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Biomedical subjects

B Harris

Publications and source records attributed to B Harris.

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

Preproricin expressed in Nicotiana tabacum cells in vitro is fully processed and biologically active.

Ricin, the highly toxic glycoprotein expressed in the endosperm of castor seeds, is composed of a galactose-binding lectin B chain (RTB) disulfide linked to a RNA N-glycosidase A chain (RTA). Chemically modified ricin has been conjugated to monoclonal antibodies and used for targeted therapy of cancer and autoimmune diseases. Replacement of chemically coupled molecules with a genetically engineered targeted ricin would improve homogeneity and yield and permit structural changes in the fusion toxin to be introduced readily by oligonucleotide-directed mutagenesis. Previous methods of expression of ricin fusion proteins have been limited to expression of RTA or RTB moieties alone or expression of incompletely processed toxin in Xenopus laevis oocytes. In the present study, we introduced the cDNA encoding preproricin into cultured tobacco cells via Agrobacterium tumefaciens-mediated gene transfer. Yields of ricin in soluble cell extracts were 1 microg/g in cells or, approximately, 0.1% of the total soluble protein. The ricin was partially purified by P2 monoclonal antibody anti-RTB affinity chromatography. The RTA and RTB immunoreactive material migrated on SDS-PAGE at 65 kDa under nonreducing conditions and at 32-35 kDa under reducing conditions. The tobacco ricin bound to immobilized asialofetuin as avidly as castor bean ricin, suggesting intact sugar binding. Tobacco ricin inhibited rabbit reticulocyte lysate protein translation similar to castor bean ricin (IC50 of 3 x 10(-12) M for tobacco ricin and 1 x 10(-11) M for castor bean ricin). The human cutaneous T cell lymphoma cell line HUT102 showed similar sensitivity to tobacco ricin when compared to castor bean ricin (IC50 = 9 x 10(-13) and 2 x 10(-12) M, respectively). The efficiency of gene transfer, reasonable levels of expression, and full post-translational processing indicate that this expression system is suitable for production of ricin fusion toxins for therapeutic applications.

Agrobacterium tumefaciens↗
PubMed1996

The clinical spectrum of postpartum thyroid disease.

The clinical and biochemical features of postpartum thyroid disease were analysed in 152 antithyroid peroxidase antibody-positive (anti-TPO+ve) women and compared with 239 anti-TPO-ve age-matched control postpartum women. All were assessed monthly for up to 12 months postpartum. Seventy three anti-TPO+ve women developed postpartum thyroiditis (PPT): 19.2% hyperthyroid alone, 49.3% hypothyroid alone, and 31.5% characterized by hyper- followed by hypothyroidism. None of the antibody-negative women developed any thyroid dysfunction. A significant increase in many of eleven symptoms of hypothyroidism and some of eight symptoms of hyperthyroidism compared to control women was observed in all anti-TPO+ve women, independent of thyroid status. This was particularly seen in women who later developed PPT when they were euthyroid, but was also observed in euthyroid anti-TPO+ve women who showed no decline of thyroid function during the postpartum period. Although PPT is usually transient, this condition, and the euthyroid antibody-positive state, may be associated with significant symptomatology, including an increased incidence of minor to moderate depression. Early recognition of this syndrome by antenatal screening of thyroid antibodies may contribute to improved management of women during the postpartum period.

Adult↗
PubMed1996

Cardiff puerperal mood and hormone study. III. Postnatal depression at 5 to 6 weeks postpartum, and its hormonal correlates across the peripartum period.

BACKGROUND: We assessed associations of mood at 5-6 weeks postpartum with peripartum saliva cortisol and progesterone profiles. METHOD: A prospective study involved 120 primiparous women free of major marital, socioeconomic and health problems, who collected saliva twice daily from 2 weeks before delivery to day 35 postpartum. This allowed intensive characterisation of cortisol and progesterone profiles. At the conclusion of the study, mood was assessed according to standard criteria. RESULTS: Seven women developed major depression according to DSM-III-R criteria. No associations emerged between progesterone and mood at 5 to 6 weeks. Lower levels of evening cortisol in the immediate peripartum period, were associated with postnatal depression. CONCLUSION: The study provides no support for the treatment strategy of progesterone augmentation following delivery, as a prophylactic against postnatal depression. The HPA axis and its associations with postnatal mood warrants further investigation.

Adolescent↗
PubMed1996

Aspects of perinatal psychiatric illness.

BACKGROUND: In view of the current changes in the National Health Service, it was considered an opportune time to review the literature on perinatal psychiatric illness. METHOD: A systematic review was undertaken of relevant articles on MEDLINE, ClinPsych and Excerpta Medica Psychiatry. RESULTS: Sixty-eight articles were used in the review. CONCLUSIONS: Developments in the field of perinatal psychiatry include a greater understanding of the nosology and aetiology of the conditions, the effect of maternal illness on the child, as well as transcultural factors. The perspective of the individual sufferer has been somewhat ignored. New treatments with both pharmacotherapy and hormones are emerging, but perhaps the greatest current challenge is to adapt our management strategies to community care.

Adult↗
PubMed1996

Preoperative endovascular embolization of craniospinal hemangioblastomas.

PURPOSE: To determine whether hemangioblastomas, highly vascular tumors requiring surgery that is potentially complicated by excessive bleeding, can be embolized safely by using interventional techniques that furnish a more avascular surgical field. METHODS: Nine hemangioblastomas involving either the cerebellum or the spinal cord were embolized preoperatively. In each case the feeding artery was selectively catheterized with a microcatheter and the hypervascular tumor nidus was devascularized with polyvinyl alcohol particles. RESULTS: Two patients who had undergone recent attempts as surgical resection at another institution had repeat surgery after endovascular embolization rendered the tumor nidus avascular. At surgery, the tumor was completely removed in one case and markedly debulked in the other. In all nine cases, blood loss after embolization was reported to be less than expected by experienced surgeons. In addition, manipulation and removal of the tumor was reported to be subjectively easier in these embolized tumors. The embolization procedure caused no permanent complications; however, one patient with a posterior fossa hemangioblastoma and hydrocephalus worsened clinically within 12 hours of embolization. This event was thought to be caused by obstructive hydrocephalus resulting from tumor swelling. Emergency craniotomy, ventricular decompression, and surgical resection of the tumor produced complete resolution of the signs and symptoms. CONCLUSIONS: Our results indicate that preoperative embolization of hemangioblastomas is a safe procedure that is useful in aiding surgical resection of these highly vascular tumors.

Adolescent↗
PubMed1995

Synthesis of novel imidazobenzodiazepines as probes of the pharmacophore for "diazepam-insensitive" GABAA receptors.

The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABAA receptors. Although imidazobenzodiazepines such as Ro 15-4513, 20, are the most potent DI GABAA receptor ligands described to date, their selectivity for DI versus DS GABAA receptors is only marginal. Previous structure-activity relationship (SAR) studies of imidazobenzodiazepines have indicated that the 3- and 8-positions are critical for high-affinity binding to DI GABAA receptors (J. Med. Chem. 1993, 36, 479-490. J. Med. Chem. 1993, 36, 1001-1006. J. Med. Chem. 1993, 36, 1820-1830). In order to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted imidazobenzodiazepines. The SAR analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABAA receptors. Furthermore, the imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABAA receptors. Thus, a pharmacophore is proposed for DI GABAA receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABAA receptors are consistent with those predicted by the DI GABAA receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABAA receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABAA receptor selective ligands in the future.(ABSTRACT TRUNCATED AT 400 WORDS)

Affinity Labels↗
PubMed1995

Cognitive function, thyroid status and postpartum depression.

Impairment of cognitive function can occur with thyroid disorder and also with depression. Since depression occurs in conjunction with postpartum autoimmune thyroiditis, the question arises as to whether any impairment of cognitive function in postpartum women is related to change in thyroid status or to depressed mood. A total of 242 women (110 thyroid antibody-positive and 132 antibody-negative) were assessed at 8, 12, 20 and 28 weeks postpartum in the outpatients of a district general hospital. Thyroid antibody levels (antimicrosomal and antithyroglobulin) were monitored at monthly intervals, together with plasma T3, T4 and thyroid-stimulating hormone. The main outcome measures were Research Diagnostic Criteria for depression, the 17-item Hamilton Depression Rating Scale and the Edinburgh Postnatal Depression Scale, together with reaction time and digit span. Subjects with postnatal depression showed detectable cognitive impairment independent of thyroid antibody status and actual thyroid dysfunction.

Antibodies↗
PubMed1995

Human fiber size and enzymatic properties after 5 and 11 days of spaceflight.

Biopsies from the vastus lateralis muscle were obtained from three astronauts before and after two 5-day flights and from five astronauts before and after one 11-day flight (space shuttle flights: STS-32, -33, and -34). Muscle fibers from two separate samples from each biopsy were classified as type I and II or as type I, IIA, and IIB by using qualitative myofibrillar adenosinetriphosphatase (ATPase) staining. Cross-sectional area (CSA), number of capillaries per fiber, and the activities of succinate dehydrogenase (SDH), alpha-glycerophosphate dehydrogenase (GPD), and myofibrillar ATPase were determined from one sample of fibers of each myofibrillar ATPase type. Postflight biopsies had 6-8% fewer type I fibers than preflight. Mean fiber CSAs were 16-36% smaller after the 11-day flight with the relative effect being type IIB > IIA > I. Mean fiber CSAs were 11 and 24% smaller in type I and II fibers after 5 days of flight. Myofibrillar ATPase activities increased in type II but not in type I fibers after flight, whereas SDH activity was unaffected in either fast or slow fibers. GPD activity in type I fibers was approximately 80% higher (P > 0.05) postflight compared with preflight. Myofibrillar ATPase/SDH ratios in type II fibers were higher after than before flight, suggesting that some fast fibers were more susceptible to fatigue after flight. The GPD/SDH ratios were elevated in some type I fibers after spaceflight. The number of capillaries per fiber was 24% lower after than before flight, whereas the number of capillaries per unit CSA of muscle tissue was unchanged. These data suggest that adaptations in the size, metabolic properties, and vascularity of muscle fibers can occur rapidly in the space environment. These adaptations were qualitatively similar to those observed in animals after actual or simulated spaceflight conditions for short periods.

Adenosine Triphosphatases↗
PubMed1995

Effects of variable sources of distillers dried grains plus solubles on milk yield and composition.

This study compared diets supplemented with distillers dried grains plus solubles originating from whiskey distilling with those from fuel alcohol production or soybean meal. Forty-eight cows in mid and early lactation were offered a different dietary treatment in each of three 28-d periods. Dietary design included three supplements at 14 or 18% CP of dietary DM, with or without blood meal. Additionally, a third, darker, fuel ethanol source was added at 14 and 18% CP without blood meal during period 3 to incorporate greater variation in quality of distillers grains. No detectable differences occurred in DMI or in any variables because of blood meal. Milk yield was higher when cows were fed diets at 18% rather than at 14% CP. Cows fed the two lighter distillers grains diets yielded .8 kg/d more milk than cows fed soybean meal diets, and cows fed whiskey distillers grains yielded 1.3 kg/d more SCM than cows fed diets with darkest distillers grains. Milk protein percentage was depressed when the darkest distillers grains were fed. Distillers dried grains plus solubles can provide an excellent substitute for soybean meal and corn in dairy cow diets.

Analysis of Variance↗
PubMed1995

Effects of varying forage types on milk production responses to whole cottonseed, tallow, and yeast.

Four forage treatments (45% corn silage, 33.75% corn silage plus 11.25% alfalfa hay, 11.25% bermudagrass hay, or 11.25% cottonseed hulls on a DM basis) were arranged factorially with no added fat, 12.5% whole cottonseed, or 2.5% tallow. Different diets were fed during three 28-d periods to 20 control Holstein cows and to 20 cows receiving yeast continuously in a split-plot design. Milk yield of cows fed cottonseed hulls with corn silage was 2.4 kg/d higher than with corn silage plus bermudagrass hay and .7 kg/d higher than with corn silage only or corn silage plus alfalfa hay. Whole cottonseed depressed milk yield by 1 kg/d. Cows fed yeast had increased DMI, and yeast interacted with forage so that more milk was produced by cows fed alfalfa diets. Yeast depressed milk protein percentage. Holstein cows in a commercial Florida dairy were fed no yeast or 10 g/d continuously for 60 d; milk fat percentage was greater (3.51 vs. 3.37%) with yeast. In summary, effects on milk and SCM were positive when cottonseed hulls were utilized with corn silage, negative with whole cottonseed, and neutral with supplemental tallow. Yeast effects on SCM, although not significant for either experiment, tended to be positive for both (mean +1.2 kg/d per cow).

Animal Feed↗
PubMed1994

5-Hydroxytryptamine1A receptor synthetic peptides. Mechanisms of adenylyl cyclase inhibition.

The 5-hydroxytryptamine1A receptor (5-HT1AR) is a G-protein-coupled receptor negatively coupled to adenylyl cyclase (AC). We have studied the functional domains of 5-HT1AR using synthetic peptides to block or mimic receptor function. The entire second intracellular loop (5-HT1AR-i2) and the carboxyl end of the third intracellular loop (5-HT1AR-i3-C) strongly inhibited forskolin-stimulated AC activity. These effects were not additive with those of 5-HT. Like 5-HT, the peptides 5-HT1AR-i3-C and -i2 weakly inhibited AIF4- and Mn2+ stimulated AC activity. 5-HT1AR binding assays indicated that peptides could interact with the same G-protein pool as the 5-HT1AR. 5-HT1AR-i3-C- and -i2-stimulated [35S]guanosine 5'-O-(thiotriphosphate) binding on Go/Gi proteins. Only 5-HT1AR-i3-C partially adopted an alpha-helical conformation in solution. These data show that different domains in the 5-HT1AR second and third intracellular loops can couple to and activate Gi proteins in order to mediate AC inhibition. Peptide-induced AC inhibition was not sensitive to pertussis toxin as opposed to the 5-HT1AR-mediated effect. Our data show that the 5-HT1AR and the 5-HT1AR peptides activate Gi proteins in a slightly different manner.

3T3 Cells↗
PubMed1994

Maternity blues and major endocrine changes: Cardiff puerperal mood and hormone study II.

OBJECTIVES: To define relation between mood and concentrations of progesterone and cortisol during perinatal period to test hypothesis that rapid physiological withdrawal of steroid hormones after delivery is associated with depression. DESIGN: Prospective study of primiparous women from two weeks before expected date of delivery to 35 days postpartum. SETTING: Antenatal clinic in university hospital, obstetric inpatient unit, patients' homes. SUBJECTS: 120 of 156 primiparous women interviewed. Remainder excluded because of major marital, socioeconomic, or medical problems or because caesarean section required. MAIN OUTCOME MEASURES: Concentrations of progesterone and cortisol in saliva samples; women's moods assessed by various scores for depression. RESULTS: Changes in salivary progesterone and cortisol concentrations were similar to those already characterised for plasma. Peak mean score for maternity blues (5.3 on Stein scale) was on day five postpartum (P < 0.02 compared with mean scores on other postpartum days). High postpartum scores for maternity blues were associated with high antenatal progesterone concentrations on day before delivery (P < 0.05), with high rate of rise of antenatal progesterone concentrations (P < 0.05), with decreasing progesterone concentrations from day of delivery to day of peak blues score (P > or = 0.01), and with low progesterone concentrations on day of peak blues score (P < 0.01). Seventy eight women were designated as having maternity blues (peak score > or = 8 on Stein scale) while 39 had no blues. Women with blues had significantly higher antenatal progesterone concentrations and lower postnatal concentrations than women without blues (geometric mean progesterone concentrations: one day before delivery 3860 pmol/l v 3210 pmol/l respectively, P = 0.03; ten days postpartum 88 pmol/l v 114 pmol/l, P = 0.048). Cortisol concentrations were not significantly associated with mood. CONCLUSION: Maternal mood in the days immediately after delivery is related to withdrawal of naturally occurring progesterone.

Adult↗
PubMed1994

Synthesis of benzo-fused benzodiazepines employed as probes of the agonist pharmacophore of benzodiazepine receptors.

The synthesis and in vitro evaluation of benzo-fused benzodiazepines 1-6 are described. These "molecular yardsticks" were employed to probe the spatial dimensions of the lipophilic pocket L2 in the benzodiazepine receptor (BzR) cleft and to determine the effect of occupation of L2 with respect to agonist activity. Of the new analogs synthesized, the 7,8-benzo-fused benzodiazepine 6 displayed moderately high affinity for the BzR (IC50 = 55 nM) and exhibited both anticonvulsant (ED50 approximately 15 mg/kg) and muscle relaxant (ED50 approximately 15 mg/kg) activity. As expected, 2 and 4 interacted with the repulsive regions of interaction, S1 and S2, and exhibited low affinities for BzR. The rigid nature of these molecular yardsticks (especially 6, Figure 7) has been employed to probe the depth of L2. Moreover, in the case of 6 full occupation of L2 has resulted in an increase in the muscle relaxant effect at the expense of the anticonvulsant/anxiolytic effect.

Animals↗