facial.

BACKGROUND: Cyproterone acetate is a potent antiandrogen with strong progestational activity. In combination with ethinyloestradiol, it has been shown to be of clinical benefit to women displaying signs of androgenization, such as acne, seborrhoea and hirsutism. In addition, this combined oestrogen/progestogen preparation provides effective contraceptive protection. OBJECTIVE: The aim of this open-label, multicentre study was to determine the efficacy and tolerability of a preparation containing cyproterone acetate and ethinyloestradiol in women with various grades of facial acne. PATIENTS: A total of 890 women aged from 15 to 50 years with grade I-IV facial acne according to the classification of Plewig and Kligman, participated in the study. METHODS: Patients received six cycles of a preparation containing 2 mg cyproterone acetate and 0.035 mg ethinyloestradiol (EE/CPA). Changes from baseline counts of individual acne lesions (open and closed comedones, papules, pustules, nodes and cysts) were monitored together with the simultaneous presence of seborrhoea and hirsutic signs. Reductions in the number of all and individual lesions were classified as: 75-100%, "very good"; 50-75%, "good"; 25-50%, "moderate"; < or = 25%, "absence of therapeutic effect". Body weight and blood pressure were recorded throughout the study. Adverse events and reasons for premature withdrawal from treatment were documented. RESULTS: A "good" or "very good" therapeutic response (i.e. reduction in the total lesion count of > 50%) was seen in 82.8% (95% CI 80.1-85.5) of patients after six cycles of EE/CPA. A similar response was achieved in the different grades of acne with a significant decrease in the number of all lesions throughout the study (p < 0.05). A greater than 50% reduction in open and closed comedones, papules, pustules, nodes and cysts was observed in 75.6%, 80.0%, 88.4% and 85.1% of patients, respectively. By the end of the study, 64.3% of women displayed a lower grade of acne and only 4.9% experienced exacerbation of the condition. EE/CPA was well tolerated, with only 3.4% of patients discontinuing treatment because of adverse events. The majority of events were described as mild, and their incidence declined as the study progressed. No clinically significant changes in blood pressure and body weight were recorded. CONCLUSION: EE/CPA is an effective treatment for acne of all grades and all types of lesion. The preparation is well tolerated and would appear to be an appropriate treatment for women with these symptoms of androgenization.

Large observational trial of a new low-dose oral contraceptive containing 20 micrograms ethinylestradiol and 100 micrograms levonorgestrel (Miranova) in Germany.

The aim of this observational trial was to obtain clinical data from a large cohort of women using the new low-dose contraceptive (Miranova) and therefore to eliminate the restrictions which are normally present in clinical studies. Data were gathered in a clinical practice setting regarding cycle control and tolerance from women who were using Miranova (20 micrograms ethinylestradiol and 100 micrograms levonorgestrel). A total of 13,085 subjects were initially evaluated for this observational trial; data were available for 12,843 subjects during the treatment cycles. A total of 10,736 subjects (84.2%) completed all six treatment cycles. The method failure (Pearl index), calculated for 70,796 cycles, was 0.44. Cycle control was considered good during the trial; the length of cycle, duration of withdrawal bleeding and intensity of withdrawal bleeding did not significantly change during treatment. Intracyclic bleeding occurred mainly in the first cycle (31.4%) and declined significantly thereafter to a value of 14.5% in the third cycle. In the sixth (final) cycle, the intracyclic bleeding rate was 7.0%. There were no clinically relevant changes in mean systolic blood pressure, mean diastolic blood pressure or body weight. Miranova was shown to be an effective, well-tolerated oral contraceptive with good cycle control.

Bipolar electrosurgical loop excision procedure for cervical intraepithelial neoplasia.

OBJECTIVES: We sought to determine the safety and efficacy of a bipolar electrosurgical loop excision instrument in the diagnosis and treatment of cervical intraepithelial neoplasia (CIN). MATERIALS AND METHODS: Twenty-eight patients underwent treatment for CIN using a 20 x 10-mm bipolar electrosurgical loop device (Valley Forge Scientific, Oaks, PA). A Malis (Valley Forge Scientific) electrosurgical generator unit (60 watts cutting) was used to remove the cervical lesion and transformation zone under colposcopic guidance. Specimens were evaluated for histopathological diagnosis, tissue depth, fragmentation of specimens, mean maximal thermal artifact, and mean maximal endocervical and ectocervical thermal artifact. RESULTS: Final pathology from bipolar electrosurgical loop excision revealed CIN3 (8), CIN2 (4), CIN1 (11), human papillomavirus changes (3), and normal findings (2). Mean operating time was less than 15 minutes, and mean estimated blood loss was less than 10 ml. Average number of tissue pieces was 1.6 (range, 1-4). No complications occurred. Mean maximal thermal artifact was 0.318 mm. Mean endocervical mucosal and ectocervical mucosal thermal artifacts were 0.177 mm and 0.176 mm, respectively. Mean tissue depth of the excised specimen was 0.40 cm. Histopathological diagnosis was possible on all specimens. In five specimens (17.9%), evaluation of the cauterized endocervical margin for CIN was not possible, owing to thermal artifact. No correlation was observed between tissue depth and thermal artifact. CONCLUSION: Bipolar electrosurgical loop excision for the treatment of CIN is a safe and effective alternative to the traditional unipolar electrosurgical loop excision. Thermal artifact did not interfere with histopathological diagnosis, and the presence of artifact at cauterized margins was similar to that reported for historically unipolar specimens. A randomized control trial comparing therapeutic effectiveness of bipolar electrosurgical loop excision and unipolar electrosurgical loop excision is planned.

Gestodene and desogestrel do not have a different influence on concentration profiles of ethinylestradiol in women taking oral contraceptives--results of isotope dilution mass spectrometry measurements.

OBJECTIVES: A new method for the quantitative determination of 17alpha-ethinylestradiol-17beta (EE2) in serum is presented here based on the principle of isotope dilution mass spectrometry (IDMS) with [13C]EE2 as internal standard. The technique was used to determine the concentration profiles of EE2 in the serum of female subjects who had taken oral contraceptives with different progestin components. The method has proved to be very reliable with respect to trueness, specificity, precision and detection sensitivity and offers considerable advantages compared with the immunological methods of measurement used to date. STUDY DESIGN: Forty-seven female volunteers took two different oral contraceptives containing EE2 combined with different progestins in accordance with a cross-over design. After the administration of 30 microg EE2 combined with 75 microg gestodene (EE2/GSD) or 150 microg desogestrel (EE2/DES), blood samples were taken from the subjects on certain days and in certain previously specified cycles in the course of 12 h after medication. RESULTS AND CONCLUSIONS: The biometric analysis of the results showed that the concentration profiles of EE2 were in their statistics, significantly equivalent after the administration of either of the two oral contraceptives. The sometimes contradictory results found in former studies after the administration of the different contraceptives were presumably due to the methodological shortcomings of the radioimmunological measurement technique. With the use of the highly accurate and specific technique of IDMS it can now be unequivocally established that the different progestins in the tested oral contraceptives have no influence on the bioavailability of EE2 (area under EE2 serum concentration curves, as usually defined in pharmacokinetics).

Minimizing the problem of poor compliance in adolescents. Clinical experience with a modern low-dose gestodene-containing oral contraceptive.

Adolescents represent a particularly difficult group with respect to compliance. Not only is incorrect pill intake a common problem, but unnecessary discontinuation also occurs regularly. Reasons for poor compliance are varied, but inadequate information and problems with cycle control and weight gain are particularly important. Choosing a well-tolerated oral contraceptive can help to improve compliance, and clinical experience from a large, multicenter trial suggests that monophasic gestodene (75 micrograms gestodene/30 micrograms ethinylestradiol) is a suitable preparation for this group of women. An investigation of 5,602 adolescents with an average age of 16.4 years found good contraceptive reliability and excellent cycle control. The incidence of spotting and breakthrough bleeding was low and declined during the course of the study. The preparation was tolerated well, and the incidence of adverse events was low, with only 4.4% of women withdrawing from the study due to adverse events. An increase in body weight was uncommon. At the end of the study, 85.0% of adolescents rated monophasic gestodene as good and 9.6% as satisfactory.

A multicenter, uncontrolled clinical investigation of the contraceptive efficacy, cycle control, and safety of a new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel over six treatment cycles.

The aim of the trial was to demonstrate the contraceptive efficacy of a new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel and to observe cycle control and safety. Data from 805 treated women resulted in 4400 treatment cycles. One pregnancy occurred while on the trial medication as a result of method failure, resulting in a Pearl index of 0.29. Cycle control was good, and cycle length as well as duration and intensity of withdrawal bleeding were not significantly changed during the trial. Intermenstrual bleeding usually occurred as spotting and decreased considerably during the treatment phase. Spotting alone was reported in 12.4% of cycles, breakthrough bleeding alone in 4.5% of cycles, and breakthrough bleeding and spotting together in 1.4% of treatment cycles. The rate of absence of withdrawal bleeding declined throughout the trial to 2.4% in cycle 6. There were no serious adverse events related to treatment, and most adverse events were those commonly observed in clinical trials with oral contraceptives. Headache, breast tension, and nausea were reported by 17.3%, 11.0%, and 7.7% of the women, respectively. There were no clinically relevant changes in laboratory parameters, blood pressure, or weight. In this trial, the new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel was shown to be effective, safe, and well tolerated. Cycle control was found to be good and there was a low incidence of adverse events.

PIP: The contraceptive efficacy, cycle control, and safety of a new low-dose oral contraceptive (OC) containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel were investigated in a multicenter clinical study involving 805 German women (average age, 25.6 years) and a total of 4400 treatment cycles. There was one case of method failure, yielding a Pearl index of 0.29. A regular withdrawal bleed occurred in 95.5% of all treatment cycles. Cycle length and the duration and intensity of withdrawal bleeding were not significantly altered by use of the low-dose OC. Spotting alone occurred in 12.4% of treatment cycles and breakthrough bleeding alone was reported in 4.5%; both symptoms occurred in 1.4% of cycles. Headache, breast tension, and nausea were reported by 17.3%, 11.0%, and 7.7% of women, respectively. Only 8.4% of women discontinued OC use due to adverse events. Finally, there were no clinically relevant changes in laboratory parameters, blood pressure, or body weight. Overall, these findings suggest that substantial reductions in the estrogen and progestogen doses of OCs do not compromise contraceptive efficacy or cycle control.

Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 micrograms ethinylestradiol/75 micrograms gestodene and 30 micrograms ethinylestradiol/75 micrograms gestodene, on lipid metabolism in an open randomized trial.

An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile.

Inhibition of ovulation by an oral contraceptive containing 100 micrograms levonorgestrel in combination with 20 micrograms ethinylestradiol.

Twenty-four healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.5 +/- 4.3), were included in a single-center, non-comparative study to investigate the effect on inhibition of ovulation of an oral contraceptive containing 20 micrograms ethinylestradiol in combination with 100 micrograms levonorgestrel. At baseline, during three treatment cycles and post-treatment, ultrasonography was used to examine the ovaries, to measure follicular size, and to measure the thickness of the endometrium. Serum levels of LH, FSH, estradiol, progesterone, total testosterone, free testosterone, SHBG, and CBG were also measured. Compared with treatment cycle 1, an increase in residual ovarian activity (follicle grades 4-5) was observed in cycles 2 and 3. Mean levels of LH, FSH, 17 beta-estradiol and progesterone remained suppressed during treatment. No escape ovulation was observed during the treatment phase of the study and there were no pregnancies. Ovulation was noted to return rapidly in the posttreatment cycle. Subjective and objective tolerance of the present regimen was noted to be good. Results indicate that the monophasic oral contraceptive containing 100 micrograms levonorgestrel combined with 20 micrograms ethinylestradiol effectively inhibits ovulation, providing adequate suppression of ovarian activity.

The influence of the dose of ethinylestradiol in oral contraceptives on follicle growth.

This prospective, randomized comparative clinical study involving 416 women investigated follicle development over a period of 12 oral contraceptive treatment cycles. Women were allocated to two groups, one group (n = 207) received a preparation containing 30 micrograms ethinylestradiol and 75 micrograms gestodene daily, and the other group (n = 209) received 20 micrograms ethinylestradiol and 150 micrograms desogestrel, daily. Follicular development was monitored by transvaginal ultrasonography of the ovaries, during days 18-21 in the pretreatment cycle and in treatment cycles 1, 3, 6, 9 and 12. Follicular development was found to be twice as frequent in the group receiving 20 micrograms ethinylestradiol/desogestrel as in the group receiving 30 micrograms ethinylestradiol/gestodene. For all cycles, follicles of 10-30 mm were found in 18% of women in the desogestrel group, compared with 9.7% in the gestodene group, whilst follicles with a diameter of >30 mm were present in 5% of the desogestrel group compared with 1.9% of the gestodene group. The difference between the treatment groups with respect to follicle diameters of 10-30 mm and >30 mm was statistically significant (p < 0.05 and p < 0.001, respectively). No ruptured follicles were observed in either group throughout the study, suggesting that there was no escape ovulation, however, there was one pregnancy in the desogestrel group that could not be explained either by drug interactions or missed pills. It can be concluded that the ethinylestradiol dose in an oral contraceptive has a significant effect on follicular ovarian activity, and that reducing the dose to 20 micrograms is associated with a significant increase in follicle size.

The importance of management information systems in a managed care environment.

Keys to successful information systems for home care providers are planning and control. With managed care's emphasis on data, agencies need to have information systems that can handle the demands managed care puts on agencies today--planning before hurrying to install a system will ensure control as the managed care contracts add up.

Clinical experience with a modern low-dose gestodene-containing oral contraceptive in adolescents.

This clinical investigation of a low-dose, monophasic gestodene-containing oral contraceptive (75 micrograms gestodene/30 micrograms ethinylestradiol), investigated contraceptive efficacy, tolerability, cycle control and compliance in 5602 adolescents. The investigation was carried out over a period of 6 cycles. The average age of the study population was 16.4 years; however, only 12 women (0.2%) were under the age of 14. With regard to contraceptive efficacy, during the course of the study there were 5 pregnancies, of which 3 were attributed to user failure. Two pregnancies were recorded as method failure, giving a Pearl Index of 0.08. Cycle control with monophasic gestodene was observed to be excellent. The incidence of spotting and breakthrough bleeding was low and declined during the course of the study, as did amenorrhea. The preparation was tolerated well and the incidence of side-effects was low, with only 4.4% of women withdrawing from the study due to adverse events. An increase in body weight was uncommon, and, at cycle 6, 91.2% of women had not gained weight. At the end of the study, 85.0% of women rated monophasic gestodene as good and 9.6% as satisfactory.

Clinical experience with a modern low-dose oral contraceptive in almost 100,000 users.

Efficacy, cycle control, tolerance, and adverse events were studied in a clinical Phase IV study using a new progestogen, gestodene, in an amount of 75 micrograms combined with 30 micrograms ethinylestradiol. The study was performed as a multicenter trial in 96,000 patients over a period of 6 cycles. Half of the patients taking the new preparation were first-time OC users, the other half switched from another OC. With regard to contraceptive efficacy, the life-table analysis showed a value of 0.032% for method failure and 0.114% for patient failure. The correspondent Pearl-Index is 0.062 and 0.22. The new drug was found acceptable by more than 90% of the women involved in the trial. Dysmenorrhea present in the "switchers" mostly disappeared on the new OC, while body weight and blood pressure remained virtually unchanged. Thus, it can be concluded that blood pressure and body weight behaviour is similar to that seen with other low-dose OCs. The new combined pill offers excellent cycle stability and has a very favourable effect on dysmenorrhea. The number of clinically diagnosed thrombotic events documented in this study was 0.65 per 1000 woman-years (TWY) and does not exceed the range of events seen in groups of women using non-hormonal methods of contraception (Oxford-FPA study 0.4/TWY and RCGP study 0.8/TWY).

PIP: Efficacy, cycle control, tolerance, and adverse events were studied in a clinical phase IV study using a new progestogen, gestodene, in an amount of 75 mcg combined with 30 mcg ethinyl estradiol. The study was performed as a multicenter trial in 96,000 patients over a period of 6 cycles. 1/2 of the patients taking the new preparation were 1st-time OC users, the other 1.2 switched from another OC. With regard to contraceptive efficacy, the life table analysis showed a value of 0.032% for method failure and 0.114% for patient failure. The correspondent Pearl Index is 0.062 and 0.22. The new drug was found acceptable by more than 90% of the women involved in this trial. Dysmenorrhea present in those who switched disappeared for the most part with this new OC, while body weight and blood pressure remained virtually unchanged. Thus, it can be concluded that blood pressure and body weight behavior is similar to that seen with other low-dose OCs. The new combined pill offers excellent cycle stability and has a very favorable effect on dysmenorrhea. The number of clinically diagnoses thrombotic events documented in this study was 0.65/1000 woman-years (TWY) and does not exceed the range of events seen in groups of women using nonhormonal methods of contraception (Oxford-FPA study 0.4/TWY and RCGP study 0.8/TWY).

Clinical experience with a low-dose oral contraceptive containing gestodene.

The monophasic combination preparation containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene was tested for contraceptive reliability, cycle control and tolerability in a total of seven phase III clinical studies. A total of 6,854 women were included in these studies, and 69,978 cycles were monitored. Following the commercial introduction of the preparation, further clinical data were obtained with a broader user population. In Germany it was possible to implement an extraordinarily extensive phase IV study in a very short period of time. A total of 523,477 treatment cycles in 95,906 women were included in the analysis. So, for what is probably the first time, a prospective general clinical study for an oral contraceptive was conducted of the same magnitude as the biggest cohort epidemiologic studies. The results of the various phase III and phase IV studies are in close agreement. The combination preparation containing gestodene proved to have high contraceptive reliability and gave excellent cycle control. It was well tolerated and the frequency of adverse reactions was low. To summarize, the monophasic gestodene completely fulfills the demands made of oral contraceptives today.