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Biomedical subjects

H Little

Publications and source records attributed to H Little.

At least 19 recordsLinked to original sources
PubMed2006

Protein kinase C delta inhibits Caco-2 cell proliferation by selective changes in cell cycle and cell death regulators.

PKC-delta is a serine/threonine kinase that mediates diverse signal transduction pathways. We previously demonstrated that overexpression of PKC-delta slowed the G1 progression of Caco-2 colon cancer cells, accelerated apoptosis, and induced cellular differentiation. In this study, we further characterized the PKC-delta dependent signaling pathways involved in these tumor suppressor actions in Caco-2 cells overexpressing PKC-delta using a Zn2+ inducible expression vector. Consistent with a G1 arrest, increased expression of PKC-delta caused rapid and significant downregulation of cyclin D1 and cyclin E proteins (50% decreases, P<0.05), while mRNA levels remained unchanged. The PKC agonist, phorbol 12-myristate 13-acetate (TPA, 100 nM, 4 h), induced two-fold higher protein and mRNA levels of p21(Waf1), a cyclin-dependent kinase (cdk) inhibitor in PKC-delta transfectants compared with empty vector (EV) transfected cells, whereas the PKC-delta specific inhibitor rottlerin (3 microM) or knockdown of this isoenzyme with specific siRNA oligonucleotides blocked p21(Waf1) expression. Concomitantly, compared to EV control cells, PKC-delta upregulation decreased cyclin D1 and cyclin E proteins co-immunoprecipitating with cdk6 and cdk2, respectively. In addition, overexpression of PKC-delta increased binding of cdk inhibitor p27(Kip1) to cdk4. These alterations in cyclin-cdks and their inhibitors are predicted to decrease G1 cyclin kinase activity. As an independent confirmation of the direct role PKC-delta plays in cell growth and cell cycle regulation, we knocked down PKC-delta using specific siRNA oligonucleotides. PKC-delta specific siRNA oligonucleotides, but not irrelevant control oligonucleotides, inhibited PKC-delta protein by more than 80% in Caco-2 cells. Moreover, PKC-delta knockdown enhanced cell proliferation ( approximately 1.4-2-fold, P<0.05) and concomitantly increased cyclin D1 and cyclin E expression ( approximately 1.7-fold, P<0.05). This was a specific effect, as nontargeted PKC-zeta was not changed by PKC-delta siRNA oligonucleotides. Consistent with accelerated apoptosis in PKC-delta transfectants, compared to EV cells, PKC-delta upregulation increased proapoptotic regulator Bax two-fold at mRNA and protein levels, while antiapoptotic Bcl-2 protein was decreased by 50% at a post-transcriptional level. PKC-delta specific siRNA oligonucleotides inhibited Bax protein expression by more than 50%, indicating that PKC-delta regulates apoptosis through Bax. Taken together, these results elucidate two critical mechanisms regulated by PKC-delta that inhibit cell cycle progression and enhance apoptosis in colon cancer cells. We postulate these antiproliferative pathways mediate an important tumor suppressor function for PKC-delta in colonic carcinogenesis.

Apoptosis↗
PubMed1995

Bilateral bullous exudative retinal detachment complicating idiopathic central serous chorioretinopathy during systemic corticosteroid therapy.

PURPOSE: To present evidence that systemic corticosteroid therapy may cause bilateral bullous serofibrinous exudative retinal detachment in some patients with idiopathic central serous chorioretinopathy. BACKGROUND: Idiopathic central serous chorioretinopathy usually causes mild, transient loss of central vision, usually in otherwise healthy men with a type A personality. A few patients have permanent visual loss because of chronic and recurrent retinal detachment. The clinical findings in these patients may lead to incorrect diagnoses and use of corticosteroid therapy. METHODS: The clinical and photographic records of three patients in whom bilateral bullous serofibrinous exudative retinal detachment associated with idiopathic central serous chorioretinopathy developed after treatment with systemic corticosteroids were reviewed. RESULTS: Systemic corticosteroid treatment was instituted (1) as a prophylaxis to prevent exacerbation of the disease while undergoing surgery in the fellow eye, and (2) as the result of misdiagnoses of multifocal choroiditis and retinal vasculitis (Eales disease). Two of the patients had a history of chronic recurrent retinal detachments before institution of corticosteroid treatment. In one of these patients, bilateral chronic inferior retinal detachment developed, causing peripheral retinal vascular nonperfusion, retinal neovascularization, and vitreous hemorrhage. All three patients had severe permanent visual loss in one or both eyes. CONCLUSION: The findings in these patients provide further evidence that systemic corticosteroid treatment may cause severe exacerbation of retinal detachment and lasting visual loss in some patients with idiopathic central serous retinopathy. Recognition of the atypical presentations of this disorder is important to avoid incorrect diagnoses and treatment.

Adrenal Cortex Hormones↗
PubMed1994

Current concepts of ethanol dependence.

Alcohol dependence is considered to be divisible into two types (although the divisions between these are indistinct). These are psychological dependence, in which the rewarding effects of alcohol play a primary role, and chemical dependence, in which adaptive changes in the brain initiate punishing effects on withdrawal of alcohol, and suppression of these becomes the primary motive for using the drug. The neurochemical basis for the rewarding effects of alcohol may be the potentiation of GABA at GABAA receptors (causing relaxation) and release of dopamine from mesolimbic neurones (causing euphoria). The adaptive changes which cause the alcohol withdrawal syndrome are not known for certain, but alterations in GABAA receptors, NMDA receptors and voltage-operated calcium channels all have a claim. However, it is distinctly doubtful whether these all contribute to the negatively reinforcing effects of alcohol that are important in chemical dependence, although they may be important in other pathological effects of alcohol abuse. Current research badly needs better communication between basic scientists and clinicians to establish research goals and to improve current models.

Alcohol Drinking↗
PubMed1992

A patient with Werner's syndrome and osteosarcoma presenting as scleroderma.

Werner's syndrome (WS) is often mistaken for scleroderma. We describe a patient with WS who presented with an enlarging, painful mass of the right knee that proved to be a juxtaarticular osteosarcoma of the distal femur. Recognition of WS and prompt investigation of any painful, enlarging masses to exclude sarcomatous degeneration will benefit these patients.

Bone Neoplasms↗
PubMed1986

Benzodiazepine-receptor mediated convulsions in infant rats: effects of beta-carbolines.

The effects of anticonvulsant and proconvulsant benzodiazepine-receptor ligands were studied in infant rats. The agonist flurazepam increased myoclonic twitching of the limbs as has previously been reported. In contrast, the convulsant beta-carbolines DMCM and beta-CCM did not produce twitching, but did produce marked increases in locomotor activity and whole body shakes. The standard convulsants pentylenetetrazol and bicuculline similarly increased locomotor activity and shaking. These findings suggest that the effects of agonist benzodiazepines cannot be interpreted as convulsant-type behaviour. In addition, the finding that DMCM and beta-CCM have equivalent effects despite showing preferential affinities for benzodiazepine-receptor subtypes argues against one particular subtype having proconvulsant effects.

Animals↗
PubMed1984

Specific effects of drugs at pressure: animal investigations.

The interactions of anaesthetics and other drugs with high pressure suggest that protection against the high pressure neurological syndrome (h.p.n.s.) can no longer be considered in terms of generalized non-specific mechanisms. The evidence from our work shows that anaesthetics may either protect, have no effect, or potentiate h.p.n.s. Structural analogues of the steroid anaesthetic Althesin have a protective effect against high pressure tremors in spite of the fact that they have no anaesthetic effects. Low doses of flurazepam are effective against tremor but can be antagonized by Ro 15-1788, which implies in this case a role for the benzodiazepine receptor complex. Pressure interactions with other drugs have included the classic anticonvulsants--which, in general, were relatively ineffective--and various agents perturbing the balance of specific neurotransmitter systems. Representative examples from different studies include 6-hydroxydopamine, muscimol, and sodium valproate. Finally, the potent protection against h.p.n.s. by 2-amino-phosphonoheptanoic acid, an antagonist with preferential action against excitation produced by aspartate and N-methyl-D-aspartate, provides the first evidence that enhanced excitatory amino acid neurotransmission may have an important role in the h.p.n.s.

Amino Acids↗
PubMed1983

The natural disease course of ankylosing spondylitis.

One hundred fifty war veterans with ankylosing spondylitis were entered into a prospective study in 1947. In 1957, 142 were traced, and they have been reviewed periodically. Eighty-one of these patients were still alive in 1980. Information was obtained from 67 (83%) of the survivors and 51 were reexamined. This report is based on the clinical findings in these 51 patients, who have a mean disease duration of 38 years. Forty-seven (92%) were functioning well. The disease in 21 (41%) had progressed to cause severe spinal restriction. Of those, 12 had peripheral joint involvement early in their course and 9 had iritis. Seventy-four percent of the patients who had mild spinal restriction after 10 years did not progress to having more severe restriction. Eighty-one percent of the patients who had severe spinal restriction in 1980 were severely restricted within the first 10 years. Hips that were normal after 10 years of disease did not become diseased subsequently. This study suggests that a predictable pattern of ankylosing spondylitis emerges within the first 10 years of the disease.

Adult↗
PubMed1976

Upward subluxation of the axis in ankylosing spondylitis. A clinical pathologic report.

Upward subluxation of the axis associated with cord compression and death was noted in a patient with a long history of idiopathic ankylosing spondylitis. Upward subluxation of the axis has been recognized in up to 8 per cent of patients with rheumatoid arthritis but it is an exceedingly rare complication of ankylosing spondylitis. In this patient psoriasis and then psoriatic dactylitis developed 26 years after the onset of his ankylosing spondylitis. It is tempting to speculate that the unusual destruction of the joints around the atlas might be due to an added effect of psoriasis on idiopathic ankylosing spondylitis.

Adult↗
PubMed1975

Psoriatic arthritis in severe psoriasis.

SUMMARY: Of 100 patients admitted to hospital for treatment of psoriasis, 32 had clinical or radiologic evidence of psoriatic arthritis and 17 had both types of evidence. Eight had radiologic evidence of spinal or sarroiliac involvement without symptoms and seven had clinical evidence of peripheral arthritis without radiologic evidence. Patients with psoriatic sacroilitis and spondylitis were most likely to have typical radiograpic changes. It was concluded that psoriatic arthritis is common in patients with severe psoriasis and that is associated with more extensive skin disease than is found in patients without arthritis.

Arthritis↗
PubMed1973

Painful feet in rheumatoid arthritis.

Pain in the feet is an important diagnostic feature and a major management problem of rheumatoid arthritis. Of 50 hospitalized patients, 28% recalled painful feet as the sole presenting symptom of their disease.RHEUMATOID DISEASE COMMONLY AFFECTS THE FEET: 90% of the patients studied complained of foot pain at some time during the course of their disease, 86% had clinical involvement and 92% had radiological changes in their feet.The forefoot is most frequently involved. Midfoot involvement was noted in 68% but was symptomatic in only 22%. Changes in the ankle were least common but always symptomatic.

Adult↗