Are the UK oncology trainees adequately informed about the needs of older people with cancer?

BACKGROUND: Outcomes for older people with cancer are poorer in the United Kingdom compared with that in other countries. Despite this, the UK oncology curricula do not have dedicated geriatric oncology learning objectives. This cross-sectional study of UK medical oncology trainees investigates the training, confidence level and attitudes towards treating older people with cancer. METHODS: A web-based survey link was sent to the delegates of a national medical oncology trainee meeting. Responses were collected in October 2011. RESULTS: The response rate was 93% (64 out of 69). The mean age of the respondents was 32.3 years (range 27-42 years) and 64.1% were female. A total of 66.1% of the respondents reported never receiving training on the particular needs of older people with cancer, 19.4% reported to have received this training only once. Only 27.1% of the trainees were confident in assessing risk to make treatment recommendations for older patients compared with 81.4% being confident to treat younger patients. Even fewer were confident with older patients with dementia (10.2%). CONCLUSION: This first study of the UK medical oncology trainees highlights the urgent need for change in curricula to address the complex needs of older people with cancer.

Inhibition of post-meningitic cochlear injury with cerebrospinal fluid irrigation.

OBJECTIVE: Labyrinthitis ossificans, the pathologic ossification of the otic capsule associated with profound deafness and loss of vestibular function occurs frequently as a sequella of bacterial meningitis and subsequent purulent labyrinthitis. Experimentally, in Streptococcus pneumoniae meningitis, it has been shown that a vigorous inflammatory response to teichoic acids in the bacterial cell wall contributes to cochlear damage and subsequent fibrosis and ossification. The hypothesis of this study is that a dilution of concentration of inflammatory mediators through cerebrospinal fluid (CSF) irrigation will lead to a reduction in both inner ear pathology and permanent hearing loss. STUDY DESIGN AND SETTING: Auditory brainstem response testing was used to determine baseline hearing thresholds in 20 Mongolian gerbils (12 irrigated, 8 sham irrigated animals) at 32 kHz, 16 kHz, 8 kHz, and 4 kHz frequencies. Their thresholds at 14 days and 120 days post-procedure were also obtained. Streptococcus pneumoniae meningitis was induced in both groups of animals by intrathecal (i.t.) injection of bacteria. Both groups received penicillin treatment. Forty-eight hours after inoculation, both groups were implanted with i.t. inflow and outflow catheters. The irrigated group was infused continuously with artificial CSF over 36 hr at a rate of 70 muL/hr and the outflow sampled. The tubing in the sham irrigated group was clamped (without sampling). They were sacrificed at 120 days post-procedure and histomorphometric analysis carried out. The concentration of interleukin 1beta (IL-1beta) for the CSF samples from the irrigated group were compared to samples collected from an additional control group of 8 non-irrigated meningitic gerbils. IL-1beta was chosen to study because it is a potent pro-inflammatory cytokines in bacterial meningitis that is unaffected by the neurosurgical trauma of the experimental protocol. RESULTS: Twenty animals survived the meningitis (6 irrigation, 6 sham irrigation, 8 non-irrigation meningitic controls). At Days 14 and 120 post-infection, the irrigated animals manifested significantly less hearing loss with a mean loss of 28.82 dB compared to the sham irrigation group mean loss of 40.76 dB (P < 0.03). The degree of hearing loss in both groups was frequency-dependent with greater loss at higher frequencies (mean loss = 22.4 dB at 32 kHz, 23.0 dB at 16 kHz, 18.6 dB at 8 kHz, and 12.5 dB at 4 kHz). Histomorphometric analysis demonstrated a marked reduction in degeneration of the spiral ligament, spiral ganglion cells, and stria vascularis in experimental animals as compared to controls. Immunohistochemistry showed a significant reduction in IL-beta1 concentrations in the irrigated animals compared to the non-irrigated, infected controls (P < 0.03). CONCLUSIONS: Irrigation of CSF resulted in a significant reduction in post-meningitic cochlear injury when compared to controls. This model for continuous cerebrospinal fluid irrigation provides a means to evaluate the effects of a dilution of inflammatory mediators on hearing loss and labyrinthitis ossificans after bacterial meningitis. SIGNIFICANCE: Despite advances in the prevention of meningitis and improved antibiotic treatment, bacterial meningitis continues to have significant associated morbidity. This study provides insight into some of the mechanisms responsible for post-meningitic hearing loss and labyrinthitis ossificans and presents a novel approach to reduce these complications.

Estrogen biosynthesis and 1beta-hydroxylation using C19 and 19-nor steroid precursors.

(1) In order to study the relationship between aromatization (estrogen biosynthesis) and 1beta-hydroxylation, the effects of a variety of factors on these processes were evaluated. (2) Using the C18 substrate, 4-estrene-3,17-dione, it was found that carbon monoxide, SU-4885, amphenone B, potassium cyanide, 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione inhibited the above transformations significantly and to varying degrees. However, within a given experiment the inhibition of each process was similar. (3) SKF-525A did not inhibit either transformation. In addition, phosphate, Tris and barbital buffers, as well as pH changes from 6.9 to 7.7, had no stimulatory or inhibitory effect on the production of estrogen and 1beta-hydroxy compounds. (4) In contrast, several inhibitors affected the aromatization of C19 and C18 steroids differently. These include carbon monoxide, SU-4885 and amphenone B. (5) When a mixture of 4-[7beta-3Hi1estrene-3,17-dione and 19-[4-14C]nortestosterone were incubated together the former was preferentially converted to estrogen. This preference for the 17-keto steroidal form mimics results observed for C19 substrates. (6) We conclude that while estrogen biosynthesis and 1beta-hydroxylation appear to be mediated by the same enzyme system, the same conclusion cannot be drawn for the aromatization of C19 and C18 substrates.

PIP: Estrogen biosynthesis and lbeta-hydroxylation using carbon-19 and 19-nor steroid precursors were evaluated. 4-estrene-3, 17-dione was used to find that carbon monoxide, SU-4885, amphenone B, potassium cyanide, 4-androstene-3,17-dione, and 1,4-androstadiene-3,17-dione inhibited the above transformations to varying degrees. SKF-525A did not inhibit either transformation, and phosphate, Tris and barbital buffers as well as pH changes from 6.9 to 7.7 had no effect on the production of estrogen and lbeta-hydroxy compounds. Carbon monoxide, SU-4885, and amphenone B affected the aromatization of carbon-19 and carbon-18 steroids differently. A mixture of 4 (7 beta-tritium) estrene-3,17-dione and 19-(4-carbon 14) nortestosterone incubated together resulted in the former preferentially converted to estrogen. It is concluded that while estrogen biosynthesis and lbeta-hydroxylation appear to be mediated by the same enzyme system, however, the same conclusion cannot be drawn for the aromatization of carbon-19 and carbon-18 substrates.

Antifertility effects of an aromatase inhibitor, 1,4,6-androstatriene-3, 17-dione.

1,4,6-Androstatriene-3,17-dione (ATD), previously reported by us to be an aromatase (estrogen synthetase) inhibitor, was found effective in inhibiting mating and ovulation in the rat. Mating did not occur for as long as treatment was continued (up to 13 days) in 68% of the rats. In the remainder, mating and ovulation were delayed for at least 4 days past the expected day of proestrus and for an average of 5.8 days. Five animals which had been treated for 6 days mated 2 days after treatment was discontinued and all were pregnant at autopsy on day 8 of pregnancy. In contrast, when treatment was continued after mating, implantation sites were absent when the animals were examined on day 8 of pregnancy, indicating ATD may also be effective postcoitally. ATD had no significant hormonal activity in bioassay but prevented the rise in ovarian estradiol secretion on the afternoon of proestrus. Estradiol benzoate counteracted the effect of ATD when administered concomitantly, so that mating occurred at the normal time in all eight rats and ovulation occurred in six of the eight rats. The above results suggest that the aromatase inhibitor, ATD, may act in vivo to inhibit fertility by inhibition of estrogen biosynthesis.

The effect of an aromatase inhibitor, 4-hydroxy-4-androstene-3,17-dione, on estrogen-dependent processes in reproduction and breast cancer.

4-Hydroxy-f-androstene-3,17-dione (4-OH-A) when tested at various concentrations was found to inhibit markedly the conversion of 4-andorstene-3,17-dione to estrogens inhuman placental and rat ovarian microsomes. To obtain evidence that estrogen biosynthesis could also be reduced in vivo with 4-OH-A, rats were treated sc at a dose level of 50 mg/kg body weight. After 3 h the ovarian veins were cannulated and blood collected. Estradiol concentrations in the plasma were reduced by 80% compared to control values during the proestrous surge and on Day 4 of pregnancy. 4-OH-A was also found to be effective in controlling estrogen-dependent reproductive and neoplastic processes. In rats treated from Day 2-7 of pregnancy, implantation of fertilized ova was completely prevented in some rats, while in others either implantation was delayed or the development of implants was retarded. 4-OH-A treatment of rats having estrogen-dependent breast tumors induced by 7,12-dimethylbenz(a)anthracene caused 80% of the tumors to regress significantly in 4 weeks of treatment; 42% of these regressed completely.

A cycle of plasma testosterone in the human male.

The object of the study was to assess the lability of testosterone levels in plasma of normal human males over a long period of time and to search for periodicities in changing levels. Blood samples obtained from 20 healthy young men every second day for 2 months were assayed for total testosterone concentration by radioligand saturation analysis with late-pregnancy plasma. The flucturations of plasma testosterone levels over the total time span were substantial for most individuals; the coefficients of variation ranged from 14 to 42% (median 21%). The presence of periodic functions in these fluctuations was tested by 4 different, relatively independent methods. Close agreement among at least 3 analytic methods was found for 12 out of the 20 subjects. These 12 subjects had cycles of plasma testosterone levels with periods ranging between 8-30 days, with a cluster of periods around 20-22 days. The majority of such cycles were significant at least at the 5% level. The mean amplitudes of these cycles ranged from 9 to 28% of the subjects' mean testosterone levels (average 17%).

Normatology: a review and commentary with reference to abortion and physician-assisted suicide.

PIP: This article opens with a review of the concept of "normatology," which was developed by Sabshin and Offer in four books published over a period of 30 years. Normatology seeks to produce an "operational definition of normality and health" over the life cycle. Such a definition can be used as a guideline in the deliver of health care. The importance of this field of study is highlighted when considering issues such as abortion or physician-assisted suicide. Fortunately, the proclivity of Americans to conduct public opinion polls helps researchers determine what is considered "normal" at any given time. Gallup Polls, which have posed the same question about the legality of abortion from 1975 to 1995, indicate that about half of all Americans continuously occupy the middle ground on this issue despite a somewhat liberalizing trend. In general, public opinion holds that it is normal to want to avoid giving birth to a damaged child, to place the mother's health and safety above that of the fetus, and to terminate a pregnancy resulting from rape. It is less normal to abort a healthy fetus on demand. Thus, abortion will likely continue to be a source of controversy and confusion in our society and among psychiatric patients. In comparison, psychiatrists express attitudes about abortion that are more liberal than normal. In the case of physician-assisted suicide, public approval has increased since 1950 as scientific advancements have facilitated the prolongation of unproductive and painful life. If legalized, physician-assisted suicide may depend upon psychiatric assessment of an absence of mental disease. Such an assessment is required in the Northern Territory of Australia, where voluntary euthanasia is legal, but not in the Netherlands, where it is government-regulated. Psychiatrists must understand public opinion in order to influence it or deal with it competently.^ieng

The role of psychiatric and behavioral factors in the practice of medicine.

The authors review the role of psychiatric and behavioral factors in the practice of medicine in three areas: 1) prevalence of psychiatric morbidity, 2) the role of behavioral or lifestyle factors in illness onset, and 3) the overlapping of psychiatric and behavioral factors with medical illness. Within each areas they review behavioral factors to the practice of medicine, the limits of current treatment approaches, and future research needs. In their final section they draw implications for health care delivery and manpower development.

How primary care physicians treat psychiatric disorders: a national survey of family practitioners.

A survey of 350 family practice physicians nationwide showed that 22.6% of their patients had significant psychiatric disorders. Physicians reported treating most psychiatric problems themselves, usually through a combination of psychotropic drugs, advice, and reassurance. The results suggest that anxiolytics are more conservatively used and referrals for mental health care more often made than past studies indicate. Physicians cited patient resistance and time limitations as the most important barriers to primary care mental health treatment, followed by limited third-party payment for mental health services, poor coordination between the primary care and mental health care sectors, and insufficient training to treat psychiatric disorders.

Aromatase inhibitors. Synthesis and biological activity of androstenedione derivatives.

The synthesis and biological evaluation of androstenedione derivatives as inhibitors of estrogen biosynthesis are described. The results show that 4-hydroxy analogues are among the most potent in vitro inhibitors of the series. Esterification of the 4-hydroxy steroids generally reduced activity. Further conjugation of the 3-keto 4-ene system to give 4-hydroxy-4,6-androstadiene-3,17-dione caused more rapid inactivation of aromatase in rat ovarian microsomes than 4-hydroxyandrostenedione. Some compounds exhibited differences in activity when tested for inhibition of human placental microsomes vs. rat ovarian microsomes. The 4-hydroxyandrostenedione derivatives and their nonbulky esters were generally more potent in vitro and in vivo inhibitors than other substituted steroids in the series. Several of the synthesized compounds markedly reduce (50-81%) estrogen levels in rats on proestrus and/or had antifertility action. To date, none of the compounds surpassed the in vivo inhibitory action of 4-hydroxy-4-androstene-3,17-dione or its 4-acetate derivative.

Suppression of water intake by immune complex formation in the hypothalamus. Implications for systemic lupus erythematosus.

Immune complex formation in the perifornical region of the hypothalamus resulted in depressed water consumption in rats, but did not consistently alter body temperature. The antibody with an unrelated antigen did not affect water consumption or body temperature. These results support the notion that immune complex reactions within the central nervous system can alter behavior.

Synthesis of deuterium- and tritium-labelled 4-hydroxyandrostene-3,17-dione, an aromatase inhibitor, and its metabolism in vitro and in vivo in the rat.

The metabolism of the aromatase inhibitor-4-hydroxyandrostenedione (4-OHA) was studied in vitro and in vivo in the rat. To accomplish this, deuterium- and tritium-labeled 4-OHA were prepared from 4-hydroxyandrosta-4, 6-dione-3,17-dione. The latter was synthesized from 4-androstene-3,17-dione. Using deuterated 4-OHA in in vitro incubations of rat ovarian microsomes, 4-hydroxytesterone (4-OHT) was identified by gas chromatography/mass spectroscopy as the major metabolite. 4-OHT constituted approximately 20% of the total radioactivity from [6,7-3H]-4-OHA in the ovarian microsomal incubations. Conversion of [6,7-3H]-4-OHA to 4-hydroxyesterone was approximately 0.1%. The major metabolite of [6, 7-3H]-4-OHA in vivo identified in the free, neutral fraction of rat blood was 3 beta-hydroxyandrostane-4,17-dione. The metabolite accounted for approximately 5% of the total radio-activity in the blood, Whereas 4-OHT accounted for only 0.1%, 4-OHT inhibited in vitro ovarian aromatization by 59%, but 3 beta-hydroxyandrostane-4-17-dione had little effect. It was concluded that the in vivo effects of 4-OHA previously reported are largely due to its own activity although additional effects of its metabolic products cannot be excluded.

Effect of an aromatase inhibitor, 1,4,6-androstatriene-3,17-dione, on 7,12-dimethylbenz[a]anthracene-induced mammary tumors in the rat and its mechanism of action in vivo.

In this study, 1,4,6-androstatriene-3,17-dione (ATD) was demonstrated to cause time-dependent loss of aromatase activity in rat ovarian microsomes in vitro. In vivo, an injection of ATD caused inhibition of ovarian aromatase and reduced estrogen secretion in pregnant mare's serum gonadotropin-primed rats for at least 24 hr after injection. In rats with 7,12-dimethylbenz[a]anthracene-induced, hormone-dependent, mammary tumors, marked regression occurred with ATD treatment. Although estrogen secretion was not reduced below the diestrus level of controls, the rats remained anestrus, indicating that the proestrus surge of estrogen was prevented. LH, FSH and prolactin levels were also basal and LH and FSH did not rise after ovariectomy. ATD had no detectable hormonal activity in bioassay. Consistent with this, the compound did not interact appreciably with either androgen or estrogen receptors, was not uterotrophic, and did not interfere with mammary tumor regression in ovariectomized rats. Thus, the major activities of the compound which cause mammary regression in the rat appear to be inhibition of estrogen synthesis, via aromatase and gonadotropin suppression.

New trends in the diagnosis and treatment of depression.

New trends in the diagnosis and treatment of depression are reviewed. The use of biologic markers as aids in diagnosing depression and in predicting response to specific antidepressant drugs is discussed, and monitoring therapeutic response by plasma tricyclic antidepressant levels is reviewed.

A multicenter evaluation of bupropion versus placebo in hospitalized depressed patients.

Bupropion, a new antidepressant with a novel structure and neurochemical profile, was compared to placebo in a three-center evaluation. Seventy-five depressed inpatients, 48 on bupropion and 27 on placebo, participated for up to 28 days. At dosages of 300-600 mg/day, bupropion was significantly more active than placebo in reducing depressive and anxious symptomology, beginning at the 3-week evaluation. Bupropion was particularly efficacious in more severely ill and older patients. Symptoms reflecting cognitive disturbance, somatic anxiety, and psychomotor retardation were most improved; sleep disturbances showed less marked effects. Appetite and diurnal variation were not markedly influenced. Adverse effects were minimal, with no significant cardiovascular or clinical laboratory findings. Three patients developed a skin rash. There was a notable absence of sedative, anticholinergic, and cardiovascular-related side effects. Bupropion has demonstrated antidepressant effects and a spectrum of activity that holds promise for a difficult subgroup: the older depressed patient with retardation and cognitive disturbance.

Nursing assistants detect behavior changes in nursing home residents that precede acute illness: development and validation of an illness warning instrument.

BACKGROUND: Acute illness causes considerable morbidity and mortality in nursing home residents but is often difficult to recognize early. Nursing assistants often notice early signs of acute illness but do not methodically document or communicate their observations with medical staff. OBJECTIVE: To enhance nursing assistants' observation and documentation of signs of acute illness by developing a validated, standardized instrument for communication with medical staff. DESIGN: Observational cohort study. SETTING: Urban not-for-profit nursing home. SUBJECTS AND METHODS: Candidate instrument items were generated in focus group interviews with nursing home staff. Twenty-three nursing assistants completed the instrument on 74 nursing home residents over 4 weeks. Acute illness, the primary outcome, was identified by nurse report and chart review and determined according to preset criteria. MEASUREMENTS: Predictive validity was assessed by determining the relationship between instrument responses and development of acute illness within 7 days. Interobserver agreement was calculated between morning and afternoon nursing assistants' responses. Convergent validity was assessed by comparing instrument responses with three standard status indicators. RESULTS: The instrument consisted of 12 items that assessed behavioral and functional status changes. Residents with an instrument-recorded change were more likely to develop an acute illness within 7 days than those with no change (risk ratio 4.1, 95% confidence interval 2.6, 6.3). A final five-item instrument had a sensitivity of 53% and a specificity of 93% for acute illness. Nursing assistants' documentation of signs of illness preceded chart documentation by an average of 5 days. Interobserver agreement between morning and afternoon nursing assistants was 76%. Correlation of responses with standard indicators of functional, mental, and global status was high. CONCLUSIONS: A new instrument developed for nursing assistants to document behavioral and functional status changes in nursing home residents demonstrates fair sensitivity and high specificity for acute illness. Close monitoring of patients with a positive instrument might avert morbidity and mortality from acute illness by allowing earlier treatment.

Comparative efficacy and safety of bupropion and placebo in the treatment of depression.

This was a 4-week, three-center, double-blind, randomized, parallel, placebo-controlled evaluation of the efficacy and safety of bupropion in hospitalized depressed patients. Results from 27 placebo and 48 bupropion-treated patients were analyzed for efficacy and safety. Assessments of efficacy and safety were made at baseline and weekly during the study. Preliminary and secondary measures of efficacy included the Clinical Global Impressions for severity (CGI-S) and improvement (CGI-I) of illness, Hamilton Depression and Hamilton Anxiety Scales, and the Zung Self-Rating Scales for depression and anxiety. Assessments of safety included vital signs, electrocardiogram, clinical laboratory tests, and adverse experiences. Dosages of bupropion were 300-600 mg/day. Results showed that bupropion was significantly (P less than 0.01) more effective than placebo at termination of study on the CGI-S, CGI-I, Hamilton Depression and Hamilton Anxiety Scales. On the Zung Self-Rating Depression and Anxiety Scales, statistical trends favored bupropion at termination of study over placebo (P less than 0.10). Adverse events in the bupropion and placebo groups were minimal with notable absence of sedation and anticholinergic- and cardiovascular-related side effects. We conclude that bupropion was significantly more effective than placebo in treating depression and accompanying anxiety in depressed inpatients.

Imaging findings of the developing temporal bone in fetal specimens.

PURPOSE: To trace the development of the normal fetal temporal bone by means of plain radiography, MR, and CT. METHODS: Eighteen formalin-fixed fetal specimens, 13.5 to 24.4 weeks' gestational age, were examined with a mammographic plain film technique, CT, and MR imaging at 1.5 T. Temporal bone development and ossification were assessed. RESULTS: The membranous labyrinth grows with amazing rapidity and attains adult size by the middle of the gestation period. The cochlea, vestibule, and semicircular canals are very prominent and easily recognized on MR images. The otic capsule develops from a cartilage model. Ossification of the otic capsule proceeds rapidly between 18 and 24 weeks from multiple ossification centers that replace the cartilaginous framework. The mastoid, internal auditory canal, vestibular aqueduct, and external auditory canal continue to grow after birth. CONCLUSION: The study of fetal developmental anatomy may lead to a better understanding of congenital disorders of the ear. Faster MR scanning techniques may provide a method for in utero evaluation of the fetal temporal bone.

MR, CT, and plain film imaging of the developing skull base in fetal specimens.

BACKGROUND AND PURPOSE: The developing fetal skull base has previously been studied via dissection and low-resolution CT. Most of the central skull base develops from endochondral ossification through an intermediary chondrocranium. We traced the development of the normal fetal skull base by using plain radiography, MR imaging, and CT. METHODS: Twenty-nine formalin-fixed fetal specimens ranging from 9 to 24 weeks' gestational age were examined with mammographic plain radiography, CT, and MR imaging. Skull base development and ossification were assessed. RESULTS: The postsphenoid cartilages enclose the pituitary and fuse to form the basisphenoid, from which the sella turcica and the posterior body of the sphenoid bone originate. The presphenoid cartilages will form the anterior body of the sphenoid bone. Portions of the presphenoid cartilage give rise to the mesethmoid cartilage, which forms the central portion of the anterior skull base. Ossification begins in the occipital bone (12 weeks) and progresses anteriorly. The postsphenoid (14 weeks) and then the presphenoid portion (17 weeks) of the sphenoid bone ossify. Ossification is seen laterally (16 weeks) in the orbitosphenoid, which contributes to the lesser wing of the sphenoid, and the alisphenoid (15 weeks), which forms the greater wing. CONCLUSION: MR imaging can show early progressive ossification of the cartilaginous skull base and its relation to intracranial structures. The study of fetal developmental anatomy may lead to a better understanding of abnormalities of the skull base.

Simple apparatus for blocking small animal brains.

A modification of previously described devices for blocking small animal brains is presented. The apparatus is easily constructed and allows for blocking at varous angles of both fixed and unfixed tissue of most small laboratory animals.