Biomedical subjects
D Murphy
Publications and source records attributed to D Murphy.
Extrahypothalamic expression of the vasopressin and oxytocin genes.
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Regulation of the extent of polyadenylation of vasopressin and growth hormone mRNAs in response to physiological stimuli.
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Enzymatic labeling of biologically active envelope glycoprotein gp120 of HIV-1.
We have found that the envelope glycoprotein gp120 of HIV-1 can be modified extensively by enzymatic oxidation of oligosaccharide chains without diminishing binding to its natural receptor, CD4. Using affinity purified galactose oxidase, over 20 sites per gp120 molecule were converted to chemically reactive aldehydes, as measured by 3H-BH4 reduction, while the conformation-dependent CD4 binding site remained intact. In contrast, periodate oxidation completely destroyed CD4 binding while producing fewer sites. Enzymatically labeled, biologically active gp120 should facilitate biochemical studies of receptor binding and viral inactivation by neutralizing antibodies.
Neuron-specific expression and physiological regulation of bovine vasopressin transgenes in mice.
We have used transgenic mice to analyse the regulation of the bovine vasopressin (BVP) gene. We find that the restriction of BVP gene expression to anatomically and functionally distinct hypothalamic neuronal groups is achieved, in part, by selective repression. The expression of a 1.25 kb BVP proximal promoter, which on its own confers general expression of a reporter to most peripheral and brain tissues, was limited by sequences in the BVP structural gene to neural cells in the adrenal medulla and brain. Transgene expression in the hypothalamus was shown to be regulated by the physiological stimulus of dehydration in parallel with the endogenous gene. The expression of a larger 13.4 kb BVP transgene, containing 9 kb of 5' upstream sequence, the VP structural gene and 1.5 kb 3' of the transcription unit, was even more restricted and resembles that of the endogenous mouse gene. Hypothalamic expression of the 13.4 kb BVP transgene was regulated appropriately in response to an osmotic challenge.
Regulation of vasopressin gene expression: changes in the level, but not the size, of vasopressin mRNA following endocrine manipulations.
1. Regulatory interactions between the hypothalamoneurohypophyseal vasopressin (VP) axis and the endocrine systems of the anterior pituitary have been investigated in the rat by observing changes in VP mRNA expression following endocrine manipulations. 2. An increase in the level, but not size, of VP mRNA was found in the supraoptic (SON) and paraventricular nuclei (PVN) of the hypothalamus and in the neurointermediate lobe (NIL) of the pituitary following hypothyroidism (induced by drinking 6-n-propyl-2-thiouracil; PTU) and adrenalectomy. Hypothyroidism induced by alternative procedures (surgical thyroidectomy or PTU injections) did not exert similar effects. 3. Treatment with the dopamine agonist bromocriptine to reduce prolactin secretion raised levels of VP mRNA in the NIL only. Castration did not up-regulate VP mRNA levels. 4. Since the observed effects on VP mRNA levels occur in the absence of changes in plasma osmolality, these results provide evidence of nonosmotic regulation of VP gene expression, an effect which is observed most clearly in the NIL pool of VP mRNA. Furthermore, the effects are distinct from changes in VP mRNA levels associated with raised plasma osmolality since the VP mRNA size was not increased.
Risk profile for Chlamydia infection in women from public health clinics in New York State.
The prevalence of chlamydial infection and associated risk factors were studied in 1531 women from ten clinics in New York State excluding New York City. Overall Chlamydia infection rates were 13.6%; 17.6% in eight high risk family planning and STD clinics, and 5.7% in two low risk college and private clinics. Risk factors for Chlamydia infection included: age < 20 years (odds ratio 1.6), use of oral contraceptives (odds ratio 2.0), a history of having more than one sexual partner (odds ratio 1.7) and, in one clinic where data was available, inflammation on Papanicolaou smears (odds ratio 2.1). These data helped secure funding for Chlamydia preventive services and permitted development of a risk profile (score card) of Chlamydia for each age group. Use of such a score card can be most helpful in assigning which patients could benefit most from Chlamydia cultures, especially in those areas where testing is unavailable or too costly to screen all patients.
Electrical impedance plethysmography: its use in studying the cerebral circulation of the rabbit.
Electrical impedance plethysmography (EIP) is a noninvasive method that may be useful for both the continuous and serial measurement of changes in pulsatile cerebral blood volume and perhaps cerebral blood flow (CBF). It has not been well validated by comparison with other methods. To attempt to validate the EIP technique, the relationship between the peak amplitude of the transcranial, cardiac-synchronous impedance waveform (dZp) and cerebral blood flow measured by the radiolabelled microsphere technique (CBFrlm) and laser Doppler spectroscopy (CBFlds) was studied in rabbits. CBF was altered by inducing hypertension using metaraminol, hypotension by controlled haemorrhage or hypocarbia by hyperventilation. Twenty-three comparisons between dZp and CBFlds and 19 comparisons with CBFrlm were made in eight rabbits. The percentage change between each measurement using the three techniques in each animal was calculated. Using pooled data from all the animals, the linear regression equations were dZp = 0.5 CBFrlm + 33 (r = 0.38, p = 0.22, SE = 79) and dZp = 0.84 CBFlds + 19.6 (r = 0.46, p = 0.09, SE = 72). It is concluded that, in the anaesthetised rabbit, when large changes in CBF are induced by the manoeuvres described above, changes in dZp correlate very weakly with changes in either cortical or global CBF, and are influenced by other factors such as pulsatile intracranial blood volume.
Neurohypophyseal peptides as regulators of growth and development. A review.
In addition to their classical hormonal role, the neurohypophyseal peptides vasopressin (AVP) and oxytocin (OT) are also implicated as regulators of growth and development. Mitogenic actions of AVP are particularly well characterized and may underly the potential role of AVP as an autocrine regulator of tumor growth. Effects of AVP and OT on neural development are suggested by numerous studies, but definitive physiological evidence is lacking. Current studies on the molecular characterization of AVP and OT receptors, and on transgenic animals will provide insights into the developmental actions of neurohypophyseal peptides.
The influence of interleukin-2 on vasopressin and oxytocin gene expression in the rodent hypothalamus.
There is growing evidence of interactions between the central nervous system and the immune system. We present evidence that the cytokine interleukin-2 (IL-2) influences expression of the genes encoding the neuropeptides vasopressin (VP) and oxytocin (OT) in the hypothalamus of the nude mouse. A single injection of recombinant mouse IL-2 (rmIL-2) caused a significant increase in VP and OT mRNA levels in the hypothalamus of nude mice. This effect was specific to the nude mouse. These observations stress the potential value of the nude mouse for studying interactions between the central nervous system (CNS) and the immune system.
Osmotic stimuli attenuate vasoactive intestinal peptide gene expression in the rat anterior pituitary gland.
Studies on vasoactive intestinal peptide (VIP) in the anterior pituitary gland have shown that it is synthesized locally, physiologically regulated, and may act as a paracrine/autocrine factor. We have now investigated the regulation of anterior pituitary VIP gene expression in rats during osmotic stimulation. Both salt-loading and dehydration resulted in a progressive and marked reduction in VIP mRNA levels as determined by Northern analysis, to 10% of control levels at 14 days of salt-loading. The 1.7 and 1.0 kb VIP RNA transcripts were equally affected. Since anterior pituitary VIP is partially localized in lactotrophs we also measured prolactin (PRL) mRNA levels. In contrast to VIP, PRL mRNA levels were increased during both osmotic paradigms, the mRNA levels being significantly raised after 5 days of salt-loading to 130% of controls. Further experiments, conducted to examine the mechanism by which VIP gene expression is down-regulated during osmotic stimulation, demonstrated that dopamine and angiotensin II do not appear to be involved. The results show dissociated regulation of VIP and PRL during osmotic stimulation and provide suggestive evidence of a role for anterior pituitary VIP in the animal's osmoregulatory responses. VIP may therefore be a paracrine factor with diverse functional roles.
A randomised dose intensity study in ovarian carcinoma comparing chemotherapy given at four week intervals for six cycles with half dose chemotherapy given for twelve cycles.
BACKGROUND: The importance of dose intensity has not been clearly defined in ovarian cancer and we present a prospectively randomised trial of dose intensity in patients with ovarian cancer. PATIENTS AND METHODS: Ninety-nine patients with FIGO stage Ic, II, III and IV epithelial ovarian cancer were randomised to receive cycles of standard dose cyclophosphamide (600 mg/m2) and carboplatin (300 mg/m2) alternating with adriamycin (50 mg/m2) and ifosfamide (5 G/m2) for 6 cycles at monthly intervals (49 patients) or cycles of half dose cyclophosphamide (300 mg/m2) and carboplatin (150 mg/m2) alternating with adriamycin (25 mg/m2) and ifosfamide (2.5 G/m2) for 12 cycles at monthly intervals (50 patients). Patients in each arm were well balanced for major prognostic factors. RESULTS: The combined clinical response rate (complete response and partial response) on the 6 month arm was 76% compared with 48% on the low dose intensity arm (p = 0.009). With a median follow up of 25.7 months the median survival on the low dose intensity arm is 20.9 months. The median survival point on the 6 month arm has not yet been reached. The median progression free interval on the 12 month arm was 19.8 months, the median value has not yet been reached on the standard arm. The amount of residual tumour following initial laparotomy was the only significant independent variable affecting survival (p = 0.0001). The mean received dose intensity of each drug was greater than 80% of the planned dose intensity. More patients had clinical disease progression during treatment on the low dose intensity arm (42%) when compared to the standard dose intensity arm (8%) (p = 0.0003). Fifteen patients on the standard dose arm experienced a total of 18 delays and 5 patients on the low dose arm experienced 17 delays. Nausea, vomiting and diarrhoea were similar for both standard and low dose cycles of chemotherapy with a consequent benefit for patients receiving fewer cycles even though these were of higher dose. CONCLUSIONS: The combination studied was more effective when given at the higher dose intensity and the improved response and survival was not accompanied by a significant increase in toxicity.
Managing patient stress in endoscopy.
Most patients experience a certain degree of stress as they prepare for and undergo endoscopy procedures. The stress they experience is correlated to Hans Seyle's General Adaptation Syndrome theory in this article. Stressful events that occur pre-, intra-, and postprocedure are identified. Examples of patient coping skills are discussed. Several nursing interventions such as patient teaching, relaxation techniques, and communication skills are described. All of these interventions assist the nurse in promoting a positive outcome for the patient. As a patient experiences a positive outcome from a stressful event, coping mechanisms are strengthened and developed. These coping mechanisms enable the patient to adapt to future stressors.
In vitro regulation of rat prolactin messenger ribonucleic acid poly(A) tail length: modulation by bromocriptine.
Recent analysis of endocrine gene transcripts has revealed that several hormone mRNAs exhibit regulated size changes (due to alterations in length of the 3' poly(A) tail) which may function as an additional level of control in the determination of gene expression. We have now shown, through the novel application of an organ culture technique, that prolactin mRNA exhibits a similar regulated change in poly(A) tail length when rat anterior pituitary glands are explanted. The effect is observed in glands of either male or female rats and is specific with respect to growth hormone and alpha-tubulin mRNAs. Furthermore, we have also found that the size change in prolactin mRNA is attenuated in the presence of bromocriptine, indicating regulation through a dopaminergic pathway.
Regulation of vasopressin (VP) gene expression in the bed nucleus of the stria terminalis: gonadal steroid-dependent changes in VP mRNA accumulation are associated with alterations in mRNA poly (A) tail length but are independent of the rate of VP gene transcription.
Forebrain vasopressin (VP) neurons of the bed nucleus of the stria terminalis (BNST) contrast with hypothalamic VP neurons in exhibiting nuclear gonadal steroid receptors which may directly effect steroid-induced changes in VP gene expression observed in BNST cells. A transcription and Northern mRNA analysis has been performed to determine the mechanism through which gonadal steroids regulate VP gene expression in the BNST. In addition to confirming a distinctive, sexually dimorphic pattern of VP mRNA expression in the BNST as compared with the hypothalamic supraoptic nuclear (SON), our results show that the marked decrease in BNST VP mRNA levels observed two weeks after castration is not associated with a change in transcriptional activity of the VP gene. Similarly, VP gene transcription is not increased, relative to castrated animals, in the BNST of castrated rats treated with testosterone which exhibit normal or somewhat elevated levels of VP mRNA in the BNST. A post-transcriptional mechanism therefore appears to underlie the gonadal steroid-regulated changes in VP gene expression in the BNST. Since modulation of mRNA size (due to changes in poly (A) tail length) was also observed following castration and testosterone treatment it is apparent that the post-transcriptional mechanism may involve regulated changes in VP mRNA poly (A) tail length. The present findings contrast with the osmotic up-regulation of VP mRNA levels in the SON which is primarily a transcriptional response, and provide a demonstration of the potential physiological importance of post-transcriptional mechanisms of hormonal gene regulation.
Primary seminal vesicle choriocarcinoma.
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An unusual case of traumatic primary amenorrhoea.
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Large DNA restriction fragment polymorphism in the Mycobacterium avium-M. intracellulare complex: a potential epidemiologic tool.
Mycobacterium avium-M. intracellulare complex (MAI) isolates were studied by comparing the large restriction fragment (LRF) patterns produced by digesting their DNAs with infrequently cutting restriction endonucleases and separating the resultant large fragments by pulsed-field gel electrophoresis. Four reference strains and 35 randomly selected clinical MAI isolates gave highly diverse LRF patterns when their DNAs were digested with XbaI or AsnI. The LRF patterns of random isolates identified to be the same species by DNA probe analysis were not similar. The LRF patterns of random isolates of the same serotype were also different. In contrast, all isolates recovered from the same patient gave identical patterns. This included 28 isolates from nine patients. One isolate from sputum, one isolate from bone marrow, and two isolates from blood recovered over a 27-month period from a patient with AIDS were identical. Seven isolates recovered from the sputum of a second patient over 37 months also had identical patterns. The LRF patterns of unrelated MAI strains are highly polymorphic, appear to be strain specific, are relatively stable, and offer exciting promise as epidemiologic markers for the study of MAI infections.