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At least 145 records · Page 8Linked to original sources
PubMed1999

Multiple abnormalities of the p16INK4a-pRb regulatory pathway in cultured melanoma cells.

The retinoblastoma protein (pRb) pathway is critical in regulating the G1 phase of the cell cycle and it is frequently disrupted in human cancers. Components of the pRb pathway which are often altered in tumour progression include the INK4 cyclin-dependent kinase (CDK) inhibitors p16INK4a/ CDKN2A and p15INK4b/CDKN2B, CDK4, D-type cyclins and pRb. Several of these components were studied in a series of cultured melanoma cell lines in order to determine the frequency and spectrum of genetic alterations and to define targets for potential gene transfer studies. Also studied were the p16INK4a alternate transcript (p14ARF) and the p21(waf1) CDK inhibitor. The majority of the melanoma cell lines tested (13 out of 17; 76%) carried mutated (two), deleted (nine) or silenced (two) p16(INK4a). CDK4 was mutated or overexpressed in two melanoma cell lines with homozygously deleted CDKN2A and CDKN2B genes. This suggests that the selective growth advantages afforded by CDKN2A inactivation and CDK4 insensitivity are distinct and may involve the mediation of other CDK inhibitors or CDKs.

Blotting, Northern↗
PubMed2006

Ultrasonography in detection of single and multiple abnormal parathyroid glands in primary hyperparathyroidism: comparison with radionuclide scintigraphy and surgery.

BACKGROUND: Among the parathyroid imaging techniques, ultrasonography (USG) has the advantage of convenience, easy availability and low cost. OBJECTIVE: To study the role of USG in localization (side and/or site) of abnormal parathyroid glands in primary hyperparathyroidism (PHPT) and to compare with radionuclide scintigraphy and the 'gold standard', surgery. METHODS: Forty-six consecutive patients undergoing USG of the anterior neck for a diagnosis of PHPT in whom a nuclear scan (technetium-99m sestamibi and/or thallium-201/technetium-99m pertechnetate scintigraphy) was also performed, were studied. The results of imaging were independently interpreted and correlated with reference to surgical findings. RESULTS: Forty-six patients had 52 abnormal parathyroid glands on surgical exploration and surgery was successful in all but one. Forty-one patients had a single adenoma, four had multigland disease and one had a paraganglioma. USG correctly localized the abnormal gland in 30 (73%) and scintigraphy was positive in 40 (98%) out of 41 patients with a single adenoma as confirmed on surgical exploration. Scintigraphy showed a positive concordant test in all 30 patients with a single abnormal gland detected on USG and picked up 10 out of 11 abnormal glands where USG was negative. The sensitivity and positive predictive value of USG for detecting a single abnormal gland was 73% and 100%, respectively, whereas the sensitivity and positive predictive value for scintigraphy was 98%. In patients with multigland disease, USG missed 3 (30%) out of 10 and scintigraphy missed 6 (60%) out of 10 abnormal parathyroid glands as confirmed on surgical exploration (P < 0.05). However, in two patients who had ectopic parathyroid gland, both the modalities localized the lesion in one (paraganglioma), whereas in the other neither test was helpful (left retro-esophageal). CONCLUSION: USG is a convenient, affordable and useful modality to localize abnormal enlarged parathyroid glands in the majority of patients with PHPT. However, when USG is negative, scintigraphy is complementary to it.

Adenoma↗
PubMed1983

Thyroid function tests in chronic liver disease: evidence for multiple abnormalities despite clinical euthyroidism.

To further evaluate thyroid function in patients with liver disease, we have measured total and free T3 and T4, thyroxine binding globulin, basal and thyrotropin releasing hormone-stimulated thyrotropin and thyroglobulin antibodies in 33 patients with liver cirrhosis, in 22 with chronic hepatitis and in 30 healthy controls. All the patients but one were clinically euthyroid. T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and thyrotropin after thyrotropin releasing hormone were significantly reduced, while FT4, thyroxine binding globulin and thyrotropin were significantly increased in liver cirrhosis. In chronic hepatitis group, FT3 and T3/thyroxine binding globulin ratio were significantly lower and thyroxine binding globulin and FT4 were higher than in healthy controls. The between patients comparison revealed a significantly lower T3, FT3, T3/thyroxine binding globulin and T4/thyroxine binding globulin ratios and delta thyrotropin in cirrhotics. Thyroglobulin antibodies were present at high titre only in two patients one of whom having evidence of Hashimoto's thyroiditis with subclinical hypothyroidism. The correlation coefficient between T4/thyroxine binding globulin ratio and FT4 were lower in patients than in controls. Furthermore an abnormal thyrotropin response to thyrotropin releasing hormone was shown in 10 cirrhotics and in four patients with chronic hepatitis. Serum T3 significantly correlated with serum bilirubin, albumin, and prothrombin time in both groups of patients. The present data confirm the existence of several abnormalities of thyroid function tests in patients with chronic liver disease, although showing that euthyroidism is almost always maintained, probably as a result of low-normal FT3 and high-normal FT4. Furthermore, T3 serum levels appear to parallel the severity of liver dysfunction.

Adult↗
PubMed2004

Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability.

To assess the functional significance of upregulation of the cardiac current (IK1), we have produced and characterized the first transgenic (TG) mouse model of IK1 upregulation. To increase IK1 density, a pore-forming subunit of the Kir2.1 (green fluorescent protein-tagged) channel was expressed in the heart under control of the alpha-myosin heavy chain promoter. Two lines of TG animals were established with a high level of TG expression in all major parts of the heart: line 1 mice were characterized by 14% heart hypertrophy and a normal life span; line 2 mice displayed an increased mortality rate, and in mice < or =1 mo old, heart weight-to-body weight ratio was increased by >100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, IK1 conductance at the reversal potential was increased approximately 9- and approximately 10-fold in lines 1 and 2, respectively. Expression of the Kir2.1 transgene in line 2 ventricular myocytes was heterogeneous when assayed by single-cell analysis of GFP fluorescence. Surface ECG recordings in line 2 mice revealed numerous abnormalities of excitability, including slowed heart rate, premature ventricular contractions, atrioventricular block, and atrial fibrillation. Line 1 mice displayed a less severe phenotype. In both TG lines, action potential duration at 90% repolarization and monophasic action potential at 75-90% repolarization were significantly reduced, leading to neuronlike action potentials, and the slow phase of the T wave was abolished, leading to a short Q-T interval. This study provides a new TG model of IK1 upregulation, confirms the significant role of IK1 in cardiac excitability, and is consistent with adverse effects of IK1 upregulation on cardiac electrical activity.

Action Potentials↗
PubMed1997

BCR/ABL induces multiple abnormalities of cytoskeletal function.

The BCR/ABL oncogene causes human chronic myelogenous leukemia (CML), a myeloproliferative disease characterized by massive expansion of hematopoietic progenitor cells and cells of the granulocyte lineage. When transfected into murine hematopoietic cell lines, BCR/ABL causes cytokine-independence and enhances viability. There is also growing evidence that p210(BCR/ABL) affects cytoskeletal structure. p210(BCR/ABL) binds to actin, and several cytoskeletal proteins are tyrosine phosphorylated by this oncoprotein. Also, at least one aspect of cytoskeletal function is abnormal, in that the affinity of beta1 integrins for fibronectin is altered in CML cells. However, isolated changes in beta1 integrin function would be unlikely to explain the clinical phenotype of CML. We used time-lapse video microscopy to study cell motility and cell morphology on extracellular cell matrix protein-coated surfaces of a series of cell lines before and after transformation by BCR/ABL. BCR/ABL was associated with a striking increase in spontaneous motility, membrane ruffling, formation of long actin extensions (filopodia) and accelerated the rate of protrusion and retraction of pseudopodia on fibronectin-coated surfaces. Also, while untransformed cells were sessile for long periods, BCR/ABL-transformed cells exhibited persistent motility, except for brief periods during cell division. Using cell lines transformed by a temperature-sensitive mutant of BCR/ABL, these kinetic abnormalities of cytoskeletal function were shown to require BCR/ABL tyrosine kinase activity. Similar abnormalities of cytoskeletal function on fibronectin-coated surfaces were observed when hematopoietic progenitor cells purified by CD34 selection from patients with CML were compared with CD34 positive cells from normal individuals. Interestingly, alpha-interferon treatment was found to slowly revert the abnormal motility phenotype of BCR/ABL-transformed cells towards normal. The increase in spontaneous motility and other defects of cytoskeletal function described here will be useful biological markers of the functional effects of BCR/ABL in hematopoietic cells.

3T3 Cells↗
PubMedDate not supplied

Alleviation of multiple abnormalities by galantamine treatment in two patients with dementia with Lewy bodies.

Two patients diagnosed with dementia with Lewy bodies (DLB) presented with prominent behavioral disturbances. The first patient experienced well-formed visual hallucinations, movement disorders, and cognitive decline and was increasingly resistant to care. He was treated with galantamine 4 mg bid, which was increased to 8 mg bid after four weeks. Improvements in behavior, attention, and cognition made it possible for this patient to be transferred back to long-term care after 32 days. The second patient had increasing confusion, fluctuating cognition, agitation, and psychosis. He was given donepezil initially, then switched to galantamine 4 mg bid. He was assessed as stable for discharge with improved behavior control after three weeks. Both patients also were receiving an atypical antipsychotic (quetiapine) and an antidepressant (venlafaxine and sertraline, respectively).

Aged↗
PubMed1991

Multiple abnormalities in insulin responses to nonglucose nutrients in neonatally streptozotocin diabetic rats.

Insulin responses to nutrient secretagogues were investigated in neonatally streptozotocin-injected (n-STZ) rats, i.e. an animal model of noninsulin-dependent diabetes. In the perfused pancreas 16 mM L-glutamine induced and 10 mM octanoate tended to induce (P less than 0.2) higher responses in n-STZ than in nondiabetic rats. Addition of 3.9 mM glucose potentiated responses to glutamine and octanoate more in n-STZ (3.3- and 3.4-fold) than in nondiabetic rats (1.5- and 1.9-fold). Conversely, the succinate derivative succinate monomethylester (Succ ME) induced lesser response in n-STZ rats (57% of that in nondiabetic rats) and coperfusion with 3.9 mM glucose increased the response less in n-STZ (1.4-fold) than in nondiabetic rats (3.8-fold). Pyruvate (20 mM) mimicked the potency of 3.9 mM glucose, i.e. pyruvate potentiated the response to Succ ME only nonsignificantly (1.2-fold) in n-STZ but markedly (4.9-fold) in nondiabetic rats. Dichloroacetate (20 mM) failed to affect the response to Succ ME together with pyruvate in n-STZ rats. To investigate the role of hyperglycemia for octanoate-induced secretion, nondiabetic rats were made hyperglycemic by 48-h glucose infusions. Octanoate-induced secretion from perfused pancreas was enhanced 3.8-fold after moderate hyperglycemia (13.2 +/- 0.6 mM) and 17-fold after marked hyperglycemia (22.7 +/- 0.6 mM). This positive association between response and degree of hyperglycemia was not found with a nonnutrient secretagogue, 3-isobutyl-1-methylxanthine. Results with glutamine and octanoate indicate that oxidation of nonglucose nutrients which normally do not regulate secretion is enhanced secondary to chronic hyperglycemia. Results with Succ ME and pyruvate suggest that early steps of oxidation of glucose are impaired in n-STZ rats.

1-Methyl-3-isobutylxanthine↗
PubMed1980

Multiple abnormalities of anterior pituitary hormone secretion in association with pseudohypoparathyroidism.

A male with pseudohypoparathyroidism presented with several hormonal abnormalities. He was clinically euthyroid with no palpable goiter, His serum T4, total T3, T3 Sephadex retention, and 131I uptake were normal. However, elevated basal TSH levels and exaggerated TSH responses to TRH which normalized during the administration of thyroid extract suggested reduced thyroidal reserve. Despite these finding the 131I uptake increased after exogeneous TSH, and the T3 level rose after TRH. Basal testosterone levels and response to hCG were normal however, gonadotropins were elevated and there was an exaggerated response after LRH treatment. Both LH and FSH levels were suppressed by testosterone propionate. The patient demonstrated intermittent basal hyperprolactinemia and impaired PRL responsiveness after metolopramide, chlorpromazine, and insulin administration. There was, however, an intact response to TRH. Basal PRL, TSH, and LH levels decreased after the administration of L-dopa and bromocriptine. Although the precise mechanism underlying these finding is unknown, the elevated basal levels of TSH, LH, and FSH and the exaggerated responses to their respective releasing hormones suggest the presence of partial degree of end-organ resistance to these pituitary trophic hormones. Together with the resistance to PTH, this may imply a common defect, presumably at a postreceptor level. However, hyporesponsiveness of PRL to metoclopramide and chlorpromazine and normal responsiveness to TRH suggest that an abnormality of dopamine tone also exists in pseudohypoparathyroidism.

Adolescent↗
PubMed1992

Vascular smooth muscle growth in genetic hypertension: evidence for multiple abnormalities in growth regulatory pathways.

OBJECTIVE: To gain insight into the mechanisms which contribute to the development of vascular hypertrophy in the spontaneously hypertensive rat (SHR). DESIGN: These experiments were performed under conditions which most closely mimic the growth of smooth muscle in blood vessels, i.e. once cell-cell contact has been achieved. METHODS: A comparison of the growth characteristics (growth rates and cell density at quiescence) of vascular smooth muscle cells (VSMC) from SHR and normotensive Wistar-Kyoto (WKY) rats. RESULTS: In the presence of foetal calf serum (1, 2.5, 5 and 10%), early passaged VSMC from SHR exhibited higher growth rates and reached higher densities at quiescence than VSMC from WKY rats. Accelerated growth rates could not be attributed to differences in cell-cell interactions. Also, growth rates and cell density at quiescence appear to be regulated by distinct mechanisms. Transforming growth factor-beta 1 (TGF-beta 1) caused an inhibition of serum-stimulated proliferation of confluent VSMC from WKY rats. In contrast, TGF-beta 1 had little, if any, inhibitory action upon the growth of VSMC from SHR. Scatchard analysis of 125I-TGF-beta 1 binding to VSMC from both strains yielded a single class of high affinity binding sites. CONCLUSIONS: VSMC from SHR exhibit enhanced proliferation, attain a higher cell density at quiescence and are less susceptible to growth inhibition by TGF-beta 1 than VSMC from WKY rats. All these characteristics of SHR VSMC may contribute to the development of vascular hypertrophy in this strain.

Animals↗
PubMed1989

[Xipho-omphalopagus--Siamese twins with multiple abnormalities of the gastrointestinal tract].

The authors describe a case of xiphoomphalpagus; one infant was dead, the other alive. They had a common umbilical cord and omphalocele, joined liver, only one gallbladder and common duodenum in the shape of a wide sac. From this originated two thin guts, one was wide and belonged to the dead foetus, the gut of the live foetus beneath the duodenum was atretic. Already six hours after delivery the authors separated the infants and in the live infant they not only resected the liver and reinserted the choledochus but also repaired the wide duodenum and atresia. The second infant died on the 4th day after operation from congenital heart disease incompatible with life. The stillborn infant has, as revealed by necropsy and histological examination, a congenital megacolon. The authors analyze the scope of diagnostic and surgical possibilities.

Digestive System Abnormalities↗
PubMed1988

Multiple abnormal beta-hexosaminidase alpha chain mRNAs in a compound-heterozygous Ashkenazi Jewish patient with Tay-Sachs disease.

Abnormal beta-hexosaminidase alpha chain cDNA clones were isolated from fibroblasts of an Ashkenazi Jewish patient with Tay-Sachs disease. Four abnormal cDNA clones were sequenced in their entirety. We showed previously that three of these mRNAs retained intron 12 with a mutation from G to C at the 5' donor site and that the patient was heterozygous with respect to this splicing defect (Ohno, K., and Suzuki, K., (1988) Biochem. Biophys. Res. Commun. 153, 463-469). One clone retained, in addition to intron 12, intron 13, which was truncated and polyadenylated due to a polyadenylation signal within intron 13. The fourth clone did not contain intron 12 and was missing exon 12. Some of these abnormal mRNAs were also missing one or more of upstream exons. The regions of exon 12-intron 12 and of upstream exons were evaluated in a total of 30 clones, including those completely sequenced, by restriction mapping and Southern analysis with appropriate probes. Of the 25 cDNA clones that included the exon 12-intron 12 region, 11 contained the exon 12-intron 12 sequence with the junctional transversion, and 11 were missing both exon 12 and intron 12. Among the 12 clones that included the region of exon 3-exon 9, 7 were missing one or more of upstream exons. Three clones gave results expected of normal cDNA in the region of exons 12 and 13. One of the three, furthermore, was 3.6-kilobases long and contained the completely normal beta-hexosaminidase alpha chain mRNA sequence on the 3' side and an abnormal 1.7-kilobase segment at the 5' end. These findings suggest that the splicing defect results in either retention of intron 12 or skipping of exon 12 in approximately equal proportions and that remote upstream exons are also frequently excised out. The three clones that were normal in the exon 12-intron 12 region could have derived from the other yet-to-be-characterized mutant allele. However, we were unable to obtain firm evidence that the abnormal upstream sequence is directly related to Tay-Sachs disease.

Base Sequence↗