Selection of oral contraceptives or hormone replacement therapy: patient communication and counseling issues.

Oral contraceptives and combination hormone replacement therapy are underused by most women. Among users, lack of compliance/adherence to oral contraceptive or hormone replacement therapy regimens can lead to discontinuation and deprive women of the full range of benefits achieved through hormone continuity. To prevent unintended pregnancy and to improve the health outcomes of women of all ages and the overall quality of life, adherence and continuation rates need to be improved for oral contraceptive and hormone replacement therapy use. Effective communication and counseling during the oral contraceptive and hormone replacement therapy regimen selection process and subsequent follow-up interactions are essential. Patients need to be informed in a clear and concise manner that, for most women, the benefits of oral contraceptives and hormone replacement therapy outweigh any associated health risks. Data should be presented without epidemiologic jargon and in terms that are easily understood. It is recommended that realistic expectations concerning the possible side effects, especially during the initial use of hormones, are established before use; furthermore, the selection of a formulation should take into account the unique needs of each patient.

Cloning, sequencing, and functional characterization of the rat homologue of receptor activator of NF-kappaB ligand.

A complementary DNA (cDNA) encoding the rat homologue of receptor activator of NF-kappaB ligand/osteoprotegerin ligand/osteoclast differentiation factor/tumor necrosis factor (TNF)-related activation-induced cytokine (RANKL/OPGL/ODF/TRANCE) was cloned and sequenced from tibias of ovariectomized (OVX) rats. The predicted amino acid sequence of rat RANKL (rRANKL) has 84% and 96% identity to that of human and mouse RANKL, respectively, and 35% and 37% similarity to that of human and mouse TNF-related apoptosis-inducing ligand (TRAIL), respectively. RANKL transcripts were expressed abundantly in the thymus and bone tissues of OVX rats. rRANKL has a single hydrophobic region between residues 53 and 69, which is most likely to serve as a transmembrane domain. The long C-terminal region containing beta-sheet-forming sequences of the TNF-like core is considered the extracellular region. Three truncated domains within the TNF-like core region were expressed as glutathione S-transferase (GST) fusion proteins and investigated for their ability to induce osteoclastogenesis. The results showed that GST-rRANKL (aa160-318) containing the full TNF-like core region had the highest capability to induce the formation of osteoclast-like cells from RAW264.7 cells. GST-rRANKL (aa239-318 and aa160-268) had lesser degrees of osteoclast inductivity. Furthermore, the GST-rRANKL (aa160-318) is capable of (1) inducing osteoclast formation from rat spleen cells in the presence of macrophage colony-stimulating factor (M-CSF), (2) stimulating mature rat osteoclast polarization and bone resorption ex vivo, and (3) inducing systemic hypercalcemia in vivo; thus the full TNF-like core region of rRANKL is an important regulator of calcium homeostasis and osteoclastic function.

Gene expression of vascular endothelial growth factor in giant cell tumors of bone.

The production of vascular endothelial growth factors (VEGF), a major cause of neoangiogenesis, is a prerequisite for tumor growth and invasion. VEGF have also been shown to be important for the formation of osteoclasts. Because giant cell tumors of bone (GCT) are frequently hypervascular and have the ability to recruit macrophages and multinucleated osteoclast-like giant cells, we evaluated the levels of VEGF gene transcript in several of these tumors using Northern blot analyses, semiquantitative reverse transcription polymerase chain reaction (RT-PCR), fluorescence in situ hybridization (FISH), and immunohistochemistry. Our results showed that three major isoforms of VEGF (121, 165, and 189) were expressed in all cases of GCT investigated, with isoform 121 transcripts the most abundant. By both FISH and immunohistochemistry, we have shown that VEGF was present in spindle-shaped stromal-like tumor cells, round macrophage-like cells, and osteoclast-like multinucleate giant cells. Moreover, we have shown that the levels of VEGF gene expression but not microvessel density correlated with Enneking's clinical stage of GCT. There were higher levels of VEGF gene expression in stage III GCT than in stage I/II GCT (P < .0357). In conclusion, our results indicate that overexpression of VEGF may be associated with the advanced stage of the neoplasm.

Treating vaginitis.

Vaginitis resulting from bacterial, fungal, or protozoal infections can be associated with altered vaginal discharge, odor, pruritus, vulvovaginal irritation, dysuria, or dyspareunia, depending on the type of infection. Bacterial vaginosis, which is primarily characterized by a malodorous discharge, is common in women with multiple sex partners and is caused by the overgrowth of several facultative and anaerobic bacterial species. Vulvovaginal candidiasis is characterized by pruritus and a cottage cheese-like discharge. Vaginal trichomoniasis, a sexually transmitted disease caused by an anaerobic protozoan parasite, is associated with a copious yellow or green, sometimes frothy, discharge. Differential diagnosis of these infections requires a thorough history, vulvovaginal examination, and simple laboratory tests, including microscopy of the vaginal discharge. The information obtained from this workup should enable an accurate diagnosis. Topical or oral metronidazole is the treatment of choice for bacterial vaginosis; terconazole, or other antifungals, for vulvovaginal candidiasis; and oral metronidazole for trichomoniasis.

The changes seen in balloon-injured porcine femoral arteries following sympathectomy.

On the basis that vasoconstriction may contribute to restenosis following angioplasty, the influence of lumbar sympathectomy on the morphometry of femoral arteries after balloon injury was examined in a pig model. Twenty-six juvenile pigs underwent balloon de-endothelialization of the right femoral artery followed by an open bilateral lumbar sympathectomy (n = 14) or a sham sympathectomy (n = 12). Four weeks later flow was measured in femoral arteries. Animals were then killed and the femoral arteries were perfusion-fixed and harvested. Sympathectomy resulted in a significant (P = 0.04) increase in flow in both the injured (right) and uninjured (left) femoral arteries. Sympathectomy did not inhibit intimal thickening following balloon injury: median (interquartile range) intimal area was 0.4 mm2 (0.3-0.9) in the sympathectomy group versus 0.5 mm2 (0.4-0.9) in the sham group. Sympathectomy did, however, result in a significant (P = 0.02) increase in the lumen area: 1.1 mm2 (0.8-1.8) versus 0.7 mm2 (0.6-0.9). Sympathectomy may reduce vasospasm following angioplasty with the potential for clinical benefit.

Clinician/patient interaction: communicating the benefits and risks of oral contraceptives.

Myths and misperceptions continue to influence women's opinions about oral contraceptives (OC), despite the immense body of evidence regarding OC safety and efficacy. Patient opinions about OC failure rates and health risks are often far from proven fact, and the health benefits of OC are too often unrecognized. Because successful OC use requires an informed patient, effective communication between clinicians and their patients is needed to correct misinformation, relieve unnecessary fears, and increase OC use. A variety of interactive counseling skills and attitudes can improve the process of patient counseling; they are especially crucial for adolescents, who may be reluctant or unable to easily articulate their concerns. Counseling messages can be geared specifically to the interests and concerns of particular age groups: adolescents, young adults, and perimenopausal women. With thoughtful planning and involvement of all members of the healthcare team, clinicians can create time and opportunities for the provision of consistent, appropriate counseling to all candidates for OC use.

Does smoking affect efficacy of the pill? Ask the experts.

PIP: This article presents insights on the efficacy of oral contraceptives (OCs) in women who smoke. It presents opinions of three Contraceptive Technology Update board members, namely, Dr. Michael Rosenberg, Dr. Andrew Kaunitz, and Susan Wysocki. Two lines support that the anti-estrogenic effect of smoking reduces the effectiveness of OCs. First, several studies indicate that spotting and bleeding were more frequent in smokers. Smoking reduces estrogen levels in the body; hence smokers experience irregular bleeding with the pill. This is the reason why smokers are at a higher risk of developing osteoporosis in the later years. Breakthrough bleeding also demonstrates higher OC failure rates among smokers. A single study on the efficacy of OCs in smokers revealed a highly diminished effectiveness of the pill in this group. Second, laboratory analysis indicates that estrogen increases the catabolism of estrogen, providing a rationale for these observed effects. The use of low-dose pills in smokers is guided by safety concerns since smoking enhances the development of thrombosis. A balance of the safety and efficacy risks is necessary especially with the increasing use of low-dose OCs.^ieng

Gene expression of monocyte chemoattractant protein-1 in giant cell tumors of bone osteoclastoma: possible involvement in CD68+ macrophage-like cell migration.

Giant cell tumor of bone (GCT) is one of a few neoplasms in which the macrophage/osteoclast precursor cells and osteoclast-like giant cells infiltrate the tumor mass. Monocyte chemoattractant protein 1 (MCP-1) is a potent chemotactic factor specific for monocytes. In search of relevant cytokines that may enhance the recruitment of these reactive cells, we evaluated the localization and regulation of MCP-1 mRNA and protein in GCT by using Northern blot analysis, in situ hybridization and immunohistochemistry. We also determined whether conditioned medium obtained from GCT cultures can recruit human peripheral blood monocytes (CD68+) in an in vitro chemotactic assay. Using Northern blot analysis, we detected the specific gene transcript for MCP-1 in all GCT samples tested. In situ hybridization and immunohistochemistry revealed that both MCP-1 gene transcript and protein were consistently present in the cytoplasm of stromal-like tumor cells of GCT. Treatment of mononuclear cells from GCT at third passage with TGF-beta1 for 24 h increased the level of MCP-1 mRNA in a dose-dependent manner, with the maximum effect at 1 ng/ml. Conditioned media from GCT cultures promoted the chemotactic migration of CD68+ peripheral monocytes, an activity which was abolished by the addition of MCP-1 antibody to the conditioned medium. Thus, the results of this study suggest that recruitment of CD68+ macrophage-like cells may be due to the production MCP-1 by stromal-like tumor cells. These CD68+ cells may originate from peripheral blood and could have the capability of further differentiating into osteoclasts in the tumor.

Improving patient success with oral contraceptives: the importance of counseling.

Oral contraceptives (OCs) are highly effective in protecting against pregnancy if used correctly and consistently. They also offer noncontraceptive health benefits. The prescriber must understand the myriad factors contributing to success with OCs and other birth control methods, including characteristics and habits of successful users, real and perceived fears about adverse effects, and packaging issues. A woman's experiences with previous methods influence later success or failure with OCs.

PIP: Individualized counseling is an essential prerequisite to effective, consistent oral contraceptive (OC) use. Prescribers must understand the many factors that determine OC compliance, including characteristics and habits of individual users, a woman's experience with previous contraceptive methods, real and perceived fears about adverse effects such as menstrual irregularities, and packaging features that can impede or facilitate proper usage. A new OC user should be seen again in 2-3 months to assess her pill-taking habits. Continuing users can benefit from reminders to take the pill at the same time every day, to keep a supply of extra pills and back-up contraception, to use condoms with new partners, and to reread periodically the patient education handouts. Included with this article is a two-page sample patient education handout on OC instructions and information.

Vascular endothelial growth factor (VEGF) expression during arterial repair in the pig.

OBJECTIVES: Vascular endothelial growth factor (VEGF) is reported to be a potent and specific mitogen for endothelial cells (EC) and an inducer of angiogenesis in vivo. Originally called vascular permeability factor (VPF), VEGF also increases permeability of microvessels to circulating macromolecules. The aim of this study was to examine whether the VEGF gene was expressed in porcine arteries following denudation of EC. DESIGN: Experimental animal model with mechanical injury to large arteries. METHODS: The right iliac artery of juvenile pigs was de-endothelialised using an inflated balloon catheter. At a number of time-points after injury, these arteries were harvested together with uninjured contralateral arteries. Sections of arteries were used for RNA analysis by Northern blots and for protein localisation studies by immunohistochemistry. RESULTS: Two VEGF transcripts (2.0 kb, 4.5 kb) were markedly elevated in pig arteries soon after injury. Newly synthesised VEGF protein was located in smooth muscle cells (SMC) throughout the media of injured arteries. CONCLUSIONS: The elevated expression of VEGF by SMC in denuded porcine arteries is evidence that this cytokine plays a role in the injury response of large arteries. Since several biological activities have been identified for VEGF, the function of this cytokine in the arterial repair process remains to be determined.

Frequent urination and Depo-Provera. Ask the experts.

PIP: This "Ask the Experts" column addresses two concerns related to use of Depo-Provera. The first question relates to the clinical significance of frequent urination. Two of the three experts assert that frequent urination in a Depo-Provera user is unlikely to be related to method use; urinary tract infection and diabetes are more probable causes. The third notes that hypoestrogenicity could be a factor and suggests examination of the vagina for atrophy, which could cause the tissue around the urethra to become atrophic. The second question addresses techniques for confirming menopause in Depo-Provera users. The experts concur that measurement of follicle-stimulating hormone in perimenopausal Depo-Provera users lacks predictive value. Recommended, instead, is continuation of Depo-Provera with supplemental estrogen until the woman is in her mid-50s. At that time, conventional hormone replacement therapy can be initiated.^ieng

Severe abdominal pain and thrombocytopenia--typical symptoms of occult jejunal diverticulum perforation?

Complicated small-bowel diverticula cause abdominal pain, gastrointestinal hemorrhage, small-bowel obstruction, and peritonitis. The present patient, had an occult perforation of a small-bowel diverticulum. There were diverticula throughout the whole small bowel. Preoperatively thrombocytopenia (98,000 thrombocytes/cc), was noted. Without any special treatment, i.e., transfusion, the thrombocyte level increased after surgical treatment to normal levels. Although the incidence of small-bowel diverticula appears to be low (0.1%-2.3%) complications may become life-threatening. The level of thrombocytopenia may reflect the extent of inflammation.

Morphometric changes seen in balloon-injured porcine iliac arteries: the influence of sympathectomy on intimal hyperplasia and remodelling.

OBJECTIVES: To assess the influence of lumbar sympathectomy on intimal thickening and arterial remodelling following balloon de-endothelialisation. DESIGN: Experimental animal model with control and treated (sympathectomy) groups. METHODS: Unilateral common iliac artery de-endothelialisation was performed in 36 male pigs using a 5F balloon catheter introduced via the profunda femoris artery. Bilateral lumbar sympathectomies were performed in 18 animals. Both iliac arteries were perfusion-fixed and harvested 4 weeks later. Arterial morphometry was assessed using computer image analysis. RESULTS: Area measurements are expressed as median (interquartile range) in mm2. Balloon injury resulted in significant intimal thickening but no loss of lumen due to compensatory enlargement of the injured artery. Sympathectomy resulted in significant lumen enlargement (4.8 (2.6-6.3) vs. 1.9 (1.7-2.9)) in balloon-injured arteries. Although intimal thickening was reduced (0.9 (0.6-1.7) vs. 1.5 (0.9-2.0)), this was not statistically significant. CONCLUSIONS: Sympathectomy increases lumen area 4 weeks after balloon injury to porcine iliac arteries. This effect is due to a combination of reduced arterial wall thickening and increased arterial size.

Monocyte chemoattractant protein-1 gene expression in injured pig artery coincides with early appearance of infiltrating monocyte/macrophages.

Monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) are potent chemokines which attract circulating monocytes and neutrophils respectively to inflamed tissues. JE/MCP-1 gene expression has been previously studied in rabbit aortae after endothelial denudation and the rapid appearance of this transcript was thought to precede emigration of phagocytes. We now report MCP-1 gene expression following de-endothelialization of iliac arteries in the pig, a species which can develop spontaneous atherosclerosis. Using Northern blot analysis, we demonstrated that MCP-1 mRNA was rapidly induced in pig arteries at 2 h and continued to increase to reach a maximum at 8 h before returning to low levels at 16-24 h after injury. The increase seen for MCP-1 mRNA at 8 h was also observed for IL-8 mRNA but was not apparent for growth-related gene expressions, urokinase-type plasminogen activator (u-PA), and plasminogen activator inhibitor-1 (PAI-1). Since smooth muscle cells, endothelial cells, and phagocytes are all capable of expressing MCP-1, we examined pig arteries for immunostaining using a monoclonal antibody to human MCP-1 (5D3-F7). At 8 h after injury, the predominant cell type staining positive for MCP-1 was the monocyte/macrophage. Staining was also observed in occasional scattered neutrophils, but MCP-1 protein could not be detected in smooth muscle cells or on extracellular matrix within the sensitivity constraints posed by our methodology. Our results are consistent with invading monocyte/macrophages having a major input into the production of this chemokine in the arterial wall following injury. The fact that MCP-1 expression accompanied monocyte/macrophage presence in damaged artery, rather than preceding it, is suggestive that continued MCP-1 expression is required for functions other than chemoattraction.

Overexpression of p53 protein is an independent prognostic indicator in human endometrial carcinoma.

The important role of the p53 gene in tumour progression and cellular response to DNA damage has prompted investigation of the clinical significance of alterations to this gene. We examined both p53 overexpression and mutation of the gene in endometrial carcinoma in order to evaluate the prognostic significance of these changes. Of 122 endometrial carcinomas, 33 (27%) showed overexpression of p53 in the nucleus and 66 (54%) in the cytoplasm. Mutation in the p53 gene was found in 16 (13%) cases but showed no significant association with patient survival. Nuclear p53 overexpression was associated with poor survival (48% vs 80% alive in negative tumours 5 years post operatively, P < 0.001). In contrast, cytoplasmic p53 overexpression was associated with better survival (85% vs 55%, P < 0.001). When patients were separated into prognostic subgroups according to established clinical markers, these associations remained significant within most subgroups examined. In multivariate analysis adjusted for surgical stage, histological grade and type and vascular invasion, both nuclear p53 overexpression [hazard ratio 4.9 (95% CI 1.3-17.6). P = 0.016] and cytoplasmic overexpression [0.25 (0.06-0.98), P = 0.047] were independent prognostic factors. Immunohistochemical assessment of p53 overexpression in the nucleus and cytoplasm could provide useful prognostic information for the management of patients with endometrial cancer.

Vitamin D3 exacerbates intimal hyperplasia in balloon-injured arteries.

Although a high dose of vitamin D3 is known to cause arterial calcification and degeneration, its effect on intimal hyperplasia has never been studied. The aim of this study was to examine the influence of a moderate supplement of vitamin D3 on intimal hyperplasia in the balloon-injured rat carotid artery. Forty-four rats had balloon injury to the carotid artery; 22 were given oral vitamin D3 supplementation (0.25 microgram kg-1 day-1). Animals were killed at 4 weeks and the carotid arteries were perfusion fixed and assessed morphometrically by means of computerized image analysis of transverse sections. Mean (s.e.m.) intimal area was significantly greater in the vitamin D3-treated animals than in controls: 0.92(0.05) versus 0.71(0.07) mm2 (P = 0.02). The area of the media of both injured and uninjured arteries was not influenced by vitamin D3 administration. A small dose of vitamin D3 resulted in significant exacerbation of intimal hyperplasia in this rat carotid artery model and raises the question of the role of dietary vitamin D3 in restenosis following vascular intervention.