Evaluating unmet needs in patients undergoing surgery for colorectal cancer: a patient reported outcome measures study.

AIM: Patient reported outcome measures (PROMs) are self-reported measures of patients' health status or health-related quality of life at a single point in time. We aimed to evaluate the use of a colorectal PROM and conducted a focus group to further explore this and other unmet needs in our patient population treated surgically for colorectal cancer. METHOD: A multidisciplinary research group consisting of colorectal surgeons, nurse specialists, psychologists, sociologists and patient representatives devised a composite tool of new and existing outcome measures which was piloted in our local population (n = 35). Participants were subsequently invited to attend a semi-structured focus group during which the PROM was reviewed and an unmet needs analysis was performed. Thematic analysis of focus group transcripts was undertaken for emergent themes. RESULTS: Initial consensus was for a tool including the EQ-5D, Functional Assessment of Cancer Therapy - Colorectal (FACT-C), the distress thermometer, a validated measure of stigma, an unmet needs analysis, and questions assessing the psychological impact of cancer. Median and interquartile range values suggested that all metrics were discriminatory with the exception of FACT-C. All participants agreed that the tool was acceptable and reflected the current state of their health and emotions. Thematic analysis of focus group transcripts identified four major themes: physical symptoms, emotional response, information provision and coping mechanisms. CONCLUSION: Through expert consensus, local piloting and patient focus groups we have evaluated a novel PROM for colorectal cancer. Furthermore, through our direct engagement with patients we have identified several unmet needs which we are currently exploring within the clinical service.

ATP-dependent exonuclease V from Micrococcus luteus. The enzyme-DNA complex, the processive mechanism, and the role of ATP.

Some kinetic predictions of the proposed processive mechanism for the hydrolysis of DNA by the ATP-dependent enzyme exonuclease V have been checked. The method is to trap enzyme molecules not attached to radioactive DNA substrate with an excess of nonradioactive DNA, so that enzyme molecules attached to the radioactive substrate contribute to the liberation of radioactive products only until they dissociate from it. The experiments show that enzyme molecules remain attached to a T7 double-stranded DNA molecule, while hydrolysing it, for about 2 min under our conditions, in agreement with the predictions of the processive mechanism. However, the mechanism of degradation of single-stranded DNA is not processive. Formation of an enzyme-DNA complex is largely dependent on the presence of ATP. This formation does not appear to be synchronous. ATP analogs do not stimulate formation of, nor stabilize, the enzyme-DNA complex. EDTA causes dissociation of enzyme molecules from the DNA complex.

Substrate preferences of human placental DNA methyltransferase investigated with synthetic polydeoxynucleotides.

A DNA methyltransferase partly purified from human placenta has been tested on a variety of synthetic polydeoxynucleotides. The results showed that: the enzyme is most active as a 'maintenance' or 'hemi-' methylase but also has some de novo methylating activity; the presence or absence of A or T in the substrate strand has little influence on maintenance or de novo activity, while polymers containing C but not G in the same strand are poor de novo substrates and bind poorly to the enzyme; single-stranded polymers are about as good substrates as double-stranded ones, and the effects of nucleotide composition (particularly G and mC content) on enzyme activity with single strands are similar to those with double-stranded polymers; strands in which all the cytosines are methylated bind the enzyme well. A mechanism is suggested involving two different sites on the enzyme that recognize CG and mCG, and which rationalizes the activity of eukaryotic DNA methyltransferases towards single-stranded DNA.

Inactivation of de novo DNA methyltransferase activity by high concentrations of double-stranded DNA.

The activity of eukaryotic DNA methyltransferase diminishes with time when the enzyme is incubated with high concentrations (200-300 micrograms/ml) of unmethylated double-stranded Micrococcus luteus DNA. Under similar conditions, single-stranded DNA induces only a limited decrease of enzyme activity. The inactivation process is apparently due to a slowly progressive interaction of the enzyme with double-stranded DNA that is independent of the presence of S-adenosyl-L-methionine. The inhibited enzyme cannot be reactivated either by high salt dissociation of the DNA-enzyme complex or by extensive digestion of the DNA. Among synthetic polydeoxyribonucleotides both poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT), but not poly(dI-dC).poly(dI-dC), cause inactivation of DNA methyltransferase. This inactivation process may be of interest in regulating the 'de novo' activity of the enzyme.

Adenosine deaminase from Saccharomyces cerevisiae: kinetics and interaction with transition and ground state inhibitors.

Several adenosine analogs, such as coformycin, 2'-deoxycoformycin and erythro-9-(3-nonyl-p-aminobenzyl)adenine (EHNA), which are strong inhibitors of mammalian adenosine deaminase, are much weaker inhibitors of the Saccharomyces cerevisiae enzyme. The specificity of the yeast enzyme is more restricted than that of mammalian adenosine deaminase, particularly towards the ribose moiety and around position 6 and 1 of the substrate. The sulphydryl group appears to be more masked in the yeast than in the mammalian enzyme. The kinetic effects of pH with adenosine substrate and with the inhibitor purine riboside are reported. The findings on specificity and pH kinetic effects can be interpreted in a model involving proton transfer from the -SH group of the enzyme to the N-1 atom of the substrate.

Distinctive effects of G-CSF, GM-CSF and TNFalpha on neutrophil apoptosis in systemic lupus erythematosus.

OBJECTIVE: To investigate the influence of culture with G-CSF GM-CSF and TNFalpha on neutrophil apoptosis, comparing neutrophils from SLE patients with rheumatoid arthritis (RA) patients and healthy control subjects. METHODS: Neutrophils were isolated from SLE (n= 10), RA (n= 10) and healthy control subjects (n= 10), and cultured with two different concentrations of G-CSF, GM-CSF and TNFalpha. Proportion of apoptotic neutrophils at T=0, T=2hrs and T=24hrs was measured using FITC-labelled annexinV and flow cytometry. RESULTS: Significantly more neutrophils were apoptotic at T=0 in the SLE subjects than in the other groups (median, range--Control 3.5% (0.3-7.9) SLE 9.5% (2.9-29.1) RA 3.0% (0.4-23.0) p<0.05). Following culture for 24 hours with 1ng/ml G-CSF the proportion of apoptotic neutrophils from SLE subjects was significantly increased (median, range = 51.6% (27.0-84.0) without G-CSF v 66.8% (31.8-89.2) with G-CSF p<0.05). This was not observed with RA or control subjects, in whom the trend was towards inhibition of apoptosis. Similar trends were seen with GM-CSF There was significant induction of apoptosis in SLE neutrophils after 2 hr culture with 1ng/ml TNFalpha (median, range = 2.3% (0.1-8.0) without TNFalpha v 5.2% (1.0-22.4) with TNFalpha). No significant change was seen in the other groups. There was an inverse correlation between total neutrophil count and the degree of induction of apoptosis by G-CSF and GM-CSF, determined at a range of time-points and cytokine concentrations CONCLUSIONS: Neutrophils from SLE patients display resistance to the apoptosis-inhibiting effects of G-CSF and possibly GM-CSF, and appear more susceptible to the apoptosis-inducing action of TNFalpha, the greatest resistance being observed in the more neutropenic patients.

A new method for rate of analgesic onset: two doses of intravenous morphine compared with placebo.

A new method of frequent early pain assessments for 1 hour only was used to determine time of onset of analgesia after intravenous administration of 10 mg morphine, 5 mg morphine, or placebo in a double-blind study; 79 patients were randomized if they required parenteral analgesia in the early postoperative period. Pain intensity was determined by a four-point categoric verbal rating scale and on a verbal ordinal scale from 0 to 100 (0 = no pain, 100 = worst pain imaginable) during the first hour after analgesic administration. The onset time of analgesia, assessed by 50% of patients achieving 25% reduction from their baseline pain assessment, was significantly faster for 10 mg morphine compared with 5 mg morphine (p = 0.02) and placebo (p less than 0.01). More familiar analgesic efficacy measures, including the sum of pain intensity differences and time to next analgesic dose, similarly showed the superiority of 10 mg morphine to placebo in the first hour, confirming sensitivity according to the conventional paradigm.

Simian T-cell leukemia virus type I infection in captive baboons.

Human T-cell leukemia virus type (HTLV-I) is a type C retrovirus that has been linked to both adult T-cell leukemia and neurological disorders in humans. Baboons and other Old World non-human primates harbor a related virus termed simian T-cell leukemia virus type 1 (STLV-I), which may also be associated with neoplastic disease. To explore the utility of the baboon as a model for HTLV-I infection and disease, 329 baboons from a colony of 3200 at the Southwest Foundation for Biomedical Research (SFBR) were analyzed for the presence of antibodies against STLV-I. An overall seroprevalence rate of > 40% was found, with higher rates in females versus males. Furthermore, seroprevalence rates increased dramatically with age, reaching greater than 80% in animals over the age of 16. Molecular and antigenic analysis of proviral DNA isolated from both tumor tissue and a cell line isolated from a baboon with non-Hodgkin's lymphoma (NHL) indicates that STLV-I in this colony is closely related to HTLV-I. Furthermore, monoclonally integrated provirus isolated from lymphoma tissue was detected, strongly implicating STLV-I in the etiology of this malignancy. DNA primer pairs homologous to HTLV-I sequences amplified both HTLV-I and STLV-I, but not HTLV-II, providing further evidence for a close genetic relationship between baboon-derived STLV-I and HTLV-I. The detailed study of a large population of naturally infected baboons may therefore shed some light into the complex processes required for the induction of disease associated with HTLV-I infection in humans.

Vulnerability of the human Leydig cell to radiation damage is dependent upon age.

Testicular function was studied in three groups of patients previously treated for malignant disease, and a control group of adult males. The adult patients in groups one and two underwent unilateral orchidectomy for a testicular tumour but only in group two was this followed by post-operative high-dose irradiation (30 Gy) to the remaining testis. Four of the five boys in group three had a unilateral orchidectomy between the ages of 1 and 4 years and all five received a similar dose of irradiation (27.5-30 Gy) to the scrotum as in group two. The five subjects in group three were studied between the ages of 12 and 34 years. In group one the median basal testosterone level (16.0 nmol/l) was normal and the basal gonadotrophin levels mildly but significantly increased, reflecting a resetting of the pituitary-testicular axis following unilateral orchidectomy. In group two the median basal testosterone level (12.5 nmol/l) was significantly lower and the median basal FSH and LH levels were significantly higher than the respective values in group one, indicating that irradiation to the testis in adult life may damage both the germinal epithelium and the Leydig cells. All five males in group three showed grossly increased FSH and LH levels, with a median basal testosterone level (less than 2.5 nmol/l) significantly lower than groups one and two. None of the five showed a testosterone response to a stimulation test with human chorionic gonadotrophin or underwent puberty spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)

Strong association of simian immunodeficiency virus (SIVagm) envelope glycoprotein heterodimers: possible role in receptor-mediated activation.

Soluble forms of a human cell-surface molecule expressed on T lymphocytes (CD4) neutralize diverse strains of both human (HIV) and simian (SIV) immunodeficiency viruses through the induction of envelope shedding and direct competition with cellular CD4 for virus binding. However, we have previously shown that sCD4 enhances infection of simian immunodeficiency viruses from African green monkeys (SIVagm) and have theorized that this enhancement is due to the induction of conformational changes leading to viral fusion (receptor-mediated activation). In this report, we compared the relative association of the envelope glycoproteins of SIVagm with HIV type 1 (HIV-1) in order to determine if a more stable association of SIVagm envelope glycoproteins might account for the differential effects of sCD4 on the infectious process. Monospecific antisera to each of the SIVagm glycoproteins were generated and used to detect stable heterodimers by radioimmunoprecipitation. Standard solubilization buffers containing both ionic and nonionic detergents or saturating concentrations of sCD4 failed to disrupt SIVagm gp120 interactions with the transmembrane protein, gp36, whereas HIV-1 heterodimers were easily dissociated. Higher concentrations of SDS (1%) were necessary to disrupt the SIVagm envelope complexes demonstrating the existence of strong noncovalent interactions between these membrane glycoproteins. In addition, morphometric analysis by electron microscopy revealed that the linear density of SIVagm spikes was stable and resisted shedding when virus was incubated with sCD4 whereas a significant decrease in linear spike density was noted for HIV-1. Based on our original hypothesis, the strong association of SIVagm glycoprotein spikes during soluble receptor binding may allow for highly stable conformational intermediates important for viral fusion, while neutralization of HIV-1 by sCD4 results from less stable envelope associations.

Amplification of simian retroviral sequences from human recipients of baboon liver transplants.

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic "passenger leukocytes" harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation.

Diabetes-related impotence in the elderly.

Because many elderly men with chronic illnesses such as diabetes have multiple causes contributing to their impotence and may still retain an interest in sexual activity, those who still are unable to adequately perform sexually after treatment of their medical problems should be informed of the alternative methods of treatment of their impotence or alternative methods of sexual fulfillment and gratification and, when necessary, should be offered supportive counseling and psychotherapy.

Diabetes-related impotence and its treatment in the middle-aged and elderly: Part II.

Primary care treatment of diabetes-related impotence frequently revolves principally around patient referral and counseling. Sex or marital counseling or psychotherapy has a moderately high success rate for patients with psychogenic impotence. However, penile prosthesis implantation in properly selected patients with irreversible diabetic impotence has a final success rate, in terms of patient and partner satisfaction, of approximately 90%. Intracorporal self-administered papaverine alone or in combination with phentolamine has a limited role in producing erections satisfactory for intercourse.

Diabetes-related impotence and its treatment in the middle-aged and elderly: Part I.

Diabetes-related impotence is commonly noted within 10 years of the onset of diabetes. It is frequently due to microangiopathy and is associated with symptomatic neuropathy. Careful history-taking, physical examination, laboratory tests, and frequently, sophisticated diagnostic tests are indicated in the evaluation of these patients. Nocturnal penile tumescence and rigidity testing has become the gold standard of noninvasive evaluation.

Love and sex after 60: how to evaluate and treat the impotent older man. A roundtable discussion: Part 2.

In the medical evaluation of older men with erectile dysfunction, obtain a detailed history to determine whether the dysfunction is organic or psychogenic. Determine if there are underlying pathologic processes--most notably vascular diseases--or other factors responsible for the dysfunction, such as medications or nerve or arterial damage from surgery. Lifestyle changes in mid-life (regular exercise, a low-fat diet, and smoking cessation) increase a man's chances of remaining potent as he grows older. Treatments for impotence include injection therapy, vacuum devices, and implants. Each therapy has advantages and disadvantages, and the informed patient plays an important role in choosing the therapy that is right for him.

Love and sex after 60: how to evaluate and treat the sexually-active woman.

In the medical evaluation of older female patients with sexual problems, you need to assess the woman's psychological state, as well as her physical condition. An important question to ask is whether her level of sexual activity is satisfactory to her. Women's early sexual experiences, in some cases including childhood sexual abuse, impact greatly on their sexuality in later life. When sexual problems are related to the menopause, customized hormone replacement therapy is the treatment of choice. Other clinical factors that impact on older women's sexuality include urinary incontinence, breast surgery, and hysterectomy.

The detection of fetal hemoglobin in bloodstains by means of thin-layer immunoassay.

A method for the detection of fetal hemoglobin in bloodstains by means of thin-layer immunoassay is described. The equivalent of 0.01 microL of blood containing 0.18 to 0.24 microgram of fetal hemoglobin may be detected by this method. Studies with stains up to two years old and blind studies have shown these methods to be sufficiently sensitive and specific to be of value in forensic serology.

Experience with a subcutaneous implantable bone conduction hearing aid (Xomed Audiant) in a district general hospital.

Patients with a conductive hearing loss may find conventional hearing aids unsatisfactory for a variety of reasons. Efforts to overcome some of these difficulties have led to the development of the osteointegrated hearing aid. Implantable bone conduction hearing aids are an important advance in the treatment of well selected patients. Only 18 patients, who have been implanted with the Xomed Audiant bone conduction hearing aid, have so far been reported on in the UK. This report concerns a further six patients who have been implanted in one centre. Five of these patients continue to use their Audiant hearing aid 14 to 24 months after being fitted. They regard it to have significant advantages over their previous hearing aids. Four of the five patients use an ear level processor. Two of the patients who had previously used conventional bone conduction hearing aids now use the ear level processor.

Large maxillary antral mucocele presenting with facial asymmetry.

Maxillary antral mucoceles are extremely rare. We report a case of a large antral mucocele presenting with facial asymmetry. The CT scan was essential for delineating the extent of the lesion and aiding in the pre-operative diagnosis. The pathogenesis, clinical features and radiological aspects of this entity are reviewed.

Use of the carbon dioxide laser with the Montgomery T-tube in the management of extensive subglottic stenosis.

Subglottic and tracheal stenosis frequently present difficulties in management. Two cases of subglottic stenosis occurring after prolonged endotracheal intubation are presented where the vertical length of complete obstruction by scar tissue was greater than 2.5 cm. One case was successfully managed by the use of the laser and immediate insertion of a stent. The other case still requires subglottic stenting, although an excellent lumen was established by laser vaporization of the stenosed segment.