Clinical inertia.

Medicine has traditionally focused on relieving patient symptoms. However, in developed countries, maintaining good health increasingly involves management of such problems as hypertension, dyslipidemia, and diabetes, which often have no symptoms. Moreover, abnormal blood pressure, lipid, and glucose values are generally sufficient to warrant treatment without further diagnostic maneuvers. Limitations in managing such problems are often due to clinical inertia-failure of health care providers to initiate or intensify therapy when indicated. Clinical inertia is due to at least three problems: overestimation of care provided; use of "soft" reasons to avoid intensification of therapy; and lack of education, training, and practice organization aimed at achieving therapeutic goals. Strategies to overcome clinical inertia must focus on medical students, residents, and practicing physicians. Revised education programs should lead to assimilation of three concepts: the benefits of treating to therapeutic targets, the practical complexity of treating to target for different disorders, and the need to structure routine practice to facilitate effective management of disorders for which resolution of patient symptoms is not sufficient to guide care. Physicians will need to build into their practice a system of reminders and performance feedback to ensure necessary care.

Liquid crystal alignment on carbonaceous surfaces with orientational order.

We used near-edge x-ray absorption fine structure (NEXAFS) spectroscopy to link the orientational bond order at three carbonaceous surfaces-rubbed polyimide, ion beam-irradiated polyimide, and ion beam-irradiated diamondlike carbon films-with the direction of liquid crystal (LC) alignment on these surfaces. We show that, in general, LC alignment can be created on any carbonaceous substrate by inducing orientational order at its surface. Our results form the scientific basis for LC alignment layers consisting of amorphous carbon films in which orientational order near the surface is induced by a directional low-energy ion beam.

Domestic violence and sexual abuse in women physicians: associated medical, psychiatric, and professional difficulties.

Physicians have been called on to identify victims of domestic violence (DV) and sexual abuse (SA). Few data exist, however, on the prevalence of DV and SA in physicians themselves or on the personal or professional sequelae of such experiences. We determined the reported lifetime prevalence of DV and SA among women physicians and the personal characteristics, health-related factors, and work-related factors associated with these forms of abuse. We used data from the Women Physicians' Health Study, a large (n = 4501 respondents), nationally distributed questionnaire study that included questions on DV and SA histories, personal characteristics, and psychiatric, medical, and work-related histories. We compared the characteristics of women physicians with and without histories of DV or SA. The logistic models indicate that women physicians reporting DV histories (3.7% of the population) were significantly (p < 0.05) less likely to be single and significantly more likely to report depression histories, suicide attempts, substance abuse, current or past cigarette smoking, severe daily stress at home, chronic fatigue syndrome, and DV experienced by their mothers. Women physicians reporting SA histories (4.7% of the population) were significantly more likely to be younger than 60 years, identify themselves as homosexual or bisexual, to have specialized in psychiatry, obstetrics and gynecology, or emergency medicine, and to report histories of depression, suicide attempts, eating disorders, and fair or poor perceived health status. Although the reported lifetime prevalence of DV and SA among women physicians is below other reported figures, such experiences are associated with medical and psychiatric difficulties that could negatively affect them personally and professionally.

Changing patterns of gene expression identify multiple steps during regression of rat prostate in vivo.

The rat ventral prostate is an androgen-dependent organ that undergoes dramatic cell death upon removal of testosterone by surgical castration. Several well characterized criteria, such as nuclear condensation, organelle blebbing, and DNA fragmentation, have been used to demonstrate that most of this cell loss is due to programmed cell death, or apoptosis, of the secretory epithelial cells. In addition to changes in morphology, it is well known that cells undergoing apoptosis show alterations in gene expression, and it is widely assumed that many of these genes are directly involved in the mechanism of programmed cell death. Using poly A+ RNA derived from normal rat prostate as well as from the regressing prostates of castrated rats, we have used a PCR-based subtractive hybridization approach to generate complementary DNA (cDNA) libraries greatly enriched in cDNAs strongly regulated during rat prostate regression. Several hundred of the genes represented in these libraries appear to be strongly regulated during prostate regression and most of these are prostate specific. Sequence analysis indicates that up to 30% of these clones are similar or identical to genes of known function, approximately 20% are similar to expressed sequence tags (ESTs), and as many as 50% of these clones have not been characterized previously. Analysis of selected clones using in situ hybridization indicates that they are expressed specifically in prostate epithelial cells, and that certain of these clones are regulated temporally in a pattern consistent with apoptosis. The patterns of gene expression include: 1) genes whose expression decreases uniformly after removal of androgen, indicative of androgen sensitive genes; 2) genes whose expression increases in apoptotic prostate cells and in other tissues, suggesting a class of genes generally involved in apoptosis; 3) and genes whose expression increases in individual regressing prostate epithelial cells, suggesting a class of prostate specific genes associated with apoptosis.

Crystal structure of the extracellular domain from P0, the major structural protein of peripheral nerve myelin.

P0, the major protein of peripheral nerve myelin, mediates membrane adhesion in the spiral wraps of the myelin sheath. We have determined the crystal structure of the extracellular domain from P0 (P0ex) at 1.9 A resolution. P0ex is folded like a typical immunoglobulin variable-like domain; five residues at the C-terminus are disordered, suggesting a flexible linkage to the membrane. The requirements for crystallization of P0ex are similar to those for maintaining the native extracellular spacing of adjacent myelin lamellae; thus, given the self-adhesive character of P0ex, the crystal itself may reveal some of the natural interactions that occur between P0 molecules in myelin. The structure leads to the suggestion that P0 extracellular domains may emanate from the membrane surface as tetramers that link to tetramers on the opposing membrane surface, to result in the formation of networks of molecules. We report analytical ultracentrifugation data for P0ex that support this idea.

Breast and cervical cancer screening in an inner-city medical walk-in clinic: taking advantage of an often missed opportunity.

BACKGROUND: Despite established evidence that screening for breast and cervical cancer reduces mortality in women, screening is underutilized, especially in poor, minority women. We hypothesized that a high percentage of women presenting for care to an inner-city medical walk-in clinic would report inadequate screening for breast and cervical cancer by current standards, accept same-day screening, and comply with recommended follow-up. METHODS: To determine how many women presenting to our medical Walk-In Clinic were inadequately screened for breast and cervical cancer and how many were willing to undergo same-day screening, we surveyed all women at this site over a three month period. We then implemented a one-year, same-day screening program and contacted patients with abnormal screening results by letter or phone to encourage follow up. We tracked patients to assess compliance with follow-up. RESULTS: Of the 2,363 women in the initial survey, 1,230 (52%) reported inadequate screening, of whom 55% reported interest in same-day screening. Over the one year screening period, we screened 403 women for breast and/or cervical cancer. Of the 48 women with abnormal Pap tests, compliance with initial Gynecology Clinic follow-up was 56%. Compliance was 49% with mammography appointments, and 77% for follow-up to Breast Clinic for clinical and/or mammographic abnormalities. These compliance rates compare favorably to those for screening performed in more traditional settings. CONCLUSION: Our results support the establishment of cancer screening programs in nontraditional settings such as walk-in clinics and emergency departments to target patients who are at high risk for remaining unscreened.

Protein zero, a nervous system adhesion molecule, triggers epithelial reversion in host carcinoma cells.

Protein zero (P(o)) is the immunoglobulin gene superfamily glycoprotein that mediates the self-adhesion of the Schwann cell plasma membrane that yields compact myelin. HeLa is a poorly differentiated carcinoma cell line that has lost characteristic morphological features of the cervical epithelium from which it originated. Normally, HeLa cells are not self-adherent. However, when P(o) is artificially expressed in this line, cells rapidly aggregate, and P(o) concentrates specifically at cell-cell contact sites. Rows of desmosomes are generated at these interfaces, the plasma membrane localization of cingulin and ZO-1, proteins that have been shown to be associated with tight junctions, is substantially increased, and cytokeratins coalesce into a cohesive intracellular network. Immunofluorescence patterns for the adherens junction proteins N-cadherin, alpha-catenin, and vinculin, and the desmosomal polypeptides desmoplakin, desmocollin, and desmoglein, are also markedly enhanced at the cell surface. Our data demonstrate that obligatory cell-cell adhesion, which in this case is initially brought about by the homophilic association of P(o) molecules across the intercellular cleft, triggers pronounced augmentation of the normally sluggish or sub-basal cell adhesion program in HeLa cells, culminating in suppression of the transformed state and reversion of the monolayer to an epithelioid phenotype. Furthermore, this response is apparently accompanied by an increase in mRNA and protein levels for desmoplakin and N-cadherin which are normally associated with epithelial junctions. Our conclusions are supported by analyses of ten proteins we examined immunochemically (P(o), cingulin, ZO-1, desmoplakin, desmoglein, desmocollin, N-cadherin, alpha-catenin, vinculin, and cytokeratin-18), and by quantitative polymerase chain reactions to measure relative amounts of desmoplakin and N-cadherin mRNAs. P(o) has no known signaling properties; the dramatic phenotypic changes we observed are highly likely to have developed in direct response to P(o)-induced cell adhesion. More generally, the ability of this "foreign" membrane adhesion protein to stimulate desmosome and adherens junction formation by augmenting well-studied cadherin-based adhesion mechanisms raises the possibility that perhaps any bona fide cell adhesion molecule, when functionally expressed, can engage common intracellular pathways and trigger reversion of a carcinoma to an epithelial-like phenotype.

Developmental regulation of multiple nicotinic AChR channel subtypes in embryonic chick habenula neurons: contributions of both the alpha 2 and alpha 4 subunit genes.

Habenula neurons from both early and late stage embryonic chickens express multiple subtypes of nicotinic acetylcholine receptor channels (nAChRs). The channel subtypes expressed by habenula neurons are similar in functional properties, but apparently distinct in subunit composition, from their peripheral counterparts in autonomic ganglia. Early in development, nicotine activates four classes of neuronal bungarotoxin (nBGT)-sensitive channels (approx. conductance = 15, 30, 50, 60pS) that are intermingled on the surface of habenula neuronal somata. In neurons removed from older animals, nAChR channel activity has increased 4- to 40-fold and channel subtypes have become spatially segregated from one another. Analysis of the profile of nAChR subunit gene expression by polymerase chain reaction indicates that several of the alpha-type subunit genes, including alpha 2,3,4,5,7, and alpha 8, as well as both beta 2 and beta 4, are expressed. Treatment of the neurons with subunit specific antisense oligonucleotides reveals that the alpha 2 and alpha 4 (but not alpha 3) subunits contribute to the functional profile of native nAChRs expressed by habenula neurons. Consideration of the functional properties and apparent subunit composition of autonomic ganglion nAChRs in the chick suggests that habenula neurons may utilize a very distinct set of subunit combinations to produce an array of nAChR channel subtypes similar in both conductance and pharmacological profile to those expressed by sympathetic neurons.

Laparoscopic cholecystectomy: potential for missed pathology.

The performance of a general exploratory laparotomy immediately after opening the abdominal cavity has long been a foundation of surgical practice. Since the introduction of laparoscopy, this procedure has been modified. This may result in certain intra-abdominal pathologies being overlooked, especially in areas that are hard to observe with the laparoscope. In this paper we describe two patients who presented with carcinomas after uneventful laparoscopic procedures, one of the lower oesophagus and the other of the pancreas. This raises questions about the extent of preoperative investigation before the performance of laparoscopic procedures.

Glial-neuron interactions and the regulation of myelin formation.

The association between neuron and glial cell that leads to the formation of a myelinated axon depends on a number of adhesion/recognition molecules whose temporal expression, localization, and in some cases removal are critical for sculpting the mature myelin sheath.

Verification of a formula for determination of preexcision surgical margins from fixed-tissue melanoma specimens.

BACKGROUND: Recently our group reported on the shrinkage of 199 malignant melanoma surgical-excision specimens. In that report, a multivariate analysis revealed that the age of the patient was the only factor that significantly affected the percentage shrinkage of a surgical specimen. In addition, a formula was presented that extrapolates the actual surgical margins (in vivo) from the (contracted) fixed-tissue pathology report measurement and the reported in vivo lesion diameter. OBJECTIVE: The goals of this study are to verify that shrinkage of surgical specimens is approximately 20% and that the margin formula can be successfully applied to a different group of patients. METHODS: Four hundred seven patients with malignant melanoma were prospectively enrolled to measure preexcision (outlined with ink) surgical margins, fixed-tissue (contracted) surgical margins, and overall specimen shrinkage. RESULTS: It is verified that overall shrinkage of cutaneous surgical specimens is approximately 20%. Surgical specimens from patients younger than 50 years of age have approximately 25% shrinkage. Those specimens from patients 50 to 59 years of age have approximately 20% shrinkage and those from patients 60 years of age or older have about 15% shrinkage. The surgical margins predicted by the margin formula were within +/- 3.5 mm of the actual measured surgical margin 86.5% of the time. CONCLUSION: The actual surgical margins (in vivo) of a malignant melanoma can be reasonably estimated from the fixed-tissue pathology measurement via the margin formula. The shrinkage of a surgical specimen is 15% to 25% depending on the patient's age.

Determination of preexcision surgical margins of melanomas from fixed-tissue specimens.

The shrinkage of cutaneous surgical specimens of 199 malignant melanomas was analyzed. A formula was derived that makes it possible to calculate the in vivo (preexcision) specimen diameter from the in vitro (fixed-tissue) specimen diameter. The age of the patient was found to significantly influence specimen shrinkage and was incorporated into this shrinkage formula. The calculated in vivo specimen diameter was then used to determine the width of the in vivo surgical margins with reasonable accuracy. Thus this method permits calculation of the width of surgical margins from fixed-tissue specimens.

Outpatient termination of pregnancy: halothane or alfentanil-supplemented anaesthesia.

Inhalation anaesthesia with halothane was compared with i.v. alfentanil in 66 unpremedicated patients undergoing suction termination of pregnancy as outpatients. Blood loss was significantly greater in the halothane group with a mean loss of 213 ml, compared with a mean loss of 89.8 ml in the alfentanil group. There was a greater frequency of nausea and vomiting in the alfentanil group, but no reduction in abdominal pain or need for analgesia after operation. Positive relationships were found between blood loss and duration of anaesthesia and between blood loss and gestational age in the halothane group, but not in the alfentanil group. We conclude that alfentanil-supplemented anaesthesia is satisfactory for suction termination of pregnancy when rapid recovery is required or the duration of the procedure is likely to be long, but that halothane anaesthesia cannot be recommended, especially if the procedure is long.