Potential Role Of Other Factors Research Articles

A Correlational Study of Hearing Loss and Severity of Diabetic Retinopathy Among Jordanian Patients.

Background Sensorineural hearing loss (SNHL) is a common complication of diabetes, but the underlying mechanisms and risk factors are not fully understood. This study investigatedthe relationship between several potential risk factors and SNHL in 118 individuals previously diagnosed with diabetes mellitus type 2 (DM2). Methods We did a cross-sectional analysis of data collected from 118 patients with diabetes mellitus at multiple tertiary hospitals in the Jordanian Royal Medical Services (JRMS). The mean age was 60.57 ± 12.8 years, with 56.8% males. Demographic and clinical data were collected, including age, gender, duration of diabetes, presence and duration of hypertension, diabetic retinopathy (DR) severity, tinnitus, and comprehension inability. In addition, a hearing assessment for SNHL was performed using pure-tone audiometry at 0.5, 1, 2, 4, and 8 kHz frequencies. Goodman and Kruskal's γ test and cumulative odds ordinal logistic regression were used to analyze the relationship between these factors and hearing assessment results for SNHL. Results Goodman and Kruskal's γ test showed a statistically significant moderate and positive association between diabetic retinopathy severity and sensorineural hearing loss. Further analysis using logistic regression revealed that retinopathy severity, age, and gender were all significant predictors of hearing loss level in this population. The odds of having a higher level of hearing loss increased by 9.1% for each additional year of age and were higher for males than females. In terms of DRseverity, a worsening SNHL had lower odds in individuals with no DR or mild nonproliferative DR compared to those with proliferative DR. Conclusion Our findings have important implications for managing SNHL in individuals with diabetes. They indicate that healthcare providers must closely monitor and manage therisk factors in patients with diabetes. Further research is needed to generalize better the relationship between these risk factors and SNHL, including the potential role of other factors, such as exposure to loud noise or certain medications.

Risk factors for high level cytomegalovirus viremia in liver transplant recipients and associated outcomes.

To evaluate epidemiology, risk-factors, and outcomes of high-level (HL) cytomegalovirus (CMV) viremia in liver transplant recipients. Adult patients receiving a liver transplant between 1/1/2017 and 9/30/2020 were evaluated. Viral loads at University of Wisconsin Health Clinical Laboratories were required to allow for numerical comparison. Primary objective was incidence and outcomes of HL CMV viremia (viral-load>100000 IU/ml). Secondary objective was to elucidate risk factors to allow targeted interventions. Two hundred nine patients met inclusion criteria; 175 kept their graft for at least 240 days. Of these nine patients developed HL CMV, 28 developed low-level (LL CMV, viral-load 250-100000 IU/ml), and 138 did not develop CMV viremia. When comparing these three groups via classic statistical methods time from transplant to viremia was similar (HL 158 ± 77 days, LL 150 ± 76 days). Clinical factors were also similar with the exception of donor seropositivity (HL 87.5%, LL 70.4%, No CMV 49.6%, p=0.025). HL CMV was significantly associated with graft loss (p<0.0001) on Kaplan-Meier analysis; graft loss in the LL CMV group did not differ from the no CMV group (p=0.96). To allow valid assessment of risk factors in the total study population (n=209), models of time-varying covariates were used, and Cox proportional hazards ratios were calculated. In this analysis, HL CMV was associated with a significantly increased risk of graft loss (HR 5.6, p=0.0016). When investigating risk factors associated with HL CMV, donor seropositivity significantly increased risk (HR 8.85, 95% CI 1.13-71.43, p=0.038). Pretransplant total bilirubin (HR 1.04, 95% CI 0.998-1.07, p=0.06) trended toward significance. Recipient seronegativity, liver disease, clinical and allocation model for end-stage liver disease (MELD), transplant surgery duration, age, sex, induction immunosuppression, and maintenance immunosuppression were not significantly associated with development of HL CMV. HL CMV after liver transplant is uncommon but is associated with a significantly increased risk of graft loss that is not present in those patients who develop LL CMV or do not develop CMV viremia. Given these negative graft effects, CMV stewardship interventions targeting recipients of CMV seropositive allografts are warranted. Future larger scale studies evaluating the potential role of other factors in risk stratification are needed.

Longitudinal Studies 2: Modeling Data Using Multivariate Analysis.

Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors' impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).

What can anisometropia tell us about eye growth?

Background/AimsBoth eyes of one individual share the same environment and genes. We examined interocular differences in biometry to determine the potential role of other factors in refractive development.Methods362 subjects (6–7...

Association of Short Interpregnancy Interval With Pregnancy Outcomes According to Maternal Age

Interpregnancy intervals shorter than 18 months are associated with higher risks of adverse pregnancy outcomes. It is currently unknown whether short intervals are associated with increased risks among older women to the same extent as among younger women. To evaluate whether the association between short interpregnancy (delivery to conception) interval and adverse pregnancy outcomes is modified by maternal age. A population-based cohort study conducted in British Columbia, Canada, evaluated women with 2 or more singleton pregnancies from 2004 to 2014 with the first (index) pregnancy resulting in a live birth. Data analysis was performed from January 1 to July 20, 2018. Risks of maternal mortality or severe morbidity (eg, mechanical ventilation, blood transfusion >3 U, intensive care unit admission, organ failure, death), small-for-gestational age (<10th birthweight percentile for gestational age and sex), fetal and infant composite outcome (stillbirth, infant death, <third birthweight percentile for gestational age and sex, delivery <28 weeks), and spontaneous and indicated preterm delivery. Risks of each outcome for 3- to 24-month interpregnancy intervals were estimated, according to maternal age at index birth (20-34 and ≥35 years). Adjusted risk ratios (aRRs) comparing predicted risks at 3-, 6-, 9-, and 12-month intervals with risks at 18-month intervals for each age group were calculated. The potential role of other factors explaining any differences (unmeasured confounding) was examined in several sensitivity analyses. Among 148 544 pregnancies, maternal mortality or severe morbidity risks were increased at 6-month compared with 18-month interpregnancy intervals for women aged 35 years or older (0.62% at 6 months vs 0.26% at 18 months; aRR, 2.39; 95% CI, 2.03-2.80), but not for women aged 20 to 34 years (0.23% at 6 months vs 0.25% at 18 months; aRR, 0.92; 95% CI, 0.83-1.02). Increased adverse fetal and infant outcome risks were more pronounced for women aged 20 to 34 years (2.0% at 6 months vs 1.4% at 18 months; aRR, 1.42; 95% CI, 1.36-1.47) than women 35 years or older (2.1% at 6 months vs 1.8% at 18 months; aRR, 1.15; 95% CI, 1.01-1.31). Risks of spontaneous preterm delivery at 6-month interpregnancy intervals were increased for women 20 to 34 years old (5.3% at 6 months vs 3.2% at 18 months; aRR, 1.65; 95% CI, 1.62-1.68) and to a lesser extent for women 35 years or older (5.0% at 6 months vs 3.6% at 18 months; aRR, 1.40; 95% CI, 1.31-1.49). Modest increases in risks of small-for-gestational age and indicated preterm delivery at short intervals did not vary meaningfully by maternal age. Sensitivity analyses suggested that observed associations were not fully explained by unmeasured confounding. The findings of this study suggest that short interpregnancy intervals are associated with increased risks for adverse pregnancy outcomes for women of all ages.

Gastrointestinal Bleeding Is Common in Children With Familial Dysautonomia: A Case-Control Study (1980-2017): Presidential Poster Award

Introduction: Familial dysautonomia (FD) is a rare hereditary disorder caused by mutations in the IKBKAP gene. The disease is characterized by sensory and afferent autonomic abnormalities. Clinical observations suggest that GI bleeds are not infrequent in patients with FD, but their actual frequency is unknown. We aimed to define the incidence of GI bleeding in patients with FD and its associated risk factors. Methods: Cases and age/sex matched controls were retrospectively identified using the NYU FD registry, which includes over 600 patients with genetically confirmed FD. Cases were defined as patients with FD with at least one episode of GI bleeding between January 1, 1980 and September 25, 2017. For each case we selected one to two age-matched controls with FD and no history of GI bleeding. Data on medication use, gastrostomy (G) tube placement, fundoplication, and ambulatory laboratory values obtained within one year before the GI bleed (or matched time period) were compared using univariate logistic regression models. Retinal fundus tortuosity scores (a noninvasive surrogate marker for the microcirculation) were collected from the most recent clinical visit. Continuous variables were evaluated with t-test and categorical variables by Chi squared test. Multivariate analysis was performed. Results: Thirty-nine FD patients with Gl bleeding and 52 controls were included. 62 GI bleeds occurred in 2,144 observed years (28.0 per 1000 person year) with a median age of bleeding at 11 years old (Figure 1). Fifty-three cases (85.5%) were upper GI bleeds from gastric and duodenal ulcers (Figure 2). Bleeds in patients with FD were more likely to occur in those with a G tube (p<0.01) or with a fundoplication (p<0.01) (Table 1). There were no differences in NSAID or SSRI use, age at fundoplication, or age of G tube placement. For a subset of the FD cohort with available ophthalmic fundus imaging (n=61), cases with GI bleeding had no difference in average arteriolar tortuosity score. Conclusion: The incidence of GI bleeding in FD is considerably higher than in the general pediatric population, which has been reported as 0.2 per 1000 person year. Rather than medications, G-tube and fundoplication appear to be the most important risk factors for gastrointestinal bleeding in patients with FD. Moreover, these procedures did not appear to be direct complications of these procedures. The potential role of other factors leading to mucosal injury remain important targets for study and potential interventions.1054_A Demographics. Bleeds in FD patients were more likely to occur in those with a G tube (p<0.01) and in those with a fundoplication (p<0.01). Statistical tests were not performed to compare medications given that zero cases had history of NSAID or SSRI use.1054_B Distribution of gastrointestinal bleed by age frequency. A total of 62 GI bleeds occurred with a median age of bleeding at 13.09 years old.1054_C Location of gastric ulcers. Fifty-three cases (85.5%) were upper GI bleeds from gastric and duodenal ulcers.

Dramatic decline and limited recovery of a green crab (Carcinus maenas) population in the Minas Basin, Canada after the summer of 2013.

This paper reports the results of a ten-year monitoring program of an Atlantic Canadian population of green crabs, Carcinus maenas, in the Minas Basin of the Bay of Fundy. Intertidal densities, sex and reproductive ratios, juvenile recruitment, subtidal catch-per-unit-effort (CPUE), and sizes of crabs in this population were recorded from 2008 to 2017. In 2013 intertidal densities, mean crab sizes, subtidal CPUE, and proportions of crabs mature and reproducing all dramatically decreased to all-time lows, and large crabs virtually disappeared from the population. From 2014 to 2017 the population partially recovered but remained in an altered state. Potential causes of interannual changes to this population were investigated by correlating intertidal densities to 257 monthly environmental variables and performing stepwise multiple regression analyses. Crab densities in a given year were best explained by potential settlement during the summer and the maximum sea-surface temperature during March of the same year. However, potential roles of other factors (e.g., autumn winds, summer temperatures, North Atlantic Oscillation index) could not be ruled out. Changes in abundances of other species in the area, particularly predators and prey of green crabs, have also been observed and present possible alternative causative agents that should be investigated. Populations of other marine species in the Gulf of Maine-Bay of Fundy region within which the Minas Basin is situated have also been reported to have undergone dramatic changes in and after 2013, suggesting the occurrence of some oceanographic event or regime shift in the region. Declines to the monitored crab population in this study may have resulted from this same 2013 event. These observations have implications for recruitment to marine populations in this region.

Longitudinal studies 2: Modeling data using multivariate analysis.

Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).

A computational proposal for the experimentally observed discriminatory behavior of hypoxanthine, a weak universal nucleobase

A computational model composed of six nucleobases was used to investigate why hypoxanthine does not yield duplexes of equal stability when paired opposite each of the natural DNA nucleobases. The magnitudes of all nearest-neighbor interactions in a DNA helix were calculated, including hydrogen-bonding, intra- and interstrand stacking interactions, as well as 1-3 intrastrand stacking interactions. Although the stacking interactions in DNA relevant arrangements are significant and account for at least one third of the total stabilization energy in our nucleobase complexes, the trends in the magnitude of the stacking interactions cannot explain the relative experimental melting temperatures previously reported in the literature. Furthermore, although the total hydrogen-bonding interactions explain why hypoxanthine preferentially pairs with cytosine, the experimental trend for the remaining nucleobases (A, T, G) is not explained. In fact, the calculated pairing preference of hypoxanthine matches that determined experimentally only when the sum of all types of nearest-neighbor interactions is considered. This finding highlights a strong correlation between the relative magnitude of the total nucleobase-nucleobase interactions and measured melting temperatures for DNA strands containing hypoxanthine despite the potential role of other factors (including hydration, temperature, sugar-phosphate backbone). By considering a large range of sequence combinations, we reveal that the binding preference of hypoxanthine is strongly dependent on the nucleobase sequence, which may explain the varied ability of hypoxanthine to universally bind to the natural bases. As a result, we propose that future work should closely examine the interplay between the dominant nucleobase-nucleobase interactions and the overall strand stability to fully understand how sequence context affects the universal binding properties of modified bases and to aid the design of new molecules with ambiguous pairing properties.

Sustained deficiency of mitochondrial complex I activity during long periods of survival after seizures induced in immature rats by homocysteic acid

Our previous work demonstrated the marked decrease of mitochondrial complex I activity in the cerebral cortex of immature rats during the acute phase of seizures induced by bilateral intracerebroventricular infusion of dl-homocysteic acid (600 nmol/side) and at short time following these seizures. The present study demonstrates that the marked decrease ( approximately 60%) of mitochondrial complex I activity persists during the long periods of survival, up to 5 weeks, following these seizures, i.e. periods corresponding to the development of spontaneous seizures (epileptogenesis) in this model of seizures. The decrease was selective for complex I and it was not associated with changes in the size of the assembled complex I or with changes in mitochondrial content of complex I. Inhibition of complex I was accompanied by a parallel, up to 5 weeks lasting significant increase (15-30%) of three independent mitochondrial markers of oxidative damage, 3-nitrotyrosine, 4-hydroxynonenal and protein carbonyls. This suggests that oxidative modification may be most likely responsible for the sustained deficiency of complex I activity although potential role of other factors cannot be excluded. Pronounced inhibition of complex I was not accompanied by impaired ATP production, apparently due to excess capacity of complex I documented by energy thresholds. The decrease of complex I activity was substantially reduced by treatment with selected free radical scavengers. It could also be attenuated by pretreatment with (S)-3,4-DCPG (an agonist for subtype 8 of group III metabotropic glutamate receptors) which had also a partial antiepileptogenic effect. It can be assumed that the persisting inhibition of complex I may lead to the enhanced production of reactive oxygen and/or nitrogen species, contributing not only to neuronal injury demonstrated in this model of seizures but also to epileptogenesis.

Selection of an omnivorous diet by the mangrove tree crab Aratus pisonii in laboratory experiments

Observational studies on leaf damage, gut content analyses, and crab behaviour have demonstrated that like numerous other mangrove and salt-marsh generalists, the mangrove tree crab Aratus pisonii feeds on a variety of food resources. This study is the first that experimentally tests feeding preferences of A. pisonii, as well as the first to test experimentally whether chemical composition of food resources is responsible for food selection. Feeding preferences were determined among a variety of plant, algal, and animal resources available in the field both in Florida and Belize, using multiple-choice feeding assays, where male and female crabs simultaneously were offered a variety of food items. To test whether chemistry of food resources was responsible for feeding preferences, chemical extracts of food resources were incorporated in an agar-based artificial food, and used in feeding assays. Results of feeding assays suggest that crabs prefer animal matter from ∼ 2.5 to 13× more than other available resources, including leaves of the red mangrove Rhizophora mangle, which contribute the most to their natural diet. Artificial feeding assays also demonstrated that chemical cues were responsible for selection of animal matter, up to 25× more than other available resources. Non-polar extracts (derived from extraction in 1:1 ethyl actetate:methanol) stimulated feeding the most, suggesting that fatty acids, triglycerides, or sterols may be important for growth, reproduction, or survival. Results for both sexes were similar across most assays. While chemical composition of food resources appears to play some role in selection, this does not discount the potential role of other factors, such as resource availability, competition, predation, or reproductive requirements in influencing feeding preferences. Bioassay-guided fractionation of extracts should aid in determining chemical constituents that play the greatest role in determining feeding preferences.

A case representing coexistence of acute myeloblastic leukemia and dedifferentiated liposarcoma: the possible role of chemotherapy in triggering dedifferentiation

Acute myelogenous leukemia (AML) is a hematological disorder that is characterized by an abnormal proliferation of immature myeloid cells. Dedifferentiated and well-differentiated liposarcomas are the two pathological subtypes of liposarcoma, based on the WHO classification. Transition from well-differentiated to dedifferentiated liposarcoma is a well-recognized phenomenon. Well-differentiated tumors are known to have low malignancy grade. However, when dedifferentiation occurs, the tumor acquires the aggressive features of a fully malignant lesion. This process largely is believed to progress in a time-dependant manner; however, time is not the only factor of importance. The potential roles of other factors in this transition are still unclear. To date, the coexistence of AML and liposarcoma has not been reported in the literature. In this paper, we report on a case of coexistence of AML and liposarcoma, and on the unusual behavior of a well-differentiated tumor after dedifferentiation occurs.

Combining palaeolimnological and limnological approaches in assessing lake ecosystem response to nutrient reduction

Summary1. Palaeolimnological data and limnological time‐series data are highly complementary. Sediment records extend time‐scales, integrate subannual variability and expand the range of sites that can be studied, but they suffer from taphonomic biases and occasionally from uncertain chronology. Observational time‐series data, on the other hand, are highly resolved but are very limited in extent both in space and time.2. Palaeolimnological and observational data‐sets need to be combined in oligotrophication research to establish (i) the past and present status of lakes needed to identify reference conditions; (ii) changes in ecosystem state; (iii) responses to nutrient reduction; and (iv) the potential role of other factors (e.g. additional stressors, climate change) that might confound predictions of future state.

The Effect of Piglet Expulsion in the Sow on Plasma Cortisol, Adrenocorticotropic Hormone and β‐endorphin

ContentsPrevious studies have shown an increase in plasma cortisol in gilts over farrowing irrespective of environment suggesting that factor(s) associated with parturition itself cause physiological stress. Factors involved in mediating the hypathalomo–pituitary–adrenal (HPA) axis at parturition are not well understood. This study examines the effect of piglet expulsion on the pituitary–adrenal axis by measurement of plasma cortisol, adrenocorticotropic hormone (ACTH) and β‐endorphin. The effect of farrowing environment in modulating the acute response to piglet expulsion is also investigated. Twelve second parity sows, with indwelling jugular catheters, were moved into either a farrowing crate or a straw‐bedded pen 5 days before their expected parturition date (EPD). Blood samples were taken from each sow during a prefarrowing baseline period and then rapid samples (2.5 mins) were taken for 10 min following the birth of two piglets. No effect of environment was found on any of the hormonal variables which reinforces the hypothesis that the physiological stress seen in parturient pigs is due to some intrinsic factor of parturition. Plasma cortisol, ACTH and β‐endorphin did not change significantly in the period following piglet expulsion suggesting that individual piglet expulsions do not play a major role in ‘parturition stress’. There was however, an increase in plasma cortisol, ACTH and β‐endorphin in response to increasing piglet number which is consistent with previous studies of general farrowing in which cortisol increased as farrowing progressed. Therefore this study reinforces the hypothesis that physiological stress increases with ongoing parturition although this does not appear to be a result of piglet expulsion. The potential role of other factors which may be involved in causing ‘parturition stress’ should be investigated.

The evolution of phally polymorphism

Phally polymorphism in snails offers an opportunity, hitherto neglected, to study the evolution of sexual polymorphism in animals. It is characterized by the co-occurrence in natural populations of regular (euphallic) individuals and aphallic individuals with no male copulatory organ. Both sexual morphs can self-fertilize but, when outcrossing, aphallic individuals can only play the female role. Using simple models, we investigated the influence of selfing rate, inbreeding depression and allocation to female function on the evolution of aphally, assuming different kinds of inheritance of aphally. These models show that high selfing rates favour the maintenance of aphally and permit polymorphic situations at equilibrium for some sets of these parameters, except with cytoplasmic inheritance. We then review the empirical data sets on aphally, mainly available in the freshwater snailBulinus truncatus, to evaluate the determination of aphally and the parameters of the models as well as the potential role of other factors, including polyploidy, parasitism, population structure and dynamics. In the light of both theoretical and empirical results, we propose likely scenarios for the evolution of aphally.

The evolution of phally polymorphism

Abstract Phally polymorphism in snails offers an opportunity, hitherto neglected, to study the evolution of sexual polymorphism in animals. It is characterized by the co-occurrence in natural populations of regular (euphallic) individuals and aphallic individuals with no male copulatory organ. Both sexual morphs can self-fertilize but, when outcrossing, aphallic individuals can only play the female role. Using simple models, we investigated the influence of selfing rate, inbreeding depression and allocation to female function on the evolution of aphally, assuming different kinds of inheritance of aphally. These models show that high selfing rates favour the maintenance of aphally and permit polymorphic situations at equilibrium for some sets of these parameters, except with cytoplasmic inheritance. We then review the empirical data sets on aphally, mainly available in the freshwater snailBulinus truncatus, to evaluate the determination of aphally and the parameters of the models as well as the potential role of other factors, including polyploidy, parasitism, population structure and dynamics. In the light of both theoretical and empirical results, we propose likely scenarios for the evolution of aphally.

Blphasic changes in the density of muscarinic and beta-adrenergic receptors in cardiac atria of rats treated with diisopropylfluorophosphate

Chronic treatment with organophosphate inhibitors of cholmesterases is known to bring about down-regulation of muscarinic acetylcholine receptors in the heart while its effect on the functionally antagonistic β-adrenergic receptors is not known. We describe experiments in which rats were exposed to daily injections of diisopropylflurophosphate (DFP) and the density of muscarinic and β-adrenergic binding sites in their cardiac atria was measured according to the binding of ( 3H)quinuclidinvl benzilate (( 3H)QNB) and (-)-4-(3-tert-butylamino-2-hydroxypropoxy)-(5,7- 3H) benzimidazol-2-one (( 3H)CGP 12177) as subtype non-specific muscarinic and β-adrenergic ligands, respectively. Biphasic course of changes was discovered with both ligands. With the dosage scheme applied, the density of betaadrenoceptors was augmented 24 h after the first dose of DFP and decreased to about one half of control values after 5 days of treatment with DFP. The density of muscarinic receptors was augmented after two days of treatment with DFP and decreased to about one half of control values after 5 days of treatment. Comparatively small changes in the heart rate were observed during the treatment; they reflected changes in the muscarinic and β-adrenergic receptor density. The finding of DFPinduced changes in the binding of ( 3H)CGP 12177 suggests that the mechanisms responsible for the control of the density of muscarinic and β-adrenergic receptors in the heart cells are interconnected but potential roles of other factors involved in in vivo experiments deserve further analysis. The transient increase in the density of muscarinic receptors after two days of DFP treatment appears related to published data on transient stimulation by cholinergic agonists of the transcription of mRNAs for muscarinic receptors.

A retrospective mortality study of workers exposed to arsenic in a gold mine and refinery in France.

A historical mortality study of a cohort of employees of a gold mining and refining company was carried out in Salsigne, France. A major goal of the study was to investigate the relationship between lung cancer mortality and exposure to arsenic, radon, silica, and other contaminants of the working environment. A twofold excess of lung cancer was found both among miners and smelters, mainly concentrated among workers who had experienced exposure to past levels of arsenic, radon, and silica. The consistency of the results in the mine and the refinery are suggestive of a carcinogenic risk from both soluble and insoluble arsenic, although the potential role of other factors cannot be dismissed.

Synergistic interactions between Pit-1 and other elements are required for effective somatotroph rat growth hormone gene expression in transgenic mice.

The role of the pituitary-specific POU-domain protein, Pit-1, in GH gene activation has been established by in vitro analyses and by the observation that mutations affecting the Pit-1 genomic locus result in genetically transmitted dwarfism. To define the quantitative contribution of the two Pit-1 response elements and the potential role of other factors in GH gene activation, we systematically assessed the ability of a series of GH promoter regions to activate transgenes in the mouse anterior pituitary gland. These studies revealed that the two GH Pit-1 binding sites are necessary, but not sufficient, for efficient transcriptional activation. Transgenes containing information including only these cis-active regions are expressed at extremely low levels in the pituitary glands of transgenic mice. The addition of 35 base pairs of 5'-flanking information, contributing other elements including a thyroid hormone/retinoic acid response element, results in much higher levels of transgene expression. Sequences located upstream of this segment contribute a further 5- to 10-fold activation. Thus, while Pit-1 is required for GH gene activation, it alone can only direct minimal expression in transgenic animals. Rather, synergistic interactions between other promoter elements and Pit-1 appear to be required for expression of the transgenes at approximately the 100-fold higher levels that are characteristic of somatotrophs, and are therefore likely to be critical components of somatotroph-specific expression of the GH gene.

Strategies based on marker information for the study of human diseases.

The goals and the ways of using genetic marker information when studying human disease are very different according to whether the disease or sub-entity of the disease is mendelian or if a 'disease gene' in the sense of a rare mutated allele does not exist but rather common genetic risk factors, each one normal if considered alone. In the former case, genetic markers are used in the aim of localizing the defective gene and a systematic screening of the genome seems to be an efficient strategy provided there is not too much ambiguity in the correspondence between phenotypes and genotypes. In the latter case, the goal is to find risk factors allowing us to predict better the risk for an individual and to define different risk groups resulting in greater power to show the potential role of other factors (genetic or environmental). In this situation, the use of the lod score method with random markers presents several disadvantages: first, the multiple testing problem is particularly crucial; second, false rejection of linkage may be induced by misspecification of the model describing the genetic basis of the disease; and last, the power of detecting linkage may be low. A strategy focusing on 'candidate gene' markers may be then more efficient.