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Biomedical subjects

M Nathan

Publications and source records attributed to M Nathan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Elements within the beta-lactoglobulin gene inhibit expression of human serum albumin cDNA and minigenes in transfected cells but rescue their expression in the mammary gland of transgenic mice.

Two new beta-lactoglobulin (BLG)/human serum albumin (HSA) hybrid gene vectors were constructed and tested for expression in COS-7 cells and in transgenic mice. The HSA sequences were inserted between the second and sixth BLG exons. Transient transfection experiments with these vectors as well as a series of additional vectors with either the BLG 5'- or 3'- intragenic sequences revealed that sequences within BLG exon 1/intron 1/exon 2 abrogated BLG- directed HSA expression in vitro, regardless of the presence of HSA introns or the origin of the 3' polyadenylation signal. In contrast, the same BLG expression cassette enabled the efficient expression of HSA cDNA or minigene in the mammary gland of transgenic mice with subsequent secretion of the corresponding protein into the milk of 56 and 82%, respectively of the mouse strains at levels up to 0.3 mg/ml. Previous attempts to express HSA cDNA inserted into exon 1 of the BLG gene had failed [Shani,M., Barash,I., Nathan,M., Ricca,G., Searfoss,G.H., Dekel,I., Faerman,A., Givol,D. and Hurwitz,D.R. (1992) Transgenic Res. 1, 195- 208]. The new BLG expression cassette conferred more stringent tissue specific expression than previously described BLG/HSA constructs [Barash,I, Faerman,A., Ratovitsky,T, Puzis,R., Nathan,M., Hurwitz,D.R. and Shani, M. (1994) Transgenic Res. 3, 141-151]. However, it was not able to insulate the transgenes from the surrounding host DNA sequences and did not result in copy number dependent expression in transgenics. Together, the in vitro and in vivo results suggest both positive and negative regulatory elements within the BLG intragenic sequences evaluated. The new BLG construct represents an extremely valuable vector for the efficient expression of cDNAs in the mammary gland of transgenic animals.

Animals↗
PubMed1996

Friction in airway smooth muscle: mechanism, latch, and implications in asthma.

In muscle, active force and stiffness reflect numbers of actin-myosin interactions and shortening velocity reflects their turnover rates, but the molecular basis of mechanical friction is somewhat less clear. To better characterize molecular mechanisms that govern mechanical friction, we measured the rate of mechanical energy dissipation and the rate of actomyosin ATP utilization simultaneously in activated canine airway smooth muscle subjected to small periodic stretches as occur in breathing. The amplitude of the frictional stress is proportional to eta E, where E is the tissue stiffness defined by the slope of the resulting force vs. displacement loop and eta is the hysteresivity defined by the fatness of that loop. From contractile stimulus onset, the time course of frictional stress amplitude followed a biphasic pattern that tracked that of the rate of actomyosin ATP consumption. The time course of hysteresivity, however, followed a different biphasic pattern that tracked that of shortening velocity. Taken together with an analysis of mechanical energy storage and dissipation in the cross-bridge cycle, these results indicate, first, that like shortening velocity and the rate of actomyosin ATP utilization, mechanical friction in airway smooth muscle is also governed by the rate of cross-bridge cycling; second, that changes in cycling rate associated with conversion of rapidly cycling cross bridges to slowly cycling latch bridges can be assessed from changes of hysteresivity of the force vs. displacement loop; and third, that steady-state force maintenance (latch) is a low-friction contractile state. This last finding may account for the unique inability of asthmatic patients to reverse spontaneous airways obstruction with a deep inspiration.

Airway Resistance↗
PubMed1995

Twenty-five-year followup of the Israeli High-Risk Study: current and lifetime psychopathology.

Current and lifetime psychopathology was assessed in 50 Israeli children of parents with schizophrenia who were either of kibbutz families and raised collectively with the help of child care workers, or of urban families and raised by their parents. Index subjects were compared with 50 matched control children of healthy parents by means of the Schedule for Affective Disorders and Schizophrenia-Israel. Subjects were evaluated in adulthood at a mean age of 31 years; schizophrenia was found exclusively among children of ill parents, and no effect of town or kibbutz rearing on risk for schizophrenia was observed. Major affective illness was more common among kibbutz index subjects. Affective symptomatology observed in some index parents was evenly distributed among town and kibbutz parents and was not related to the diagnosis of affective disorders in at-risk children. Current adult functioning was similar between town-and kibbutz-raised subjects (and in general reflected good adjustment); an excess of personality disorders was found among index subjects. The present findings support the concept that both familial and environmental factors operate in the expression of psychopathology.

Activities of Daily Living↗
PubMed1995

Reanalysis of SCOR and anxiety measures in the Israeli High-Risk Study.

In an earlier study, skin conductance orienting response (SCOR) and anxiety measures obtained when the subjects of the Israeli High-Risk Study were 11 years old were analyzed, using adult diagnostic information, when the subjects were 26 years old. The present study considers similar data obtained from most of this sample when the subjects were 16 years old. As in the earlier analysis, those subjects who would receive a schizophrenia spectrum diagnosis at 26 had higher anxiety ratings at age 16. Nondiagnosed index subjects also had significantly higher anxiety ratings than the nondiagnosed controls. The subjects who would receive affective spectrum diagnoses at age 26 had the most hyporesponsive SCORs, as predicted, while the subjects who would later be diagnosed in the schizophrenia spectrum had an unexpected hyperresponsive SCOR to the dishabituation tone in a habituation series. Further consideration of the long-term stability of SCORs seems necessary; they may be related to the developing psychopathological processes.

Adolescent↗
PubMed1995

Locus of control and mental health in adolescence and adulthood.

Eighty-nine subjects of the original sample of the National Institute of Mental Health joint study by the United States and Israel, known as the Israeli High-Risk Study, were given a clinical interview and a questionnaire measuring locus of control (LOC) during the second phase of the study, when the subjects were adolescents. During phases 3 and 4, approximately 8 and 15 years later, the subjects were psychiatrically assessed and 56 of them repeated the LOC questionnaire. The two measures of LOC were correlated, as were general assessments of mental health (MH). Adolescent LOC was related to lifetime MH, although LOC and MH were not related to each other concurrently in either adolescence or adulthood. The best predictive model for lifetime MH outcomes was a combination of adolescent MH and LOC variables; background variables, including parental schizophrenia, were superfluous. The data suggest that whereas adolescent MH is the best predictor of general MH, adolescent LOC is the better predictor of schizophrenia and major affective disorders.

Adolescent↗
PubMed1995

Overview and summary: twenty-five-year followup of high-risk children.

We report a 25-year followup of a group of 50 children at genetic risk for schizophrenia (by virtue of having a parent with the disorder) and 50 matched controls. The children who eventually developed schizophrenia spectrum disorders, including schizophrenia, were identifiable by cognitive-psychophysiological, neurointegrative, and social/personality traits in the preteenage period. The children at risk were also more likely to develop other Axis I disorders, chiefly affective. Moreover, the risk of Axis I disorders was significantly greater among children raised in the group atmosphere of a kibbutz than among those raised in their own nuclear families in cities and towns in Israel. The study is a unique contribution to knowledge of factors underlying the development of psychopathology.

Adolescent↗
PubMed1995

Dramatic heterogeneity of transgene expression in the mammary gland of lactating mice: a model system to study the synthetic activity of mammary epithelial cells.

We studied the expression of human serum albumin (HSA) driven by the ovine beta-lactoglobulin promoter in the mammary glands of lactating mice from five independent transgenic strains, by employing combined in situ hybridization and immunostaining techniques. Four strains displayed a heterogeneous pattern of expression: mice of strains 91 and 92 expressed the transgene in only a fraction of the lobules, whereas in strains 69 and 83 all lobules contained cells expressing HSA. In all four strains the patterns of expression within expressing lobules corresponded to the morphology of alveolar cells and to the extent of local milk secretion, suggesting that filling of alveolus with secreted material was accompanied by asynchronous downregulation of transgene expression. In situ hybridization to the endogenous milk protein genes alpha-lactalbumin, beta-casein, and whey acidic protein revealed a uniform pattern of expression in lactating mammary glands of transgeneic and in four out of five non-transgeneic mice. In the fifth control mouse, we detected downregulation of gene expression in lobules containing alveoli distended by secreted milk. The pattern of expression of the three endogenous genes was greatly disturbed after a short (3-hr) unilateral closure of mammary glands, and very much resembled the pattern of expression of the HSA transgenes. These results demonstrate that transgeneic mice provide a useful model to study the factors that regulate the synthetic activity of mammary epithelial cells.

Albumins↗
PubMed1994

Fluoxetine effects on cerebral glucose metabolism.

In a counterbalanced, double-blind, placebo-controlled trial, 40 mg of fluoxetine was administered to four healthy adult volunteers (three men, one woman; age range 20-39 years), 90 min before injection of 6-7.5 mCi of [18F]-2-deoxyglucose to measure cerebral metabolic rate of glucose (CMRglu). Subjects were engaged in a visual monitoring task shortly before and during scanning with a PETT-VI tomograph. Global CMRglu did not differ when placebo (8.93 +/- 0.96 mg 100 g-1 min-1) was compared to fluoxetine (8.22 +/- 0.86 mg 100 g-1 min-1; paired t-test = 0.82, df = 3, p < 0.48). However, statistical parametric mapping of differences in CMRglu between placebo and fluoxetine conditions revealed regional effects of fluoxetine shown by decreased metabolism in the amygdaloid complex, hippocampal formation and ventral striatum, and by increased metabolism centered in the right superior parietal lobe (Brodmann area 7). Parametric mapping for use in PET studies of glucose metabolism represents a significant new tool for studying drug effects in humans.

Adult↗
PubMed1994

Ectopic expression of beta-lactoglobulin/human serum albumin fusion genes in transgenic mice: hormonal regulation and in situ localization.

We produced transgenic mice carrying the native sheep beta-lactoglobulin (BLG) or fusion genes composed of the BLG promoter and human serum albumin (HSA) minigenes. BLG was expressed exclusively in the mammary glands of the virgin and lactating transgenic mice evaluated. In contrast, transgenic females carrying the BLG/HSA fusion constructs also expressed the HSA RNA ectopically in skeletal muscle, kidney, brain, spleen, salivary gland and skin. Ectopic expression of HSA RNA was detected only in strains that express the transgene in the mammary gland. There was no obvious correlation between the level of the HSA RNA expressed in the mammary gland and that found ectopically. In three transgenic strains analysed, the expression of HSA RNA in kidney and skeletal muscle increased during pregnancy and lactation, whereas in the brain HSA expression decreased during lactation in one of the strains. HSA protein was synthesized in skeletal muscle and skin of strain #23 and its level was higher in lactating mice compared with virgin mice. Expression of HSA was also analysed in males and was found to be more stringently controlled than in females of the same strains. In situ hybridization analyses localized the expressed transgene in the skin, kidney, brain and salivary glands of various transgenic strains. Distinct strain-specific and cell-type specific HSA expression patterns were observed in the skin. This is in contrast to the exclusive expression of the HSA transgene in epithelial cells surrounding the alveoli of the mammary gland. Taken together, these results suggest that the absence of sufficient mammary-specific regulatory elements in the BLG promoter sequences and/or the juxtaposition of the BLG promoter with the HSA coding sequences leads to novel tissue- and cell-specific expression in ectopic tissues of transgenic mice.

Animals↗
PubMed1994

Specific combinations of human serum albumin introns direct high level expression of albumin in transfected COS cells and in the milk of transgenic mice.

A new series of expression vectors, each comprised of the beta-lactoglobulin (BLG) promoter driving one of a variety of human serum albumin (HSA) minigenes or the entire gene, were evaluated for their ability to direct expression of HSA in vitro in COS tissue culture cells and into the milk of transgenic mice. Vectors directed a hierarchy of expression levels in vitro, dependent upon the specific complement of HSA introns included. HSA introns acted in a synergistic manner. In addition, minigenes comprised of specific subsets of introns were more efficacious than the entire HSA gene with all of its introns. Transgenic mice expressed as much as 10 mg ml-1 of HSA in their milk. Vectors comprised of specific intron subsets directed levels at 1 mg ml-1 or greater in the milk of 20% of generated transgenics. A statistical correlation between the expression level trend in vitro with the trend of expression in vivo (% which express) at detectable levels (p = 0.0015) and at the level of greater than 0.1 mg ml-1 (p = 0.0156) was demonstrated. A weak correlation existed (p = 0.0526) at in vivo levels of 1 mg ml-1 or greater. These new vectors are expected to direct the production of high levels of HSA in the milk of a large percentage of generated transgenic dairy animals.

Animals↗
PubMed1994

Umbilical warts: a new entity?

Two cases of umbilical warts are described. The occurrence of these lesions was not previously known. In both cases there was a history of long-standing genital warts.

Adult↗
PubMed1994

Osteophyte formation in the vertebral column: a review of the etiologic factors--Part II.

Osteophyte formation in the vertebral column is a well documented phenomenon that is poorly understood. The most commonly identified etiologic factors are degeneration and altered mechanics of the spine, either of which in turn have been considered to be a result of the natural aging process or the pathogenesis of spinal disease. In Part I [Contemporary Orthopaedics, 29(1): 31-37, 1994], the process of osteophyte formation was reviewed. In Part II, the sequential and consequential changes from the finely interwoven events of aging, degeneration, mechanical instability, and disease are described.

Adolescent↗
PubMed1994

Measurement and analysis of the in vivo posteroanterior impulse response of the human thoracolumbar spine: a feasibility study.

OBJECTIVES: To (i) measure lumbar intervertebral motion patterns produced during low force, high frequency posteroanterior (PA) thrusts applied to adjacent thoracolumbar spinal segments; (ii) determine the dependence of PA stiffness and impedance characteristics of the thoracolumbar spine on loading frequency; and (iii) ascertain the feasibility of using PA stiffness or impedance to characterize the in vivo mechanical response of the spine during spinal manipulation. SETTING: Hospital in Gothenburg, Sweden. SUBJECTS: Three subjects--one normal (male), one patient diagnosed with L4-5 degenerative disk disease (female), and one patient diagnosed with L5 retrospondylolisthesis (male). INTERVENTIONS: Intervertebral motion device (IMD) attached to pins inserted into the L3-4 or L4-5 spinous processes. Four repeated PA impulses were delivered to each of the spinous processes (T11-L3) using an Activator Adjusting Instrument with a force-acceleration measurement system. OUTCOME MEASURES: Peak-to-peak intervertebral axial displacement, PA shear displacement and flexion-extension (FE) rotation were obtained using the IMD. Thoracolumbar PA impedance (force/velocity) vs. frequency histories and peak PA dynamic stiffness (impedance x frequency) were determined from the force-acceleration measurements. Averages and standard deviations of these measures were calculated from the repeated interventions performed at each level. MAIN RESULTS: For the normal subject, the AAI PA impulses applied to the L2 spinous process (72 +/- 9 N) produced a 1.62 +/- 1.06 mm peak-to-peak intervertebral axial displacement, 0.48 +/- 0.1 mm PA shear displacement, and 0.89 +/- 0.49 degrees FE rotation at the L3-4 spinal segment. The amplitude of the lumbar intervertebral motion in the normal subject's spine decreased approximately sixfold when the AAI impulses were delivered further from the IMD measurement site. In both patients the axial, PA shear and FE lumbar intervertebral motions were of the same magnitude, but showed less variability than the normal subject as the AAI impulses were delivered closer to the IMD measurement site. The normal thoracolumbar spine exhibited a maximum dynamic PA impedance at a frequency of approximately 100-150 Hz, resulting in a peak PA stiffness ranging from 62 KN/m (L2 segment) to 124 KN/m (T11 segment). Thoracolumbar PA stiffness values tended to be higher for the patient with a severely degenerated disk (85-362 KN/m), whereas the patient with retrospondylolisthesis had a lower PA stiffness (32-96 KN/m). CONCLUSIONS: In vivo kinematic measurements of the normal and pathologic human lumbar spine indicate that low force, PA impulses produce measurable segmental motions and reinforce the notion that mechanical processes play an important role in spinal manipulation and mobilization. Calculations of the peak dynamic stiffness derived from impedance vs. frequency measurements indicate that the dynamic stiffness of the thoracolumbar spine is considerably greater than previously reported stiffness values obtained using static and quasistatic manipulation and mobilization procedures. Computations of spinal input impedance are relatively simple to perform, can provide a noninvasive measure of the dynamic mechanical behavior of the spine, appear to have potential to discriminate pathologic changes to the spine, and warrant further study on a larger sample of normals and patients. Ultimately, chiropractic clinicians may be able to use low force, impact type spinal manipulation, together with dynamic impedance analysis procedures, to quantify the mechanical response of the normal and abnormal spine, to perform spinal diagnosis and subsequently to prescribe therapeutic treatment to patients.

Adult↗
PubMed1993

Synthesis and secretion of human serum albumin by mammary gland explants of virgin and lactating transgenic mice.

Transgenic mice were produced, carrying hybrid genes comprised of the ovine beta-lactoglobulin (BLG) milk protein gene promoter and human serum albumin (HSA) coding sequences. In situ hybridization revealed high levels of BLG/HSA hybrid mRNA, confined to the epithelial cells of the lactating mammary gland with a several hundred fold lower concentration in virgin mammary glands. During the first 24 h in culture, exceptionally high levels of HSA were secreted from explants of virgin mice, independent of hormonal control. HSA secretion was reduced considerably during subsequent days in culture and became dependent on the presence of insulin, hydrocortisone and prolactin. This temporal and hormonal pattern of regulation of HSA was different than that found for the secretion of caseins. In contrast to the vast difference in the mRNA content, the amount of HSA secreted from explants derived from lactating mice during the first 24 h in culture was only 2- to 5-fold higher than that found with explants from virgin transgenic mice, suggesting post-transcriptional control of HSA synthesis. The high-level synthesis and secretion of HSA in mammary explants of lactating mice was also dependent on the presence of insulin, hydrocortisone and prolactin. This study confirms previous suggestion that mammary explants from virgin transgenics may serve as a powerful tool for screening the potential of transgenic animals to secrete foreign proteins in their milk.

Animals↗
PubMed1992

Expression of human serum albumin in the milk of transgenic mice.

We have tested the feasibility of producing large quantities of human serum albumin (HSA) in the milk of transgenic livestock by generating transgenic mice as a model system. The sheep beta-lactoglobulin (BLG) 5'-regulatory promoter sequences were used to support expression of BLG or HSA in transgenic mice. Transgenic animals generated from the entire BLG gene including 3, 5.5 or 10.8 kb of 5'-sequences demonstrated that 3 kb of 5'-sequences were sufficient to support high levels of expression of BLG, and that the longer 5'-sequences did not improve upon the levels of expression. As such, the 3 kb 5'-sequences were used to drive expression of HSA in BLG-HSA constructs. HSA was not detectably expressed in eight transgenic lines generated from a BLG-HSA construct containing the HSA cDNA. Two transgenic lines of 26 generated, using five different constructs, with an HSA minigene possessing the first intron expressed HSA in their milk. One of these expressed HSA at high levels (2.5 mg ml-1) and has stably transmitted this ability to its progeny. A high percentage of transgenic mouse lines (four of six) generated from a vector containing an HSA minigene possessing introns 1 and 2 expressed HSA in their milk at levels which ranged from 1 to 35 micrograms ml-1. In a similar trend, levels of expression of HSA by transfected tissue culture cells from BLG-HSA vectors containing an introduced SV40 enhancer were low with the HSA cDNA, increased with the HSA minigene with intron 1 and increased further with the minigene containing introns 1 and 2. This study demonstrates that high levels of HSA can be expressed in the milk of transgenic animals, that introns of the HSA gene play a role in its expression and that transfected cell lines may be used to quickly evaluate the relative expression efficiencies of various vector constructs intended for future transgenic evaluation.

Animals↗
PubMed1992

Lichen sclerosus and acute urinary obstruction.

A case of acute urinary obstruction due to early lichen sclerosus disease is described. In this case both histological corroboration and efficacy of potent topical steroid have been beneficial.

Acute Disease↗
PubMed1990

Permissiveness-restrictiveness for twins and controls in two educational settings: The Swedish compulsory school and the Israeli kibbutz.

In a previous longitudinal twin project a model was developed for studying heredity-environment interaction. One important environmental dimension in this model is permissiveness-restrictiveness. The purpose of the present study has therefore been to investigate perceived and imposed restrictiveness at the societal and classroom level and possible interactional effects on pupil behavior. Results are reported from grade 4 to grade 6 in Israeli kibbutzim and Swedish compulsory school. One major finding is that no systematic differences have been found between twins and controls in the two countries. In both Swedish schools and Israeli kibbutzim permissiveness-restrictiveness will vary depending upon perspective (perceived or imposed) and upon content (type of subject or rule-breaking activity). Preliminary within-pair comparisons for the Swedish twins are reported for different types of test results. In agreement with the model, logical abstract thinking as well as reading and mathematics achievement seem to be less influenced by hereditary factors in a restrictive educational setting than in a permissive one.

Child↗