Modified oligonucleotides--synthesis, properties and applications.
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Amides↗
Biomedical subjects
K Ghosh
Publications and source records attributed to K Ghosh.
The effect of estrogens and antiestrogens in a rat model for hot flush.
The present studies evaluated the effect of estrogens and the selective estrogen receptor modulator (SERM) tamoxifen and raloxifene in a rat model for hot flush. In this model, ovariectomized rats were treated for 8 or 9 days either sc or po. Rats were dependent to morphine by implanting a morphine pellet (75 mg each) sc on days 3 and 5 of treatment. On the last day of treatment, a thermistor, connected to a data acquisition system, was placed on the tail of each animal and morphine addiction was withdrawn by naloxone injection (1.0 mg/kg, sc). Temperature measurements were taken for 1 h under ketamine (80 mg/kg, im) anesthesia. In general, vehicle treated rats showed a 5-6 degrees C elevation of their tail skin temperature with the peak occurring about 15 min after naloxone injection. 17 alpha-Ethinyl estradiol (EE) was evaluated both sc and po using a broad range of doses. The IC50 for inhibition of tail skin temperature rise was approximately 0.1 mg/kg, sc and 0.2 mg/kg, po. 17 beta-Estradiol and 17 alpha-estradiol were also active in this model whereas non-estrogenic steroids were inactive. Raloxifene and tamoxifen were tested for estrogen agonist and antagonist activity administered sc and po. Raloxifene did not demonstrate reproducible estrogen agonist activity at doses up to 10 mg/kg, whereas it demonstrated significant antagonistic activity at the 10 mg/kg dose regardless of the route of administration. Tamoxifen exhibited significant estrogen agonist activity at all doses tested (0.1-10.0 mg/kg) and was a significant antagonist of EE at the 1.0 mg/kg dose. Our results demonstrate the potential utility of this model to evaluate and discriminate among classes of compounds with varying degrees of estrogen agonist and antagonist activity.
Animals↗
A double-masked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Dorzolamide Corneal Effects Study Group.
OBJECTIVE: To compare the long-term effects of dorzolamide hydrochloride (Trusopt, Merck and Co Inc, White-house Station, NJ), timolol maleate, and betaxolol hydrochloride on corneal endothelial cell density and corneal thickness. METHODS: This 1-year multicenter study was conducted in 298 patients with ocular hypertension or open-angle glaucoma who had a baseline central corneal endothelial cell density greater than 1500 cells/mm2 and central corneal thickness less than 0.68 mm in each eye. Patients were randomized to 0.5% betaxolol twice daily, 0.5% timolol twice daily, or 2.0% dorzolamide 3 times daily. Specular microscopy and ultrasonic pachymetry of the central cornea was performed at baseline and 6 and 12 months following institution of therapy. Endothelial cell densities were determined by a single masked observer. RESULTS: The mean percent changes from baseline for both outcome measures were similar in all 3 treatment groups at both 6 and 12 months. After 1 year of treatment, the mean percent loss in endothelial cell density from baseline was 3.6%, 4.5%, and 4.2% for the dorzolamide, timolol, and betaxolol groups, respectively. The mean percent change from baseline for corneal thickness was 0.47%, -0.25%, and 0.39% for the dorzolamide, timolol, and betaxolol groups, respectively. CONCLUSIONS: Dorzolamide is equivalent to timolol and betaxolol in terms of the change in central endothelial cell density and thickness after 1 year of therapy. All 3 treatments exhibit good long-term corneal tolerability in patients with normal corneas at baseline.
Adrenergic beta-Antagonists↗
Diagnostic and therapeutic advances in gynecologic oncology: screening for gynecologic cancer.
Endometrial carcinoma is associated with a good prognosis because patients tend to present with early disease. Mass screening is therefore unlikely to be of benefit. High-risk populations may benefit from screening, but no prospective studies have demonstrated a benefit in any population. The most promising modality for screening appears to be TVS, and a normal TVS may also preclude the need for further evaluation of symptomatic patients. The appropriate use of TVS in patients on tamoxifen is currently unknown. Hysteroscopy and endometrial biopsy may have a role in the evaluation of symptomatic patients but do not appear promising as screening modalities.
Biomarkers, Tumor↗
A [35S]GTPgammaS binding assessment of metabotropic glutamate receptor standards in Chinese hamster ovary cell lines expressing the human metabotropic receptor subtypes 2 and 4.
The activities of metabotropic glutamate receptor (mGluR) standards were evaluated in the [35S]GTPgammaS binding assay and in the forskolin (FSK)-enhanced cyclic AMP assay using Chinese hamster ovary (CHO) cells or homogenates which expressed the human mGluR (hmGluR) subtypes 2 and 4. Though distinct rank orders of activities were determined for the agonists between the cell lines expressing individual hmGluRs, similar rank orders of agonist activities were determined for the standards between assays. O-phospho-L-serine (L-SOP) and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) antagonized agonist EC90 responses in the cell lines expressing the hmGluR 2 and 4 subtypes, respectively. In addition to its antagonist effect, L-SOP increased the baseline level of cAMP when tested in the absence of agonist. In spite of this anomalous effect, L-SOP was found to be a competitive antagonist in the cAMP assay as well as in the [35S]GTPgammaS binding assay with a pA2 value of 5.2 in both assays. MAP4 was a competitive antagonist of L(+)-2-amino-4-phosphonobutyric acid (L-AP4)-induced responses in the CHO cell line expressing hmGluR4 with pA2 values of 4.4 and 4.5 determined in the [35S]GTPgammaS binding and cAMP assays, respectively.
Animals↗
A randomized trial comparing the dorzolamide-timolol combination given twice daily to monotherapy with timolol and dorzolamide. Dorzolamide-Timolol Study Group.
OBJECTIVE: To compare the efficacy and safety of a fixed combination of 2.0% dorzolamide and 0.5% timolol administered twice daily with each of the individual components administered in their usual monotherapy dose regimens in patients who had washed out all ocular hypotensive medications. DESIGN: A 3-month, parallel, randomized, double-masked, active-controlled, multicenter clinical trial. PARTICIPANTS: A total of 335 patients with bilateral ocular hypertension or open-angle glaucoma participated. INTERVENTION: After completing a washout of ocular hypotensive medications, patients were randomized to receive either the dorzolamide-timolol combination twice daily plus placebo once daily, 0.5% timolol twice daily plus placebo once daily, or 2.0% dorzolamide three times daily. MAIN OUTCOME MEASURES: Intraocular pressure (IOP) was measured at morning trough (hour 0) and peak (2 hours postdose) on day 1, week 2, and months 1, 2, and 3. Ocular and systemic safety were evaluated at each study visit. RESULTS: Intraocular pressure reduction was greater on average in the combination group than in the dorzolamide and timolol groups. At morning trough (month 3, hour 0), the mean reduction in IOP from baseline was 27.4% (-7.7 mmHg) for the combination, 15.5% (-4.6 mmHg) for dorzolamide, and 22.2% (-6.4 mmHg) for timolol. At morning peak (month 3, hour 2), the mean IOP reduction from baseline was 32.7% (-9.0 mmHg), 19.8% (-5.4 mmHg), and 22.6% (-6.3 mmHg) for the combination, dorzolamide, and timolol, respectively. Overall, the incidence of clinical adverse experiences was comparable between the combination and each of its components. The proportion of patients who discontinued from the study because of clinical adverse experiences was also comparable between the combination and dorzolamide, although it was significantly greater in the combination group than in the timolol group (7% vs. 1%, P = 0.035). Similarly, comparable numbers of patients in the combination and dorzolamide groups reported ocular symptoms; however, when compared to the timolol group, more patients receiving the combination reported blurred vision, burning eye, stinging eye, and tearing eye. CONCLUSIONS: After a washout of ocular hypotensive therapy, the IOP-lowering effect of the dorzolamide-timolol combination was greater than that of either of its components administered as monotherapy. The combination is generally well-tolerated and provides a convenient alternative to concomitant therapy with its individual components.
Adrenergic beta-Antagonists↗
Acute GVHD involving the gastrointestinal tract and infestation with Blastocystis hominis in a patient with chronic myeloid leukaemia following allogeneic bone marrow transplantation.
A 21-year-old female underwent allogeneic bone marrow transplantation (ABMT) from her HLA matched brother for chronic myeloid leukaemia in the chronic phase. Four weeks post transplant she developed tenesmus, mucoid stool mixed with blood and lower abdominal pain. This rapidly progressed to greenish watery diarrhoea with flakes of mucous membrane floating in it, conforming to the classical clinical description of acute GVHD of the bowel. Stool microscopy showed profuse numbers of Blastocystis hominis, a parasite with doubtful pathogenicity in an immunocompetent host. In the present case the parasite played a pathogenic role as evidenced by the profuse number in the stool sample, focal neutrophil infiltration of the rectal mucosa, initial presentation of the patient with dysentery, and requirement for prolonged metronidazole therapy to eradicate the parasite and cure the diarrhoea. She also had grade I GVHD of the liver and skin. In developing tropical countries, hitherto unreported parasitic infestations may complicate the picture of acute GVHD.
Acute Disease↗
Surgery in haemophilia: experience from a centre in India.
The present paper describes various kinds of surgery carried out with great success in 16 cases which included both severe and moderate haemophilia patients with modest amounts of factor concentrates and anti-fibrinolytic drugs. This is very important in developing countries where factor concentrates are not easily available. In one patient haemophilia was diagnosed only after surgery. None of the patients had inhibitor pre- or post-operatively. One patient who was HIV positive underwent orchidectomy successfully with only 6000 IU of factor VIII concentrate.
Adult↗
Molecular characterization of haemophilia A & B in Indians.
Forty-seven haemophilia A patients from 43 pedigrees and 34 haemophilia B patients from 31 pedigrees were screened for the presence of mutations by Southern blotting using factor VIII and IX cDNA and genomic DNA probes. Three deletions and two restriction site variants were detected among 47 haemophilia A patients and one deletion and two restriction site variants were detected in 34 haemophilia B patients. Overall, the frequency of mutations in haemophilia A was 10.6%; the frequency of deletions was 6.4% and that of point mutations was 4.2%. In haemophilia B, the frequency of mutations detected was 9%; deletions 9% and point mutations 6%. The present report, the first from India, shows that like other earlier published reports from Europe and the United States, mutations in haemophilia are heterogeneous, and that RFLP using Southern blotting did not detect most of the mutations in this disorder and is an insensitive and inefficient procedure.
Adolescent↗
Recurrent haemoperitoneum in a female patient with type III von Willebrand's disease responded to administration of oral contraceptive.
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Adult↗
A global model to define the behavior of partial agonists (bell-shaped dose-response inducers) in pharmacological evaluation of activity in the presence of the full agonist.
The dose-response models for full agonists and for a particular type of partial agonist can be described by sigmoidal curves and bell-shaped curves, respectively. The methods currently used to evaluate the interaction of a full agonist and a partial agonist require a large number of experimental units and base their analysis on nonlinear regression analysis, which may not be statistically appropriate. We propose an appropriate design and a global nonlinear model to evaluate such interactions. The new model allows us to estimate the interaction parameters and the parameters that characterize the individual partial agonist curve and the full agonist curve.
Animals↗
A patient with congenital dyserythropoietic anaemia type III presenting with stillbirths.
A 28-year-old female patient presented with recurrent stillbirths between 28 and 30 weeks of gestation. At least one of the stillborn was hydropic at birth; alpha-thalassaemia and Rh isoimmunisation were ruled out. The patient was found to be suffering from congenital dyserythropoietic anaemia (CDA) type III, a rare form of congenital anaemia inherited as an autosomal dominant character in some families. It is tempting to speculate that at least the hydropic stillborn inherited the same disorder from the mother. CDA type III as a cause of hydrops fetalis has not been reported in the literature. The patient, who was transfusion-dependent, underwent splenectomy. Subsequently she did not need any transfusion for the last 6 months.
Abortion, Habitual↗
Genetic variability in biochemical characters of Brazilian field populations of the Leishmania vector, Lutzomyia longipalpis (Diptera: Psychodidae).
The phlebotomine sand fly Lutzomyia longipalpis is the insect vector of visceral leishmaniasis, a protozoan disease of increasing incidence and distribution in Central and South America. Electrophoretic allele frequencies of 15 enzyme loci were compared among the L. longipalpis populations selected across its distribution range in Brazil. The mean heterozygosity of two colonized geographic strains (one each from Colombia and Brazil) were 6% and 13% respectively, with 1.6-1.9 alleles detected per locus. In contrast, among the seven widely separated field populations, the mean heterozygosity ranged from 11% to 16% with 2.1-2.9 alleles per locus. No locus was recovered that was diagnostic for any of the field populations. Allelic frequency differences among five field strains from the Amazon basin and eastern coastal Brazil were very low, with Nei's genetic distances of less than 0.01 separating them. The two inland and southerly samples from Minas Gerais (Lapinha) and Bahia (Jacobina) states were more distinctive with genetic distances of 0.024-0.038 and 0.038-0.059, respectively, when compared with the five other samples. These differences were the consequence of several high frequency alleles (glycerol-3-phosphate dehydrogenase [Gpd1.69] and phosphoglucomutase [Pgm1.69]) relatively uncommon in other strains. The low genetic distances, absence of diagnostic loci, and the distribution of genes in geographic space indicate L. longipalpis of Brazil to be a single, but genetically heterogeneous, polymorphic species.
Animals↗
Intron 22 inversions in factor VIII gene in Indian hemophiliacs.
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Chromosome Inversion↗
The influence of alpha-thalassaemia on the haematological & clinical expression of sickle cell disease in western India.
We evaluated the clinical and haematological features of 29 sickle cell anaemia patients with associated alpha-thalassaemia and 22 sickle cell homozygotes with a normal alpha-globin genotype from western India. The presence of alpha-thalassaemia resulted in significantly higher haemoglobin (Hb), haematocrit (HCT), red blood cells counts (RBC) and haemoglobin A2 (HbA2) levels but lower mean cell haemoglobin (MCH) and mean cell volume (MCV). The clinical presentation in these patients was also milder with fewer episodes of painful crisis, chest syndromes, infections, requirement of hospitalization and blood transfusions. However, splenomegaly was more common as compared to the patients with a normal alpha-globin genotype. It is evident from the present study that alpha-thalassaemia could be an important genetic factor modulating the clinical expression and haematological severity of sickle cell anaemia in this region.
Adolescent↗
Ultrastructural, cell culture and karyotype study of bone marrow in a patient with congenital dyserythropoietic anaemia (CDA)-type III presenting with recurrent still-births.
A 28 year old female patients presented with refractory anaemia since childhood and recurrent still-births at 28-30 weeks of gestation. One still-born child was hydropic at birth. Bone marrow showed characteristic morphological changes of congenital dyserythropoietic anaemia (CDA)-Type III. Electron microscopy showed disruption of the nuclear membrane, spongy appearance of nuclei, stacks of microtubules in intermediate normoblasts and myelin figures in erythroid cells. In vitro culture and karyotype data from the bone marrow of the patient is presented. Recurrent still-births in association with congenital dyserythropoietic anaemia has rarely been reported in the literature.
Adult↗
Genetic polymorphism of morphological and biochemical characters in a Natal, Brazil, population of Lutzomyia longipalpis (Diptera: Psychodidae).
The phlebotomine sand fly, Lutzomyia longipalpis, is the vector of visceral leishmaniasis in the New World. Variability in its tergal spot morphology has led to conflicting interpretations of the species status of the various forms. An L. longipalpis field population from eastern Brazil was found with three co-occurring morphological variations--1-spot, 2-spot, and an intermediate form. Genetic profiles were established for each form. Fifteen isoenzyme loci provided the data matrix for comparison of genetic variation among the forms. Spot patterns and isoenzyme frequencies fit Hardy-Weinberg expectations, and no significant differences in isoenzyme frequencies were associated with morphological phenotype. The spot phenotype appears to be a polymorphic character not related to genetic isolation or differentiation at the species level.
Alleles↗
Infertile women of advanced reproductive age. Variability of day 3 FSH and E2 levels.
OBJECTIVE: To evaluate the variability of basal (day 3) levels of follicle stimulating hormone (FSH) and estradiol (E2) in infertile women of advanced reproductive age. STUDY DESIGN: Retrospective analysis of day 3 FSH and E2 concentrations measured serially in patients of advanced reproductive age at a tertiary university fertility center. RESULTS: Forty-seven infertile women > or = 38 years of age (range, 38-47) undergoing ovulation induction therapy had basal FSH and E2 levels measured on two or more cycles within a two-year periods. During the study period all live births occurred in patients with day 3 FSH values < or = 13 mIU/mL and E2 values < or = 80 pg/mL, and these values were used as normative cutoffs for favorable ovarian reserve. Eleven of 38 women (28.9%) demonstrated a shift in basal values of FSH and/or E2 from the normal to the abnormal range in a subsequent cycle. Of these 11 women, 10 (90.9%) demonstrated a shift of only one hormone (FSH, n = 6) or (E2, n = 4) from the normal to the elevated range. One of 47 women (2.1%) had a shift of both basal FSH and E2 from the normal to the elevated range in a subsequent cycle. All patients who presented with or later developed an elevated day 3 level of FSH and/or E2 had persistent elevations of one or both hormones in all subsequent measurements. CONCLUSION: Day 3 FSH and/or E2 concentrations shifted from the normal to the abnormal range in 28.9% of an infertile patient population of advanced reproductive age screened serially within a two-year period. We hypothesize that serial assessment of basal FSH in combination with E2 will improve the ability to detect diminished ovarian reserve in infertile women of advanced reproductive age.
Adult↗