The psychiatrist as philosopher: an appreciation of Dr Séamus Mac Suibhne (Sweeney) (1978-2019).

Dr Séamus Mac Suibhne (Sweeney), consultant psychiatrist and writer, who died on 8 September 2019, was a unique, much admired figure in Irish psychiatry. His interests ranged from clinical care to philosophy, from medical education to history, from innovative technology to the natural world. He was a dedicated family man as well as a doctor, scholar and writer who moved between academic fields with ease and erudition. As a clinician, he consistently placed compassion at the centre of care. Séamus's work appeared in the Lancet, BMJ, British Journal of Psychiatry, International Journal of Social Psychiatry and Irish Journal of Psychological Medicine, among other publications. He also wrote for the Guardian, Spectator, Scotsman and Times Literary Supplement. Séamus had a particular passion for better acknowledgement and treatment of mental illness among psychiatrists, and his compelling advocacy on this theme is one of his lasting legacies.

Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats.

Subchronic administration of (R,S)-ketamine, (R,S)-Ket, is used in the treatment of neuropathic pain, in particular Complex Regional Pain Syndrome, but the effect of this protocol on the metabolism of (R,S)-Ket is unknown. In this study, daily administration of a low dose of (R,S)-Ket for 14-days to Wistar rats was conducted to determine the impact of sub-chronic dosing on the pharmacokinetics of (R,S)-Ket and its major metabolites. The data indicate that, relative to a single administration of (R,S)-Ket, subchronic administration resulted in increased clearance of (R,S)-Ket and the N-demethylated metabolite norketamine measured as elimination half-life (t1/2) and decreased plasma concentrations of these compounds. Subchronic administration produced a slight decrease in t1/2 and an increase in plasma concentration of the major metabolite, (2S,6S;2R,6R)-hydroxynorketamine, and produced significant increases in the plasma concentrations of the (2S,6R;2R,6S)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine metabolites. The metabolism of (R,S)-Ket predominately occurs via two microsomal enzyme-mediated pathways: (R,S)-Ket⇒(R,S)-norketamine⇒(2S,6S;2R,6R)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine and the (R,S)-Ket⇒(2S,6R;2R,6S)-hydroxyketamine⇒(2S,6R;2R,6S)-hydroxynorketamine and (2S,6S;2R,6R)-hydroxynorketamine. The results indicate that the activity of both metabolic pathways are increased by subchronic administration of (R,S)-Ket producing new metabolite patterns and potential differences in clinical effects.

Attitudes towards patients with mental illness in Irish medical students.

BACKGROUND: A positive attitude to patients with mental illness is important in all branches of medicine, as it can impact on the quality of care patients receive from doctors. Attitudes of preclinical medical students is an under researched area. AIMS: This study aims to (1) assess the attitudes of preclinical and clinical medical students to patients with mental illness and (2) assess the effect of two modules taught using different teaching methods on students' attitudes to patients with mental illness. METHODS: During the same academic year all students (N = 394) completing the year 3 preclinical psychiatry module and the final year psychiatry module completed an attitudinal questionnaire at the beginning and following completion of the module. Seventy-two percent of students completed both pre- and post-module questionnaires in full (n = 285). RESULTS: There was no significant difference in attitudes displayed by preclinical and clinical medical students prior to starting their respective modules. An association was found between female gender and more tolerant attitudes (r = 0.20, p = 0.02). Students who knew someone with experience of mental illness were associated with more tolerant attitudes (r = 0.32, p < 0.001). Final year students who completed the clinical module demonstrated a positive attitudinal shift (p < 0.001), and the attitudes of third and final year male students improved significantly following the module (p < 0.05). CONCLUSIONS: Given the high rates of physical illness in patients with mental health problems, specific educational initiatives to address medical student's attitudes to patients with mental health problems should be an educational priority in medical school.

Breast cancer resistance protein (BCRP/MXR/ABCG2) in acute myeloid leukemia: discordance between expression and function.

Data on breast cancer resistance protein (BCRP, MXR, ABCG2) expression in acute myeloid leukemia (AML) have been inconsistent, possibly due to use of different assays in different studies. BCRP mRNA was studied by the reverse-transcription polymerase chain reaction and BCRP protein expression (BXP-21, BXP-34 or anti-ABCG2 antibody, with anti-CD34 and anti-CD33) and function (fumitremorgin C modulation of mitoxantrone retention) by flow cytometry in eight cell lines and in pretreatment blasts from 31 AML patients. BCRP mRNA levels, antibody staining and function correlated strongly in cell lines (Pearson r values, 0.73-0.97), but not in AML samples. AML sample BCRP mRNA levels were between those in parental 8226 and 35-fold mitoxantrone-resistant 8226/MR20 cells in all but one case, and BCRP mRNA had the wild-type sequence at codon 482 in all. In AML, unlike in cell lines, BCRP protein expression or function, when present, was only detected in small subpopulations. BCRP mRNA and protein expression did not correlate, nor did staining with different BCRP antibodies, and function did not correlate with mRNA nor protein expression. Presence of BCRP only in subpopulations and discordance among BCRP measurements suggest complex biology of BCRP in AML and incomplete modeling by cell lines.

Prevalence and clinical features of HTLV neurologic disease in the HTLV Outcomes Study.

BACKGROUND: Almost 20 years after its discovery, the prevalence and clinical course of human T-lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM, also known as tropical spastic paraparesis [TSP]) remain poorly defined. Whereas the causative association of HTLV-I and HAM/TSP is generally recognized, controversy still surrounds the relationship between HTLV-II and HAM/TSP. METHODS: The HTLV Outcomes Study (HOST-formerly Retrovirus Epidemiology Donor Study [REDS]) is a prospective cohort study including 160 patients with HTLV-I, 405 patients with HTLV-II, and 799 uninfected controls who have been followed every 2 years since 1990-1992. Clinical outcomes are measured by health interviews and examinations, and blood samples are obtained. RESULTS: Six cases of HTLV-I-associated myelopathy (3.7%, 95% CI 1.4 to 8.0) and four cases of HTLV-II myelopathy (1.0%, 95% CI 0.3 to 2.5) have been diagnosed since the formation of the cohort. There have been no cases of HAM/TSP diagnosed among HTLV-negative subjects (0.0%, 95% CI 0.0 to 0.5). Clinical features of the cases include lower extremity hyperreflexia, variably associated with weakness, spasticity, and bladder dysfunction. CONCLUSIONS: Systematic screening of HTLV-infected blood donors reveals a high prevalence of HAM/TSP. The clinical course of HAM/TSP appears highly variable. HTLV-II-associated myelopathy generally presents with milder and more slowly progressive signs and symptoms.

A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation.

Oral mucositis is a complication common to many cancer therapies and produces considerable pain and morbidity. The present study reports a double-blind, prospective, randomized clinical trial testing the efficacy of a calcium phosphate mouth rinse (Caphosol) with fluoride treatments vs a standard regimen of fluoride rinsing and placebo tray treatments in 95 patients undergoing hematopoietic stem cell transplantation (HSCT). The days and severity of mucositis were prospectively evaluated. There were statistically significant decreases in days of mucositis (3.72 vs 7.22 P=0.001), duration of pain (2.86 vs 7.67, P=0.0001), dose of morphine (34.54 mg vs 122.78 mg), days of morphine (1.26 vs 4.02, P=0.0001) and days to the onset of engraftment ANC (absolute neurotrophil count)>200 mm(3) (11.12 vs 12.56) in the Caphosol and fluoride treatment group vs fluoride-rinse group, respectively. Caphosol, a neutral, supersaturated, Ca(2+)/PO(4)(3-) mouth rinse, used in combination with topical fluoride treatments, is superior to fluoride rinse alone in reducing the frequency, intensity and duration of oral mucositis in patients undergoing HSCT.

Acute myeloid leukemia in the setting of low dose weekly methotrexate therapy for rheumatoid arthritis.

Methotrexate is in widespread use as second-line therapy for rheumatoid arthritis. Treatment with methotrexate in this and other settings has not been associated with the development of therapy-related leukemias. Four patients with rheumatoid arthritis are reported who developed acute myeloid leukemia (AML) while receiving low dose weekly methotrexate therapy in the absence of previous or concomitant treatment with known leukemogenic agents. AML in these four patients was of different morphologic subtypes and was associated with heterogeneous cytogenetic abnormalities, cell surface marker expression and multidrug resistance protein expression. None of the recognized features of therapy-related leukemia were present in these four nor in five previously-reported patients. It is likely that the occurrence of AML in patients with rheumatoid arthritis in the setting of methotrexate therapy represents the coincidence of these two diseases, and does not reflect a causal relationship.

Erythropoietin-dependent transformation of myelodysplastic syndrome to acute monoblastic leukemia.

Acute monoblastic leukemia (acute myeloid leukemia [AML], French-American-British type M5a) with leukemia cutis developed in a patient 6 weeks after the initiation of erythropoietin (EPO) therapy for refractory anemia with ringed sideroblasts. AML disappeared from both marrow and skin after the discontinuation of EPO. Multiparameter flow cytometric analysis of bone marrow cells demonstrated coexpression of the EPO receptor with CD45 and CD13 on the surface of blasts. The incubation of marrow cells with EPO, compared to without, resulted in 1.3- and 1.6-fold increases, respectively, in tritiated thymidine incorporation and bromodeoxyuridine incorporation into CD13(+) cells. Clinical and laboratory findings were consistent with the EPO-dependent transformation of myelodysplastic syndrome (MDS) to AML. It is concluded that leukemic transformation in patients with MDS treated with EPO may be EPO-dependent and that management should consist of the discontinuation of EPO followed by observation, if clinically feasible.

Psoas hitch ureteral reimplantation in adults--analysis of a modified technique and timing of repair.

OBJECTIVES: The psoas hitch ureteral reimplantation technique has been used with great success to bridge defects in ureteral length due to injury or planned resection. Several surgical principles have been historically stressed when performing this procedure, including adequate mobilization of the bladder, fixation of the bladder to the psoas tendon before reimplantation, the use of a submucosal nonrefluxing-type ureteral anastomosis, and a 6-week delay before attempting repair after a surgical injury. We retrospectively reviewed patients who underwent ureteroneocystostomy with a psoas hitch, evaluated the relevance of these principles, and describe a modification of the technique. METHODS: All patients undergoing psoas hitch ureteral reimplantation were reviewed. The indications, complications, and long-term outcomes were assessed. RESULTS: Between 1989 and 1999, 24 patients underwent psoas hitch reimplantation at our institution. The indications were operative injury in 11, planned surgical resection during nonurologic pelvic surgery in 4, cancer in 4, stricture in 4, and trauma in 1. Refluxing-type ureteral anastomoses were performed in 17 cases. One case of postoperative urosepsis occurred. A delayed repair after operative injury did not improve the operative time or overall morbidity. No cases of chronic flank pain, recurrent pyelonephritis, persistent severe hydronephrosis, or compromised renal function, as measured by a change in baseline serum creatinine level, occurred. No patient required reoperation for either early or delayed complications or failure of the repair at a follow-up of 1 to 122 months (mean 32.75). CONCLUSIONS: Psoas hitch ureteral reimplantation is an effective means of treating defects in ureteral length. Immediate repair may be safely undertaken as soon as the ureteral injury is recognized. Long-term sequelae are unusual in adults, even when using refluxing-type ureteral anastomoses.

The use of hydrogen peroxide to enhance the efficacy of doxorubicin hydrochloride in a murine bladder tumor cell line.

PURPOSE: We determined whether the cytotoxicity of doxorubicin hydrochloride would be enhanced by adding hydrogen peroxide as a source of oxygen free radicals. MATERIALS AND METHODS: Mouse bladder tumor cells (MBT-2) were grown in RPMI 1640 medium and treated with various concentrations of doxorubicin hydrochloride for 2 hours. Protein content was assayed as a measure of cell growth. A similar set of experiments was done with cells exposed to hydrogen peroxide only and combined doxorubicin and hydrogen peroxide. Protein content was again assayed as a measure of cell growth. Cells were also assayed for glutathione peroxidase and malonyl dialdehyde, a product of lipid peroxidation, to determine the mechanism of cell damage. Furthermore, MBT-2 cells were incubated with 100 M. alpha-tocopherol, a free radical scavenger, before exposure to hydrogen peroxide to determine whether the effects of hydrogen peroxide could be reversed. RESULTS: We observed a dose dependent inhibition of MBT-2 cell growth after exposure to doxorubicin hydrochloride. Exposure to doxorubicin and hydrogen peroxide resulted in greater cell growth inhibition than exposure to either agent alone. The effects of hydrogen peroxide on cell proliferation were reversed by pre-incubation with alpha-tocopherol. CONCLUSIONS: As a source of oxygen free radicals, hydrogen peroxide enhances the antiproliferative effect of doxorubicin hydrochloride on a mouse bladder tumor cell line. Thus, hydrogen peroxide may be a relatively inexpensive, nontoxic method of augmenting the cytotoxicity of doxorubicin hydrochloride. Further studies are warranted to determine whether these observations may have clinical application.

"Having lived much in the world": inhabitation, embodiment and English women travellers' representations of Russia in the eighteenth century.

This article examines representations of Russia in the travel writings of British women in the eighteenth and nineteenth centuries. Using a mid-nineteenth- century text, The Englishwoman in Russia, to introduce the more familiar racialised models of difference deployed by imperial travel writers, the article connects these with two mid-eighteenth-century travel texts by virtue of the women writers' shared preoccupation with the female body as a sign of national culture, and cultural difference. Through a reading of Mrs Vigor's Letters from a Lady (1775), and Eliza Justice's Voyage to Russia (1746), it is argued that images of the female body are not only significant as a mode of cultural negotiation for foreign bodies and practices in this period, but that strategic "inhabitations" of Russian culture contribute to the women travellers' production of themselves as national and authorial "subjects" within their published texts.

DAZ family proteins exist throughout male germ cell development and transit from nucleus to cytoplasm at meiosis in humans and mice.

The human DAZ gene family is expressed in germ cells and consists of a cluster of nearly identical DAZ (deleted in azoospermia) genes on the Y chromosome and an autosomal homolog, DAZL (DAZ-like). Only the autosomal gene is found in mice. Y-chromosome deletions that encompass the DAZ genes are a common cause of spermatogenic failure in men, and autosomal homologs of DAZ are essential for testicular germ cell development in mice and Drosophila. Previous studies have reported that mouse DAZL protein is strictly cytoplasmic and that human DAZ protein is restricted to postmeiotic cells. By contrast, we report here that human DAZ and human and mouse DAZL proteins are present in both the nuclei and cytoplasm of fetal gonocytes and in spermatogonial nuclei. The proteins relocate to the cytoplasm during male meiosis. Further observations using human tissues indicate that, unlike DAZ, human DAZL protein persists in spermatids and even spermatozoa. These results, combined with findings in diverse species, suggest that DAZ family proteins function in multiple cellular compartments at multiple points in male germ cell development. They may act during meiosis and much earlier, when spermatogonial stem cell populations are established.

The balance of benefit: a review of intergenerational transfers in Australia.

PURPOSE: This article reviews the financial and nonfinancial transfers taking place intergenerationally and between older people and the community. DESIGN AND METHOD: Secondary data were used in the analysis and discussion to provide an overview of the Australian context. RESULTS: Within the public arena, governments provide major financial contributions through money transfers and the provision of residential support. Older people provide considerable community support by undertaking voluntary services. This article concludes that the balance of benefit is difficult to determine; however, in terms of public expenditure older people are major recipients. Within the family, the balance of benefit is reversed. Older people are major monetary contributors to adult children and their families in the transition to an independent status. Older people are also the principal carers of their frail-aged partners, thus reducing both the burden of care on their adult children and government institutions. IMPLICATIONS: The analysis reported here has major implications for the development of policy and structural change and for reducing negative stereotypes of dependency in old age.

Evaluation of cyclin expression in testicular germ cell tumors: cyclin E correlates with tumor type, advanced clinical stage, and pulmonary metastasis.

The measurement of proliferative index has yielded promising yet conflicting results in the evaluation of testicular tumors. We have examined the role of Ki-67, along with the cyclins A and E in testicular tumorigenesis. We compared the immunoreactivity of 20 pure seminomas with 20 mixed germ cell tumors composed predominantly of embryonal carcinoma with a variety of proliferation markers, including Ki-67, cyclin A, and cyclin E. All 40 tumors stained for Ki-67, and 19 of 20 (95%) seminomas and 18 of 20 (90%) embryonal carcinomas stained positively for cyclin A. Cyclin E stained 14 of 19 (74%) of the embryonal carcinomas and only 4 of 20 (20%) of the seminomas (Fisher's exact two-tailed test, P = .0012). There was a trend toward larger tumor size for cyclin E-positive seminomas (median, 5.92 cm versus 3.96 cm; P = .08), although the same correlation was not significant in embryonal carcinomas. For both seminomas and embryonal carcinomas, staining with cyclin E did not correlate with the presence of lymphovascular invasion or capsular invasion. However, patients who had cyclin E-positive tumors presented with higher clinical stage (P = .0015). In addition, pulmonary spread in embryonal carcinomas (four patients) and seminomas (one patient) occurred only in patients whose tumors were cyclin E positive (P = .014). Although Ki-67 and cyclin A offer little prognostic information in testicular germ cell tumors, cyclin E immunoreactivity correlates with tumor type and is strongly predictive of distant tumor spread.