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Purpose: Estrogen receptor (ER) alpha signaling is a known driver of ER-positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Combining endocrine therapy (ET) such as fulvestrant with CDK4/6, mTOR, or PI3K inhibitors has become a central strategy in the treatment of ER+ advanced breast cancer. However, suboptimal ER inhibition and resistance resulting from the ESR1 mutation dictates that new therapies are needed., Experimental Design: A medicinal chemistry campaign identified vepdegestrant (ARV-471), a selective, orally bioavailable, and potent small molecule PROteolysis-TArgeting Chimera (PROTAC) degrader of ER. We used biochemical and intracellular target engagement assays to demonstrate the mechanism of action of vepdegestrant, and ESR1 wild-type (WT) and mutant ER+ preclinical breast cancer models to demonstrate ER degradation-mediated tumor growth inhibition (TGI)., Results: Vepdegestrant induced ≥90% degradation of wild-type and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro, and achieved substantial TGI (87%-123%) in MCF7 orthotopic xenograft models, better than those of the ET agent fulvestrant (31%-80% TGI). In the hormone independent (HI) mutant ER Y537S patient-derived xenograft (PDX) breast cancer model ST941/HI, vepdegestrant achieved tumor regression and was similarly efficacious in the ST941/HI/PBR palbociclib-resistant model (102% TGI). Vepdegestrant-induced robust tumor regressions in combination with each of the CDK4/6 inhibitors palbociclib, abemaciclib, and ribociclib; the mTOR inhibitor everolimus; and the PI3K inhibitors alpelisib and inavolisib., Conclusions: Vepdegestrant achieved greater ER degradation in vivo compared with fulvestrant, which correlated with improved TGI, suggesting vepdegestrant could be a more effective backbone ET for patients with ER+/HER2- breast cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Diffuse intrinsic pontine glioma (DIPG) is an invasive and treatment-refractory pediatric brain tumor. Primary DIPG tumors harbor a number of mutations including alterations in PTEN, AKT, and PI3K and exhibit activation of mammalian Target of Rapamycin Complex 1 and 2 (mTORC1/2). mTORC1/2 regulate protein translation, cell growth, survival, invasion, and metabolism. Pharmacological inhibition of mTORC1 is minimally effective in DIPG. However, the activity of dual TORC kinase inhibitors has not been examined in this tumor type. Nanomolar levels of the mTORC1/2 inhibitor TAK228 reduced expression of p-AKT S473 and p-S6 S240/244 and suppressed the growth of DIPG lines JHH-DIPG1, SF7761, and SU-DIPG-XIII. TAK228 induced apoptosis in DIPG cells and cooperated with radiation to further block proliferation and enhance apoptosis. TAK228 monotherapy inhibited the tumorigenicity of a murine orthotopic model of DIPG, more than doubling median survival (p = 0.0017) versus vehicle. We conclude that dual mTOR inhibition is a promising potential candidate for DIPG treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

NOTCH regulates stem cells during normal development and stemlike cells in cancer, but the roles of NOTCH in the lethal pediatric brain tumor diffuse intrinsic pontine glioma (DIPG) remain unknown. Because DIPGs express stem cell factors such as SOX2 and MYCN, we hypothesized that NOTCH activity would be critical for DIPG growth. We determined that primary DIPGs expressed high levels of NOTCH receptors, ligands, and downstream effectors. Treatment of the DIPG cell lines JHH-DIPG1 and SF7761 with the γ-secretase inhibitor MRK003 suppressed the level of the NOTCH effectors HES1, HES4, and HES5; inhibited DIPG growth by 75%; and caused a 3-fold induction of apoptosis. Short hairpin RNAs targeting the canonical NOTCH pathway caused similar effects. Pretreatment of DIPG cells with MRK003 suppressed clonogenic growth by more than 90% and enhanced the efficacy of radiation therapy. The high level of MYCN in DIPG led us to test sequential therapy with the bromodomain inhibitor JQ1 and MRK003, and we found that JQ1 and MRK003 inhibited DIPG growth and induced apoptosis. Together, these results suggest that dual targeting of NOTCH and MYCN in DIPG may be an effective therapeutic strategy in DIPG and that adding a γ-secretase inhibitor during radiation therapy may be efficacious initially or during reirradiation.

Purpose: New research findings have revealed a key role for vascular endothelial growth factor (VEGF) in the stimulation of angiogenesis in clear cell renal carcinoma (RCC) which is a highly vascularized and treatment-resistant tumor. Sorafenib (BAY 43-9006, Nexavar) is a multi-kinase inhibitor which targets receptor tyrosine and serine/threonine kinases involved in tumor progression and tumor angiogenesis. The effect of sorafenib on tumor growth and tumor histology was assessed in both ectopic and orthotopic mouse models of RCC., Methods: Sorafenib was administered orally to mice bearing subcutaneous (SC, ectopic) or sub-renal capsule (SRC, orthotopic) tumors of murine (Renca) or human (786-O) RCC. Treatment efficacy was determined by measurements of tumor volume and tumor growth delay. In mechanism of action studies, using the 786-O and Renca RCC tumor models, the effect of sorafenib was assessed after dosing for 3 or 5 days in the SC models and 21 days in the SRC models. Inhibition of tumor angiogenesis was assessed by measuring level of CD31 and alpha-smooth muscle actin (alphaSMA) staining by immunohistochemistry (IHC). The effect of sorafenib on MAPK signaling, cell cycle progression and cell proliferation was also assessed by IHC by measuring levels of phospho-ERK, phospho-histone H3 and Ki-67 staining, respectively. The extent of tumor apoptosis was measured by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) assays. Finally, the effects of sorafenib on tumor hypoxia was assessed in 786-O SC model by injecting mice intravenously with pimonidazole hydrochloride 1 h before tumor collection and tumor sections were stained with a FITC-conjugated Hypoxyprobe antibody., Results: Sorafenib produced significant tumor growth inhibition (TGI) and a reduction in tumor vasculature of both ectopic and orthotopic Renca and 786-O tumors, at a dose as low as 15 mg/kg when administered daily. Inhibition of tumor vasculature was observed as early as 3 days post-treatment, and this inhibition of angiogenesis correlated with increased level of tumor apoptosis (TUNEL-positive) and central necrosis. Consistent with these results, a significant increase in tumor hypoxia was also observed 3 days post-treatment in 786-O SC model. However, no significant effect of sorafenib on phospho-ERK, phospho-histone H3 or Ki-67 levels in either RCC tumor model was observed., Conclusion: Our results show the ability of sorafenib to potently inhibit the growth of both ectopically- and orthotopically-implanted Renca and 786-O tumors. The observed tumor growth inhibition and tumor stasis or stabilization correlated strongly with decreased tumor angiogenesis, which was due, at least in part, to inhibition of VEGF and PDGF-mediated endothelial cell and pericyte survival. Finally, sorafenib-mediated inhibition of tumor growth and angiogenesis occurred at concentrations equivalent to those achieved in patients in the clinic.

Over the past decade, high throughput screening (HTS) has become the focal point for discovery programs within the pharmaceutical industry. The role of this discipline has been and remains the rapid and efficient identification of lead chemical matter within chemical libraries for therapeutics development. Recent advances in molecular and computational biology, i.e., genomic sequencing and bioinformatics, have resulted in the announcement of publication of the first draft of the human genome. While much work remains before a complete and accurate genomic map will be available, there can be no doubt that the number of potential therapeutic intervention points will increase dramatically, thereby increasing the workload of early discovery groups. One current drug discovery paradigm integrates genomics, protein biosciences and HTS in establishing what the authors refer to as the "gene-to-screen" process. Adoption of the "gene-to-screen" paradigm results in a dramatic increase in the efficiency of the process of converting a novel gene coding for a putative enzymatic or receptor function into a robust and pharmacologically relevant high throughput screen. This article details aspects of the identification of lead chemical matter from HTS. Topics discussed include portfolio composition (molecular targets amenable to small molecule drug discovery), screening file content, assay formats and plating densities, and the impact of instrumentation on the ability of HTS to identify lead chemical matter.

Assessment and care management (ACM) of elderly patients prior to discharge from hospital has been in place since 1993. It involves a complex multi-disciplinary assessment of needs which may delay discharge from hospital. We prospectively studied the process of ACM in a group of patients discharged from hospital over a three month period. The times taken for completion of the necessary reports, and any delays in the process were recorded. The times of each individual step in the process were correlated to overall length of stay and to the length of the care management process. The effect of intercurrent illnesses or other delays was studied. Of the available sample (n = 83), 16 patients died and two required long term hospital care. The median length of stay of the remainder (n = 65) was 36 days (range 5-149 days). The median time from the start of the ACM process to discharge was 22 days (0-89 days). The strongest correlation with total length of stay was the time from admission until ACM commenced (rho = 0.661, p < 0.0001). The time spent in the ACM process was related strongly to the time taken for the Care Manager to process the applications (rho = 0.682, p < 0.0001). Delay was recorded in 17 (24%) cases, resulting in an increased length of stay (p < 0.001). While care management may help in appropriate placement after hospital discharge, these results suggest that it is prone to delays outside the hospital setting. Such delays result in patients waiting in hospital for care packages to be set up in the community. This has implications for acute hospital services.

Objective: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure., Results: After a single dose of 100 mg, Cmax of the parent compound (2.52 mg.l-1) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (Cmax 8.4 vs 3.21 mg.l-1). No adverse effects were observed., Conclusion: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity.

Most receptor tyrosine kinases are activated by dimerization induced by their cognate ligands. Protein S, an abundant serum protein previously shown to be a potent anticoagulation factor, has been proposed to be a ligand for the Sky tyrosine kinase (Stitt et al., 1995). Here we show that Sky, when expressed to high levels, is tyrosine phosphorylated even in the absence of a ligand. Furthermore, a version of Sky (termed Sky delta SS) engineered to be overexpressed in the cytoplasm and thus in a ligand-free environement, can function as a dimeric tyrosine kinase. Sky delta SS can transform RatB1a fibroblasts and thus retains all the properties of the full-length Sky kinase. These data suggest that Sky, when overexpressed either at the cell surface or in the cytoplasm, is competent to form dimers even in the absence of its ligand. We also demonstrate that an isoform of Sky, originally reported as Brt and here termed Sky Isoform I, resides in the cytoplasm. Therefore, the activities of Sky delta SS we describe may reflect those of the naturally occurring Isoform I.

Depression in the elderly is a common problem, cited as occurring in up to 10% of elderly people living at home, half of whom may need specialist referral. The introduction of selective serotonin reuptake inhibitors has been reported as a major advance in the treatment of depression in that they are less sedating, have fewer anticholinergic effects and are less toxic in overdose. We report three cases of severe hyponatraemia, seen in the past 12 months, associated with the selective serotonin reuptake inhibitors fluoxetine and sertraline. Hyponatraemia has been reported as a rare adverse effect of selective serotonin reuptake inhibitors.

Patients admitted to a 30 bedded acute geriatric medical ward in 1993 were followed up to discharge. The admission rate on weekend days was half that for weekdays. Six percent of ward discharges occurred at weekends, over half being due to death. Respiratory, cardiovascular and central nervous systems disorders were the commonest reasons for admission (56%) and death (73%). Greater emphasis should be placed on discharging patients at weekends.

To gain insight into the signal transduction pathways utilized by the Wnt-1-responsive mammary epithelial cell line C57MG, we screened for non-src family member tyrosine kinases expressed in these cells using a polymerase chain reaction-based technique. We identified five cDNA clones encoding receptor tyrosine kinases for which the ligand is known (fibroblast growth factor receptor, platelet-derived growth factor receptor, epithelial growth factor receptor, insulin receptor, and insulin-like growth factor receptor), two putative receptor tyrosine kinases for which the ligand remains to be identified (the products of ryk and the mouse klg homolog), and a novel tyrosine kinase. We cloned cDNAs encoding both the murine and human homologs of this kinase, the sequences of which were subsequently published under the names sky (Ohashi, K., Mizuno, K., Kuma, K., Miyata, T., and Nakamura, T. (1994) Oncogene 9, 699-705) and rse (Mark, M. R., Scadden, D. T., Wang, Z., Gu, Q., Goddard, A., and Godowski, P. J. (1994) J. Biol. Chem. 269, 10720-10728). Mouse sky RNA levels are abundant in mammary tumors derived from transgenic mice that express wnt-1, fgf-3, or both oncogenes in their mammary glands. However, little or no expression of sky is detected in mammary glands from virgin animals or in preneoplastic mammary glands from wnt-1 transgenic mice. Moreover, we find that the human homolog of sky is expressed at elevated levels when normal human mammary epithelial cells are rendered tumorigenic by the introduction of two viral oncogenes. Transient transfection of the human SKY cDNA into the quail fibrosarcoma cell line QT6 reveals that SKY is an active tyrosine kinase that augments the level of cellular phosphotyrosine. Introduction of murine Sky into RatB1a fibroblasts by retrovirus-mediated gene transfer results in morphological transformation, growth in soft agar, and the formation of tumors in nude mice. These data raise the possibility that the Sky tyrosine kinase is involved in the development and/or progression of mammary tumors.

Patients placed from hospital to nursing or residential homes or to home under the intensive domiciliary care scheme were compared before and after the introduction of 'assessment and care management' on the 1st April 1993. In geriatric medical wards there was a 69% increase in the average length of stay for patients assessed and care managed and a 52% increase in the length of stay for self-funding patients compared with patients placed before the introduction of assessment and care management. Care managed patients discharged on the intensive domiciliary care scheme had a 66% increase in their length of hospital stay compared with care managed patients placed in private nursing homes. In contrast, the length of stay for care managed patients in other hospital wards was half that for geriatric medical wards.

We have studied workloads and patterns of care in geriatric medicine from 1982 to 1993 in the Ulster Hospital. There was a 137% rise in admissions, a 16% reduction in domiciliary visits and a 31% increase in ward assessments. The continuing care waiting list fell to zero in 1993. The number of new outpatients rose by a factor of 8.6 between 1987 and 1993. Between 1990 and 1993 there was an increased admission rate from nursing homes and of patients suffering from respiratory system diseases. Mortality rates fell from 27.8% in 1982 to 19.3% in 1990 and to 12.1% in 1993. Mean age and sex ratios remained unchanged over the years while the average length of stay halved from 43.3 to 22.6 days between 1990 and 1993. 81% of admissions in 1993 were emergencies. Care of the elderly in hospital and the interface with general medicine are changing.

Comparison was made between patients admitted from a nursing home and all other patients admitted to a geriatric medical unit in 1990 and 1993. The number of nursing home patient admissions rose from 26 in 1990 to 106 in 1993. Nursing home patients were frailer both physically and mentally with a dementia rate of 78% (in those who survived, 1993) and a mortality rate of 19.8% (1993), compared with a dementia rate of 19% and a mortality rate of 11.3% in all other admissions in 1993. Male patients admitted from a nursing home were more likely to die than females (33% versus 14.5%, 1993). Lengths of stay of nursing home patients were shorter, largely due to the availability of a 'safe environment' when discharged, but also related to shorter survival times. 61% of patient admissions from nursing homes in 1993 were considered 'unnecessary' and could have been avoided if specialist advice had been available before admission.

The relationship between exocrine pancreatic function and plasma pancreatic polypeptide levels was studied in 14 normal elderly subjects and in ten elderly patients with exocrine pancreatic insufficiency determined by the para-amino-benzoic acid test. There was a decrease in the total pancreatic polypeptide response after a standard mixed meal in the group with pancreatic insufficiency (t = 2.753, p = 0.01). An increase above basal of less than 100% in plasma pancreatic polypeptide levels 30 min after a standard mixed meal is strongly associated with exocrine pancreatic insufficiency (Fisher's exact test, p = 0.005).

A pilot study on exocrine pancreatic function, using the 2-day para-aminobenzoic acid (PABA) test, was performed on 21 healthy elderly and 26 healthy young subjects. A PABA excretion index (PEI) less than 55%, indicating moderate to severe exocrine pancreatic insufficiency (EPI), was found in 19% of the elderly group (95% confidence limits 5-42%). While the mean value of the PEI was significantly lower in the elderly compared with the young group (Mann-Whitney Z = 2.8, p less than 0.01), there was no significant difference when the elderly subgroup with PEI less than 55% was excluded. There was no evidence of a generalized moderate to severe decline in pancreatic exocrine function with increasing age; a mild to moderate decline cannot be excluded.

The steady-state pharmacokinetic profile of indomethacin was examined in twelve healthy volunteers (4 m, 8 f; 20-34 y) and in 12 elderly subjects (7 m, 5 f; 70-88 y). Two formulations of indomethacin were examined, providing duplicate data for each subject group. The subjects received each formulation of indomethacin (25 mg tid) for 6 days in a single blind crossover fashion. On day 7, after an overnight fast, a final 25 mg dose of indomethacin was given and plasma concentrations measured over the following 12 h. Kinetic parameters Cpmin, Tmax and AUC (0-12 h) were determined. There were no differences in the pharmacokinetic parameters between young and elderly subjects or between data for the two formulations of indomethacin. AUC values (micrograms.ml-1.h), for example, for the two formulations in the young subjects were 5.85 and 6.85 while the values for the elderly subjects were 6.55 and 6.50 respectively. When each treatment period was considered independently there was a significant difference between young and elderly subjects with regard to compliance. The rates of non compliance (over and under compliance) using a capsule count technique were, however, low with a mean maximum value of 5.8% being recorded for the elderly subjects.

The largest subunit of RNA polymerase II contains a unique carboxy-terminal domain (CTD) that consists of repeats of the heptapeptide YSPTSPS. RNA polymerase II CTD truncation mutations affect the ability to induce transcription of a subset of yeast genes in vivo, and the lack of response to induction maps to the upstream activating sequences of these genes. Here, we report that progressive truncation of the yeast RNA polymerase II CTD causes progressive loss of trans-activator-dependent transcription in nuclear extracts but has little effect on elongation or termination. Specific transcription, which is reduced by up to 50-fold in these assays, can be restored in the defective nuclear extracts by adding purified wild-type RNA polymerase II. The defects in factor-dependent transcription are observed with templates that are assembled into nucleosomes as well as with templates that are not so assembled. Defects in factor-independent transcription are also observed, but these are not as profound as those observed in the presence of trans-activators. These results indicate that the RNA polymerase II CTD functions during transcription initiation and is required for normal levels of activated transcription in vitro.

Regulatory factors must contend with chromatin structure to function. Although nucleosome structure and position on promoters can be important in determining factor access, the intrinsic ability of factors to bind to nucleosomal DNA might also play an essential regulatory role. We have used templates where nucleosomes were either randomly positioned or rotationally phased to demonstrate that two transcription factors, heat shock factor (HSF) and GAL4, differ significantly in their ability to bind to nucleosomes. GAL4 was able to bind to nucleosomal templates. Surprisingly, in contrast to its behavior on naked DNA, GAL4 bound better to multiple GAL4 sites than to a single GAL4 site on these templates. HSF alone was not able to bind to nucleosomal templates. HSF was able to bind to nucleosomal templates, however, when the TATA-binding factor TFIID was present. Consequently, binding to nucleosomal templates could be facilitated by adjacent binding of the same protein in the case of GAL4 but required binding of a second protein in the case of HSF. Taken together, these data demonstrate that regulatory factors differ in their inherent ability to bind to nucleosomal templates. These differences are likely to be important to the function of these factors in vivo.

GAL4 derivatives containing an activation domain alleviated repression of a promoter during nucleosome assembly. A GAL4 derivative lacking an activation domain stably bound the promoter during nucleosome assembly but was not sufficient to preserve promoter function. The activation domain of GAL4 derivatives was essential for preserving promoter function, and thus the transcriptional stimulatory activity attributable to these activation domains increased dramatically during nucleosome assembly. Furthermore, promoter-bound activation domains allowed the formation of preinitiation complexes after nucleosome assembly. Finally, GAL4 derivatives containing activation domains significantly stimulated transcription through bacterially produced yeast TFIID only from nucleosome-assembled templates. These data indicate that acidic activation domains stimulate transcription by enhancing the ability of basal transcription factors to compete with nucleosomes for occupancy of the promoter.

We have analyzed 41 deletion, linker scan, and substitution mutants of the human HSP70 gene promoter for activation by the adenovirus E1a region. No natural element of the HSP70 gene promoter was required for activation. To investigate specific interactions between E1a and transcription factors, a set of 24 promoters containing all possible combinations of eight different upstream or TATA motifs was investigated for E1a stimulation. E1a transactivated the promoter regardless of the particular TATA motif present. Furthermore, there was no dramatic correlation between any upstream motif and activation by E1a. These data suggest that E1a does not stimulate transcription via an interaction with any specific transcription factor but instead suggest that E1a interacts via the general transcription machinery.

To investigate interactions between transcription factors on mammalian promoters, we constructed a set of 24 variations of the human HSP70 gene promoter in which six upstream sequence motifs are paired in every possible combination with four TATA motifs. These promoters were analyzed for in vivo expression, and selected constructs were examined by in vitro template commitment studies. Activation transcription factor (ATF) and CP1 showed dramatically different interactions with the factor(s) bound to the TATA region. CP1 functioned in vivo regardless of the TATA motif that it was paired with and was not capable of sequestering the core promoter complex in a template commitment assay. ATF activity was dramatically altered by changing the TATA motif, and ATF was able to sequester the core promoter complex. These data suggest that CP1 and ATF function by distinct mechanisms that differ with respect to interaction with the factor(s) at the TATA box. Factor Sp1 also appeared to function by a TATA-independent mechanism. These data imply that the ability of a factor to function is determined not only by the intrinsic properties of the factor but also by promoter context.

Episodic diffuse cerebral symptoms and unexpected falls were investigated by ambulatory electrocardiography in nine men and 19 women aged 65 years or more. Eight subjects with episodic dizziness or syncope had cardiac arrhythmias which are known to be capable of causing these symptoms and four of these had symptoms at the time of the arrhythmia. However, only one was detected by ambulatory electrocardiography alone. No significant arrhythmias were found in any of the remaining subjects. When 17 symptomatic subjects were compared with 17 age- and sex-matched asymptomatic controls, cardiac arrhythmias known to be capable of causing symptoms were commoner in the symptomatic group, but the differences were not statistically significant. Ambulatory electrocardiography is of no more value than standard electrocardiography in the detection of arrhythmias associated with diffuse cerebral symptoms in elderly people.

A prospective study of 419 patients aged 70 and over admitted to acute medical wards was carried out by medical staff from a geriatric unit. Data, including presenting problem, housing, social support, mental state, continence, and degree of independence before and after admission, were recorded. Of the 419 patients, 143 remained in hospital after 14 days and 65 after 28 days. The major factors associated with prolonged stay in hospital included advanced age, stroke, confusion and falls as reasons for admission to hospital, incontinence, and loss of independence for everyday activities. Social circumstances did not predict length of stay. Although these factors are interrelated, the most important influence on length of stay was the medical reason for admission. Early contact with the geriatric medical unit in these patients may speed up the recovery or result in more appropriate placement.

Fifty of 62 applicants for residential accommodation underwent assessment at a geriatric day hospital. Twenty-five were suitable, 11 were suitable following rehabilitation and 14 were unsuitable for placement in residential accommodation. Around 35% of all applicants were not assessed. Seventy-nine per cent of assessed applicants, without dementia, either were unsure of how their application had been initiated or did not understand the implications of a move to residential accommodation. Twenty-two per cent of all applicants assessed were taking four or more drugs. To maximise the use of residential accommodation, all applicants should be assessed to reduce inappropriate referrals.

Nineteen of 45 consecutive patients admitted to hospital with fracture of the neck of femur had ambulatory electrocardiography performed on the fourteenth post-operative day. The frequency of cardiac arrhythmias was compared with control subjects who had undergone total hip replacement operations. No significant difference was found. None of the cardiac arrhythmias in the fracture or control subjects was associated with symptoms. Two fracture patients and three control subjects suffered an acute myocardial infarct peri-operatively and were excluded from the study. Fracture patients on drug therapy for heart disease had an increased six-month mortality rate compared with those not on such therapy. Episodic cardiac arrhythmias do not appear to be an important contributory factor to fracture of the neck of femur in the elderly.

Twenty-four-hour ambulatory electrocardiography was performed in 25 young and 29 active elderly subjects. Sinus bradycardia and sinus arrhythmia were common in the young but uncommon in the elderly. Ventricular and supraventricular premature beats and brief runs of supraventricular tachycardia were common in the elderly but uncommon in the young. Complex ventricular arrhythmias only occurred in the elderly but brief episodes of nocturnal Wenckebach AV block were quite common in young and old alike. No significant difference in arrhythmia frequency was found between elderly subjects with heart disease and those without heart disease or between elderly subjects without symptoms and those with non-episodic symptoms such as dizziness. None of the arrhythmias in the young or elderly subjects was associated with symptoms. In follow-up at 30 months, only one elderly subject was deceased (from pneumonia) and none had suffered a stroke or heart attack. It is concluded that transient cardiac arrhythmias are commoner in the elderly than in the young. However, their long-term significance remains unknown, but it is likely that they are relatively benign.

Simian virus 40 large tumor (T) antigen stimulates transcription from the SV40 late promoter and some cellular genes. We report here the novel finding that purified T antigen preferentially stimulates transcription from the human heat shock protein 70 promoter in an in vitro transcription system. T antigen is thus capable of stimulating transcription by a process that does not require synthesis of other proteins and that may involve a direct interaction with preexisting cellular factors.

Ambulatory electrocardiography was performed on 21 consecutive acute stroke patients on the day of admission and 14 and 42 days later. There was no statistically significant difference in cardiac arrhythmias between stroke patients and a group of age- and sex-matched controls. There was considerable variation in the frequency of cardiac arrhythmias on each day but none of the arrhythmias was associated with a sudden deterioration in the condition of the patients and no arrhythmias produced symptoms in either the stroke or the control groups. Fourteen per cent of stroke patients had an associated acute myocardial infarction and 57% had a history of previous heart disease. While a history of previous heart disease or the occurrence of major ventricular arrhythmias were associated with an increased six-week mortality rate, routine continuous monitoring of cardiac rhythm would not appear to be of value in acute stroke.