Search PubMed⌕ Search

Biomedical subjects

J Larkin

Publications and source records attributed to J Larkin.

At least 19 recordsLinked to original sources
PubMed1998

Cytokine-receptor complexes as chaperones for nuclear translocation of signal transducers.

A variety of ligands that include interleukins, interferons, and growth hormones activate STAT transcriptions factors. When activated, STATs are translocated to the nucleus apparently through the well described importin/Ran system where they activate target genes. Molecules utilizing this nuclear import system require specific nuclear localization sequences (NLSs). Paradoxically, such NLSs are not identifiable on STATs, raising the question of how they are imported into the nucleus. Surprisingly, most ligands and/or receptors that signal through STATs contain putative NLSs, and where examined either ligand or receptor undergo nuclear translocation. We hypothesize that these ligands and/or their receptors serve as chaperones in the nuclear translocation of STATs, and that they may be directly involved in signal transduction. Using IFN gamma as a model system we provide a possible mechanism for how this direct role is fulfilled. A C-terminal domain of IFN gamma has been identified that contains a functional NLS. Besides the fact that this domain, and the NLS in particular, is crucial for the biological properties of IFN gamma, a peptide encompassing this domain is sufficient to induce an antiviral state. Moreover, this domain interacts exclusively with an internal cytoplasmic domain of a subunit of the receptor complex in a region that is directly involved in the recruitment and activation of the elements of the JAK/STAT pathway. We suggest that this novel mode of receptor recognition and activation may be a driving force for nuclear translocation of molecules like STATs that are associated with the ligand-receptor complex.

Amino Acid Sequence↗
PubMed1998

Human IFN gamma receptor cytoplasmic domain: expression and interaction with HuIFN gamma.

To investigate the structural basis for human interferon gamma (huIFN gamma) binding to intracellular regions of the human IFN gamma receptor (huIFN gamma R), we have subcloned and expressed the huIFN gamma R free of fusion proteins in the yeast strain Pichia pastoris. HuIFN gamma bound to the cytoplasmic domain of the receptor via the IFN gamma C-terminus. Binding was inhibited by both human and mouse C-terminus peptides. N-terminus peptides failed to inhibit cytoplasmic binding. Thus, while extracellular receptor domain binding is species specific, binding to the cytoplasmic domain of the receptor is species non-specific. In solid-phase binding assays, IFN gamma had a Kd of 3.7 x 10(-8) M for the newly expressed cytoplasmic domain. Peptide competitions showed that IFN gamma bound to a receptor site corresponding to the membrane proximal residues 253-287, which is adjacent to the site of binding of the tyrosine kinase JAK2. The cytoplasmic binding affinity and binding site specificity suggest that the huIFN gamma R cytoplasmic domain can function independent of the extracellular domain to bind huIFN gamma and induce the biological activity previously associated with internalized huIFN gamma.

Animals↗
PubMed1998

Hypothesis: ligand/receptor-assisted nuclear translocation of STATs.

The STAT transcription factors are mediators of signal transduction of a variety of factors, including interferons (IFNs), interleukins, growth factors, and peptide hormones. Subsequent to activation, STATs are translocated to the nucleus apparently through the well-described importin/Ran system, where they activate target genes. Molecules utilizing this nuclear import system require specific nuclear localization sequences (NLSs). Paradoxically, such NLSs are not identifiable on STATs, thus raising the question of how they are imported into the nucleus. Of considerable interest is the observation that ligands and/or receptors that signal through STATs contain putative NLSs and, where examined, either ligand or receptor undergoes nuclear translocation. We hypothesize that ligands and/or their receptors serve as vehicles for the nuclear translocation of STATs, and that they may be directly involved in signal transduction. Using IFNgamma as a model system, we provide a possible mechanism for how this direct role is fulfilled. A functional NLS has been identified in a C-terminal domain of IFNgamma. This domain and the NLS contained within are crucial for the biological properties of IFNgamma in that a peptide encompassing this domain is sufficient to induce an antiviral state. Further, this domain binds specifically to a membrane-proximal region internal cytoplasmic domain of the alpha subunit of the receptor complex in a region that is directly involved in the recruitment and activation of the JAK/STAT pathway. We suggest that this novel mode of receptor recognition and activation may be a driving force for nuclear translocation of molecules like STATs that are associated with the ligand-receptor complex.

Amino Acid Sequence↗
PubMed1998

STD interactive case challenge--diagnosing and treating chronic vulvar pain and erythema.

A 36-year-old Caucasian woman arrives in your office, her chief complaint being vulvar pain and discomfort of 2 years' duration. She says that the onset of vulvar erythema and pain was gradual, beginning with mild tingling discomfort and eventually developing into dyspareunia and pain whenever she attempted to insert tampons, wore tight-fitting pants, or went horseback riding. The patient denies having vaginal discharge, change in menstrual pattern, or dysuria. She says she complained of the problem to several previous clinicians, who recommended anti-infective treatment for candidal vulvovaginitis, bacterial vaginosis, and recurrent cystitis, yet the symptoms persisted. One physician suggested a psychiatric evaluation, but the patient refused. She switched soap, shampoo, and even underwear fabric in an unsuccessful effort to ameliorate the symptoms. Over the past 6 months she has become increasingly frustrated with this problem.

Adult↗
PubMed1997

Acute intermittent porphyria: clinicopathologic correlation. Report of a case and review of the literature.

Acute intermittent porphyria (AIP), an autosomal dominant disorder, results from a deficiency of the enzyme hydroxymethylbilane synthase. Despite important advances in the characterization of AIP, the pathophysiology of the neurologic manifestations is not clearly understood. We present a patient with AIP followed for 31 years with multiple episodes of hyponatremia during AIP exacerbations. We discuss the clinicopathologic correlation and possible explanations for the morphologic findings, including discrete hypothalamic changes.

Adult↗
PubMed1996

Polyunsaturation in cell membranes and lipid bilayers and its effects on membrane proteins.

The effect of variation of the degree of cis-unsaturation on cell membrane protein functioning was investigated using a model lipid bilayer system and protein kinase C (PKC). This protein is a key element of signal transduction. Furthermore it is representative of a class of extrinsic membrane proteins that show lipid dependent interactions with cell membranes. To test for dependence of activity on the phospholipid unsaturation, experiments were devised using a vesicle assay system consisting of phosphatidylcholine (PC) and phosphatidylserine (PS) in which the unsaturation was systematically varied. Highly purified PKC alpha and epsilon were obtained using the baculovirus-insect cell expression system. It was shown that increased PC unsaturation elevated the activity of PKC alpha. By contrast, increasing the unsaturation of PS decreased the activity of PKC alpha, and to a lesser extent PKC epsilon. This result immediately rules out any single lipid bilayer physical parameter, such as lipid order, underlying the effect. It is proposed that while PC unsaturation effects are explainable on the basis of a contribution to membrane surface curvature stress, the effects of PS unsaturation may be due to specific protein-lipid interactions. Overall, the results indicate that altered phospholipid unsaturation in cell membranes that occurs in certain disease states such as chronic alcoholism, or by dietary manipulations, are likely to have profound effects on signal transduction pathways involving PKC and similar proteins.

Animals↗
PubMed1996

Breathing, sleep state, and rectal temperature oscillations.

Overheating may cause terminal apnoea and cot death. Rectal temperature and breathing patterns were examined in normal infants at home during the first 6 months of life. Twenty one infants had continuous overnight rectal temperature and breathing recordings for 429 nights (mean 20.4 nights, range 7-30) spaced over the first six months of life. Periods when breathing was 'regular' were directly marked on single night records. Sleep state was determined from respiratory variables. 'Regular' breathing was a reliable marker of 'quiet' sleep (specificity 93%). The duration of 'quiet' sleep increased from 6 to 22 minutes from two weeks to three months of age and then remained static, as did the proportion of sleep spent in the quiet phase (9% to 34%). Rectal temperature fell during 66% of quiet sleep and usually rose during rapid eye movement (REM) sleep. The drop in rectal temperature was maximal at the start of quiet sleep, whereas the maximum rise during REM sleep was reached after 10 to 15 minutes. Oscillations in rectal temperature are associated with changes in sleep and breathing state. The maturation of rectal temperature patterns during the first six months of life are closely related to a maturation of sleep state and breathing patterns.

Aging↗
PubMed1996

Contemporary Strategies for Detecting Chlamydial Infection in Women.

Chlamydia trachomatis infections are the most common bacterial cause of sexually transmitted disease in the US. In women, these infections often result in such serious reproductive tract complications as pelvic inflammatory disease, infertility, and ectopic pregnancy, and an infected woman can pass the infection to her newborn during delivery. The pervasiveness of this often asymptomatic disease necessitates that health care providers actively look for C trachomatis infection, especially in young women. The diagnosis of chlamydial infections has historically been difficult, but newer chlamydia diagnostic tests have become clinically available in the past decade.

Journal Article↗
PubMed1996

HIV in Women: Recognizing the Signs.

The rates of gynecologic disease in HIV-positive women have been shown to be as high as 42%; given this high percentage, a routine GYN exam can be an invaluable opportunity for the detection of subtle signs of HIV infection.

Journal Article↗
PubMed1995

Apnoea detection: human performance and reliability of a computer algorithm.

We examined the consistency of apnoea recognition between three human experts. The hypothesis was that computer detection of apnoea could emulate human expert apnoea recognition. The aim was to detect apnoeas with the highest possible accuracy from a single breathing signal, by both human experts and computer. Three human experts independently examined recordings of breathing wave-form from overnight sleep studies from 10 infants aged 3-17 weeks. All apnoeas of 5 s or more were identified and reviewed. However, there still remained 10% disagreement. A computer apnoea detector was implemented. An algorithm analysed statistical properties of the signal to find breathing pauses. Optimal performance was 1% missed apnoeas (compared with the agreed apnoeas identified by the three experts) and 29% false detections. This computer algorithm reliably identified most apnoeas but did not replace the human expert.

Algorithms↗
PubMed1994

Infant home apnoea monitors in Christchurch: an audit.

AIM: To audit parental perception of the apnoea monitor service given to neonatal graduates and infants surviving an apparent life threatening event in Christchurch. METHODS: Seventy-five of 103 sets of parents (74%), who had monitored their infants, between November 1990 and November 1992, were interviewed using a structured telephone questionnaire (apparent life threatening event (ALTE) n = 44, significant recurrent apnoea (NNU) n = 31. RESULTS: Anxiety present in most parents (83%) was relieved by monitoring (89%). Parents (97%) were satisfied with the instruction in monitor use. Eighty-nine percent had good contact with the technician, 73% called her to solve a problem. Most parents (84%) thought that initial instruction in cardiopulmonary resuscitation (CPR) was adequate. Sixty-eight percent would have liked a refresher course which only 7% of NNU and 22% of ALTE parents received. Sixty percent of parents had at least one significant alarm. Nine percent performed CPR to abort an apnoea. Ten percent of parents would have liked to monitor their child longer. CONCLUSIONS: Apnoea monitoring allays parental anxiety and may save the lives of a few infants. A technician is essential to coordinate all aspects of the service. Improvements could be made to instruction for cardiopulmonary resuscitation.

Anxiety↗
PubMed1994

Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.

The First International Workshop on Hypertrophic Osteoarthropathy crystallized the current knowledge of this puzzling syndrome. Cytokine release by large thrombocytes in the periphery is the favored etiology, although specific therapy remains unavailable. An article on the rheumatologic consequences of alcohol is reviewed, along with a number of case reports of joint problems in rare skin and metabolic diseases. Understanding the mechanisms of rarities, including rheumatic fever, interleukin-2-induced arthritis, and a unique "menstrual arthritis" might give insight into the etiology of more common arthropathies.

Alcoholism↗