A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans.

Holoprosencephaly (HPE), the most common malformation of the human forebrain, may arise due to interacting genetic and environmental factors. To date, at least 12 contributory genes have been identified. Fibroblast growth factor 8 (Fgf8) belongs to the FGF family of genes expressed in several developmental signaling centers, including the anterior neural ridge, which is implicated in midline anomalies in mice. In humans, FGF8 mutations have been previously reported in facial clefting and in hypogonadotropic hypogonadism, but have not been reported in patients with HPE. We screened 360 probands with HPE for sequence variations in FGF8 using High Resolution DNA Melting (HRM) and sequenced all identified variations. Here we describe a total of 8 sequence variations in HPE patients, including a putative loss-of-function mutation in 3 members of a family with variable forms of classic HPE, and relate these findings to the phenotypes seen in other conditions.

Selection-based versus topography-based responding: An important distinction for stimulus equivalence?

English-speaking subjects were taught 16 English-French word pairs. Within any given trial, one word from each pair was presented; for eight items, subjects were to select its counterpart from an array of words in the other language (selection-based training), and for the other eight items there was no array and subjects were to type its counterpart (topography-based training). In Experiment 1, all items were trained from French to English, and later, interspersed no-feedback probe trials tested for the emergence of the reversed relations. Half of the eight selection-trained items were tested in the selection-based mode and half were tested in the topography-based mode; similarly, half of the eight topography-trained items were tested in the selection-based mode and half were tested in the topography-based mode. On the first reversal test trial, all 7 subjects scored 100% correct for the selection-tested items; in contrast, 5 of the 7 subjects scored 0% or near 0% correct for the topography-tested items, which improved to varying degrees with repeated testing. The training response mode affected neither acquisition rate nor reversal test trial performance. In Experiment 2, all items were tested in the topography-based mode only, and subjects were exposed to nine consecutive reversal test trials prior to interspersed probe testing. Improved accuracy across reversal test trials was not observed until the conditions of probe testing were instated, an indication that reexposure to the trained relations was a crucial component of delayed emergence. In Experiment 3, all items were trained from English to French, resulting in subjects typing a familiar rather than an unfamiliar word on reversal test trials. Accuracy on reversal test trials was considerably better than in the previous two experiments. We discuss the implications of our findings for stimulus equivalence research.

Characteristics associated with exposure to and participation in a televised smoking cessation intervention program for women with high school or less education.

OBJECTIVES: This paper estimates the prevalence of exposure to and participation in a televised smoking cessation intervention targeting women with high school or less education and describes characteristics related to exposure and participation. METHODS: A random sample of the population of female smokers with high school or less education in the Chicago metropolitan area was used to estimate the prevalence of exposure to a targeted smoking cessation intervention with television and booklet components (n = 722). Multiple logistic regression analysis was used to examine characteristics related to exposure to each component and participation, defined as simultaneous use of both components, in a sample of population and registrants combined (n = 1,727). RESULTS: About one of every four women in the target population either saw the television series or called for the booklet (24.5%); 17.5% saw the television series, 9.4% called for the booklet, and 2.4% both saw the television series and called for the booklet. Independent predictors of booklet exposure were black, older age, annual income $40,000 or less, heavier smoking, and higher stage of readiness to quit. Adjusting for booklet exposure, independent predictors of television exposure were older age and nonblack. Independent predictors of participation were black, older age, and higher stage of readiness to quit. CONCLUSIONS: The intervention reached a substantial portion of low-educated female smokers. Women who were older, black, or at higher stages of readiness to quit were most likely to be exposed and to participate. Heavier smokers or lower income women were most likely to be exposed but not necessarily to participate.

Measuring readiness and motivation to quit smoking among women in public health clinics: predictive validity.

We conducted an independent pilot test of the internal consistency, stability, and predictive validity of the instrument presented by Crittenden, Manfredi, Lacey, Warnecke, and Parsons (1994) using a two-wave panel of female smokers in 12 public health clinics. This instrument subdivides the precontemplation stage proposed by Prochaska and DiClemente into three more distinct stages: not contemplating quitting or cutting down, not contemplating quitting, and not contemplating quitting within 6 months. Findings confirm that the instrument is useful for evaluating movement toward quitting for populations that are largely concentrated in the precontemplative stage. The concurrent and predictive validity of the elaborated stages and the reliability and stability of smoking motivation and confidence indicate that the instrument is sensitive enough to track changes in readiness and motivation across the full readiness continuum.

Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06.

PURPOSE: This study was conducted to see what fraction of prostate cancer patients with biopsy-proven nodes are free of cancer 10 years after radiation treatment. METHODS AND MATERIALS: RTOG protocol #75-06 included 90 patients with biopsy-proven pelvic nodal involvement treated with radiation. They have been continuously follow-up since treatment. When feasible, current prostate-specific antigen (PSA) levels have been solicited from patients clinically cancer-free (no evidence of disease, NED) at 10 years, to confirm cure. RESULTS: The 10-year survival was 29%, the 10-year clinical NED survival 7%. PSA levels were obtained in 2 of 5 10-year clinical NED patients, they were both less than 0.8 ng/ml. The 2 proven cures were both clinical stage T-3, Gleason Score 6 and 8, and had 2 and 1 positive nodes, respectively. Multivariate analysis showed Gleason sum was significantly associated with clinical survival without disease. CONCLUSION: A small fraction of node-positive patients are cured at 10-year follow-up by radiation therapy (2 of 90 with PSA +3 of 90 by clinical endpoints). Innovative treatment programs should be directed at node-positive patients in an effort to improve the fraction cured.

Substance abuse and homelessness: social selection or social adaptation?

Although substance abuse has for many years been documented as a serious problem among homeless populations, there is as yet no clear understanding of the nature of the relationship between substance abuse and homelessness. We evaluate alternative social selection and social adaptation models of this process. Using data from a random probability sample, the substance abuse and homeless experiences of 303 homeless people and people at risk of homelessness in Cook County, Illinois, were investigated. Proportional hazards regression models were employed to assess both social selection and social adaptation models. Drug but not alcohol abuse was associated with first homeless episode. Prior homeless experiences were found to be predictive of first symptoms of both alcohol and drug abuse. Other variables, including the availability of social and economic resources, were also associated with each of these outcomes. Models of both selection and adaptation processes are necessary to account for the association between homelessness and substance abuse, indicating that a multi-directional model is more appropriate. In addition findings suggest that, in recent years, drugs may have displaced alcohol as an important precursor of homelessness for many individuals.

Intraverbal stimulus-response reversibility: Fluency, familiarity effects, and implications for stimulus equivalence.

English-speaking subjects with little knowledge of the French language used a computerized flashcard program, Think Fast, to learn 16 English-French word pairs (intraverbals) by typing one word of the pair when presented with the other word as a textual stimulus. In Phase 1, half of the intraverbals were taught from French to English (FE-1) and half from English to French (EF-1). Then, in Phase 2, training continued with the stimulus and response items of each intraverbal reversed, i.e., cards previously in the FE-1 condition were trained from English to French (EF-2) and cards previously in the EF-1 condition were trained from French to English (FE-2). Feedback was provided throughout the experiment. Reversing the stimulus and response items in Phase 2 significantly reduced rate correct and accuracy scores for eight of the nine subjects. In Experiments 1 and 2, this effect was more pronounced for cards in the EF-2 condition; in Experiment 3, when the criterion for a "correct" response was more lenient, there was no consistent difference between cards in the EF-2 and FE-2 conditions. Symmetry, as indicated by accuracy scores on the first trial in Phase 2, was generally poor: eight of the nine subjects averaged only 29% correct when asked to respond to the reversed relations for the first time. We relate our paradigm and results to recent developments in fluency, verbal behavior, and stimulus equivalence, and provide directions for future research.

Carcinogenic activities of various steroidal and nonsteroidal estrogens in the hamster kidney: relation to hormonal activity and cell proliferation.

The therapeutic use of estrogens has been associated with an increased risk of some of the most predominant, as well as less prevalent, cancers in women. The estrogen-induced renal tumor is one of the primary animal models to evaluate the carcinogenic properties of estrogens. Correlations were made with various estrogens by using parameters of estrogenicity end points such as competitive binding, progesterone receptor induction, and alterations in prolactin levels; in vitro renal proximal cell proliferation; and in vivo estrogen-induced carcinogenicity. The most potent estrogens were Moxestrol (MOX), diethylstilbestrol (DES), and 17 beta-estradiol, followed by indenestrol B, 16 alpha-hydroxyestrone, and 11 beta-methoxyestradiol with moderate estrogenic activities, whereas 11 beta-methylestradiol, 17 alpha-estradiol, indanestrol, and deoxoestrone were all relatively weaker. As expected, hydrolyzed Premarin (unconjugated estrogens) was strongly estrogenic. Of the estrogens tested, MOX was the most potent carcinogenic estrogen in the hamster kidney. Both 16 alpha-hydroxyestrone and 11 beta-methoxyestradiol induced intermediate tumor incidences with distinctly lower frequencies of renal tumor foci compared to the most potent carcinogenic estrogens. However, hamsters treated for 9.0 months with 11 beta-methylestradiol, 17 alpha-estradiol, deoxoestrone, and indanestrol exhibited no tumors. In contrast, treatment with estrone, equilin plus d-equilenin, and hydrolyzed Premarin for the same time period resulted in 100% renal tumor incidences and numerous tumor foci. Cell proliferation studies of cultured hamster kidney proximal tubule cells were carried out at varying estrogen concentrations (0.01-100 nM). Exposure to MOX resulted in consistently high renal cell proliferative response over a concentration range of 0.1-10 nM. Strongly carcinogenic estrogens such as estrone had a maximal renal cell proliferation response (2.4-fold above untreated control levels) between 0.1 and 10 nM, DES and 17 beta-estradiol responded at 1.0 nM, and 4-hydroxyestradiol responded at 10 nM. Interestingly, exposure to ethinylestradiol, a potent estrogen, at similar or higher doses as those used for DES and 17 beta-estradiol, yielded only a 10% renal tumor incidence and induced only a 1.7-fold increase in proximal tubule cell proliferation. In contrast, 17 alpha-estradiol, deoxoestrone, indanestrol, and 11 beta-methylestradiol, all weakly estrogenic and noncarcinogenic agents, had relatively little effect on tubule cell proliferation. The hydrolyzed Premarin exhibited a maximal 2.0-fold cell proliferative response at 10 nM. The present results provide clear evidence that, in the hamster kidney, the degree of carcinogenicity of a given estrogen correlates with its ability to induce proximal tubule cell proliferation in vitro.(ABSTRACT TRUNCATED AT 400 WORDS)

Pacemaker and defibrillator lead entrapment: case studies.

Cadavers and cineradiographic analysis have been used to document the effects of the medial subclavicular musculotendinous complex (MSMC) upon lead function. Four cadavers with pacemakers were dissected and photographed to demonstrate the course a lead takes as it passes through the costoclavicular region. One lead had been placed into the cephalic vein. In the other three cadavers, leads placed by currently accepted techniques of subclavian venipuncture were all found to pass through the soft tissues of the subclavicular region before entering the venous system. Cineradiographic results from a patient with a defibrillator, taken before and after replacement of a broken lead, show the effect of clavicular motion on a lead that passes through the MSMC. Furthermore, cineradiography makes it possible to identify the point where the lead entered the vein, and whether or not it escaped being caught up in the soft tissues of the MSMC.

Number and size of islets of Langerhans in pregnant, human growth hormone-expressing transgenic, and pituitary dwarf mice: effect of lactogenic hormones.

To determine the effects of lactogenic hormones on pancreatic islet size and numbers, islets of 3-month-old female mice were intravitally stained by an ip injection of an alkaline-alcohol solution of diphenylthiocarbazone (dithizone; 100 micrograms/g BW). After 15 min, animals were killed, and pancreases were removed, diced, cleared in glycerol, and whole mounted on slides. Major and minor axes of Zn dithizoate-stained islets were measured at x40 magnification. Islet areas and volumes were calculated. Animals and appropriate controls studied included 16-day pregnant, two lines of human GH-expressing transgenic, and two lines of pituitary PRL- and GH-deficient dwarf mice. Islet numbers per pancreas ranged from about 500-1200 in all groups except the transgenic mice, in which two of five animals in one group and one of five in the other showed significant increases in islet numbers (> 3 x SD control mean). In all cases, significant (P < 0.05) changes in both islet area and volume occurred. Area increased 2-fold in both pregnant and transgenic mice and decreased by a similar amount in dwarf mice. Islet volume increased 2- and 3-fold in pregnant and transgenic animals, respectively, and decreased 2- to 5-fold in dwarf mice. Analysis of the distributions of islet sizes revealed that almost all of the volume increases in the pregnant and transgenic mice and the decreases in dwarf mice were accounted for by alterations in the numbers and sizes of large (diameter, > 150 microns) islets. Our results with dwarf mice show that maintenance of islet numbers is not dependent upon pituitary PRL or GH; however, results with transgenic mice suggest that prolonged high levels of lactogens may induce islet neogenesis. The islet area and volume results for all of the mice studied support the hypothesis that lactogenic hormones are potent regulators of islet mass.

Extracorporeal cardiopulmonary life support with heparin-bonded circuitry in the resuscitation of massively injured trauma patients.

BACKGROUND: Patients who have massive but potentially survivable injuries frequently die from complications of hypovolemia, hypoxemia, hypothermia, metabolic acidosis, and coagulopathy. Emergency cardiopulmonary bypass has been unsuccessful in preventing such deaths because it involves systemic anticoagulation that exacerbates coagulopathy. PATIENTS AND METHODS: A simplified extracorporeal cardiopulmonary life support (ECLS) system was assembled consisting of a centrifugal pump head, heat exchanger, membranous oxygenator, percutaneous cannulas, and heparin-bonded circuitry. The entire system has heparin-bonded surfaces. Patients were resuscitated with the system after femoral vein-femoral artery cannulation. ECLS was used to resuscitate massively injured patients who were deteriorating despite maximal conventional therapy. RESULTS: While receiving maximal conventional therapy, 6 patients developed hypothermia, metabolic acidosis, and coagulopathy causing pulmonary hemorrhaging and hypoxemia from severe underlying lung injuries. ECLS with heparin-bonded circuitry provided cardiopulmonary support and rewarming while physicians addressed coagulopathies and surgical bleeding and assessed survivability. Three patients survived. CONCLUSIONS: ECLS with heparin-bonded circuitry offers supplemental capability in the resuscitation and cardiopulmonary support of selected massively injured patients while their primary injuries are being evaluated and treated.

Precurrent contingencies: Behavior reinforced by altering reinforcement probability for other behavior.

The present study explored the effects of a precurrent contingency in which one (precurrent) activity increased the reinforcement probability for another (current) activity. Four human subjects responded on a two-key computer mouse. Each right-key press was reinforced (points exchangeable for money) with .02 probability. In one condition (no precurrent contingency), pressing the left key had no scheduled consequence; in another condition (precurrent contingency), pressing the left key increased the reinforcement probability for right-key responding to .08 for 15 s. Initial exposure to the precurrent contingency resulted in acquisition of precurrent left-key responding for 3 subjects, but for the 4th subject a special contingency was required. Right-key responding occurred at a high stable rate across the conditions. Changeovers to left-key responding dropped to near zero when the precurrent contingency was absent and were maintained at enhanced levels when the precurrent contingency was present. Contacts with the left key consisted of short response runs. Right-key responses were more frequently emitted within 15 s of a left-key response when the precurrent contingency was present, an efficient adaptation to the contingency. Continued research on precurrent behavior may produce insights into complex phenomena such as autoclitics and self-control.

Regulation of islet beta-cell proliferation by prolactin in rat islets.

This study examined the effects of prolactin on beta-cell proliferation in pancreatic islet of Langerhans. Insulin secretion and beta-cell proliferation were significantly increased from neonatal rat islets cultured for 4 days in the presence of either 500 ng/ml ovine prolactin (oPRL) or rat prolactin (rPRL). These effects could be prevented by including anti-oPRL serum in the culture media. Although insulin secretion and beta-cell proliferation were slightly higher during the first 24 h of exposure to rPRL, maximal response was observed after 4 days for insulin secretion and 6-10 days for beta-cell proliferation. The initial mitogenic response of beta-cell to rPRL occurred by the limited recruitment of nondividing beta-cells into the cell cycle and by most daughter cells proceeding directly into additional cell division cycles. Subsequently, the maximal effect of rPRL on beta-cell proliferation was maintained by a higher rate of recruitment of previously nondividing beta-cells into cell cycle with only one fourth of the daughter cells continuing to divide. These observations are difficult to reconcile with the proposal that a limited pool of beta-cells capable of undergoing cell division exists in islets. Instead, these observations suggest that individual beta-cells are transiently re-entering the cell cycle and dividing infrequently in response to rPRL. In this case, the majority of the beta-cells would not be expected to be in an irreversible Go phase. We also demonstrated that the effects of rPRL on beta-cell proliferation occur at normal serum glucose concentrations and are affected by inhibitors of polyamine metabolism. Additional studies on the effects of rPRL on beta-cells should provide important information on the regulation of beta-cell proliferation during conditions of increased insulin demand.

Interviewer effects on self-reported substance use among homeless persons.

This study examines respondent editing of survey responses to questions regarding substance use. Previous research has identified several types of interviewer effects that may be associated with respondent editing, including direct and social distance effects. Little is known, however, regarding how these potential effects may influence self-reported substance use behavior. Data analyzed for this study were collected as part of a survey of substance use among homeless persons conducted in Cook County, Illinois. A total of 481 respondents were sampled at random in emergency and transitional shelters, soup kitchens, drop-in centers, and single room occupancy (SRO) hotels. Overall, a direct, gender-based effect was observed, with homeless respondents of both genders more willing to reveal substance use behaviors to male interviewers. Some race- and age-related direct effects were also identified, with White and older interviewers obtaining more reports of substance use. These findings yield important evidence regarding respondent editing of self-reported substance use and have implications for the common practice of demographically matching interviewers and respondents.

Interhospital transport of the patient on extracorporeal cardiopulmonary support.

Portable extracorporeal cardiopulmonary support systems have enhanced the resuscitation and support of moribund patients outside of the operating room environment. The literature documents the successful application of emergency cardiopulmonary support within the hospital setting. Clinicians have reported the use of helicopter and ground ambulance to transport patients requiring intraaortic balloon counterpulsation and fixed-wing transport of neonates requiring extracorporeal membrane oxygenation. As medical transport capabilities extend the sphere of tertiary care to outlying medical facilities, there is a role for extracorporeal cardiopulmonary support in the initial stabilization and safe transport of critically ill patients, via air or ground ambulance. Potentially, the early application of life-sustaining technology can lower mortality and morbidity in patients with a survivable pathology. This is a report on the experience with the resuscitation and interhospital transport of patients on extracorporeal cardiopulmonary support.

Anatomical mechanisms explaining damage to pacemaker leads, defibrillator leads, and failure of central venous catheters adjacent to the sternoclavicular joint.

The literature suggests that approximately 93% of all pacemaker lead fractures occur in the segment of the lead lateral to the venous entry, and costoclavicular compression has been implicated. While blood vessels can be compressed by movements of the clavicle, our research suggests that lead and catheter damage in that region is caused by soft tissue entrapment rather than bony contact. Dissection of eight cadavers with ten leads revealed that two entered the cephalic vein, and were not included in the study. Of the other eight leads, four passed through the subclavius muscle, two through the costoclavicular ligament, and two through both these structures before entering the subclavian, internal jugular, or brachiocephalic vein. Anatomical studies demonstrated that entrapment by the subclavius muscle or the costoclavicular ligament could cause repeated flexing of leads during movements of the pectoral girdle. Cineradiology of patients with position dependent catheter occlusion confirmed entrapment by the subclavius muscle. Soft tissue entrapment imposes a static load upon leads and catheters, and repeated flexure about the point of entrapment may be responsible for damage previously attributed to cyclic costoclavicular compression.

Awareness and knowledge of alcohol beverage warning labels among homeless persons in cook county, illinois.

In 1988 Congress passed the Alcohol Beverage Labeling Act, requiring that two specific health warning labels appear on all alcoholic beverage containers sold in the United States after November 1989. The following year, a random sample of 481 homeless persons interviewed in shelters, soup kitchens, drop-in centers, and single room occupancy (SRO) hotels in Cook County, Illinois were asked about their awareness and knowledge of these messages. As a group traditionally considered at high risk for alcohol abuse, the degree to which the newly-mandated warning messages have been communicated to homeless persons has important implications for the success of this public health measure. Findings revealed that age and level of alcohol consumption were each associated with label awareness and content familiarity, suggesting that alcohol beverage warning labels may be reaching homeless persons.

Adaptation of islets of Langerhans to pregnancy: increased islet cell proliferation and insulin secretion correlates with the onset of placental lactogen secretion.

To elucidate the temporal profile of adaptive changes of the islets of Langerhans to the increased insulin demands of pregnancy, we have studied islet cell proliferation and insulin secretion during gestation in the rat. 5-Bromo-2'-deoxyuridine incorporation into dividing islet cells was significantly (P less than 0.05) increased over age-matched controls by day 10, rose continuously to a peak at day 14, and then returned to control levels by day 18. By day 20, cell division was significantly inhibited (P less than 0.05). The pattern of changes in insulin secretory profiles observed with perfused pancreata of pregnant animals was similar to that obtained for islet cell proliferation. Both the threshold of glucose-stimulated insulin secretion and the amount of above threshold insulin secretion began to diverge from controls by day 10. By day 12, the glucose-stimulation threshold was significantly decreased from 5.7 mM glucose to 3.3 mM (P less than 0.05), remained at this low level through day 15, and returned toward normal by day 20. Concomitant with the increased sensitivity of B cells to glucose, the above threshold insulin secretion was significantly increased by day 12 (P less than 0.05), peaked at day 15, and returned to control levels by day 20. This insulin secretory data demonstrates that the increased sensitivity of B cells to glucose is an important component of the adaptation of islets during pregnancy to the increased demand for insulin at physiological concentrations of plasma glucose. To correlate the above changes in islet cell proliferation and insulin secretion with levels of placental lactogen (PL), serum lactogenic hormone activity was measured by Nb2 lymphoma cell replication assays. This analysis revealed the expected biphasic pattern: a midpregnancy peak at day 12, followed by a nadir at day 14, and then continuously elevated levels until term. The bioassay data agreed with the known secretory profiles of rat (r) PL-I (midpregnancy) and rPL-II (late pregnancy). Our results provide the first systematic evaluation of changes in islet function during pregnancy in the rat. In addition, they provide evidence that rPL-I may be the critical hormonal signal which triggers the primary adaptive changes in islet function characteristic of pregnancy. The return to normal values of insulin secretion and inhibition of cell division observed at day 20 in the presence of high concentrations of rPL-II suggests that other inhibitory influences become dominant in the later stages of rat pregnancy.(ABSTRACT TRUNCATED AT 400 WORDS)