How to Capitalize on the Retest Effect in Future Trials on Huntington’s Disease

The retest effect—improvement of performance on second exposure to a task—may impede the detection of cognitive decline in clinical trials for neurodegenerative diseases. We assessed the impact of the retest effect in Huntington’s disease trials, and investigated its possible neutralization. We enrolled 54 patients in the Multicentric Intracerebral Grafting in Huntington’s Disease (MIG-HD) trial and 39 in the placebo arm of the Riluzole trial in Huntington’s Disease (RIL-HD). All were assessed with the Unified Huntington’s Disease Rating Scale (UHDRS) plus additional cognitive tasks at baseline (A₁), shortly after baseline (A₂) and one year later (A₃). We used paired t-tests to analyze the retest effect between A₁ and A₂. For each task of the MIG-HD study, we used a stepwise algorithm to design models predictive of patient performance at A₃, which we applied to the RIL-HD trial for external validation. We observed a retest effect in most cognitive tasks. A decline in performance at one year was detected in 3 of the 15 cognitive tasks with A₁ as the baseline, and 9 of the 15 cognitive tasks with A₂ as the baseline. We also included the retest effect in performance modeling and showed that it facilitated performance prediction one year later for 14 of the 15 cognitive tasks. The retest effect may mask cognitive decline in patients with neurodegenerative diseases. The dual baseline can improve clinical trial design, and better prediction should homogenize patient groups, resulting in smaller numbers of participants being required.     

Salt-poor Human Albumin in Management of Nephrotic Syndrome

Thirteen patients with the nephrotic syndrome were treated with a high-protein diet, a 0·5 g sodium intake (equivalent to 1·3 g sodium chloride), and frusemide in increasing dosage. One became oedema-free with frusemide 240 mg daily, three became oedema-free with frusemide 500 mg daily, and two required a combination of high-dose frusemide and spironolactone. In three there was an appreciable increase in the blood urea, one patient developed hyponatraemia, and in two there was no weight loss. In these six patients infusions of human salt-poor albumin produced a prompt diuresis, loss of weight, and correction of the abnormal biochemical findings. In the seventh severely oedematous patient combined albumin and diuretic therapy led to a loss of 27 kg in 14 days.     

Bumetanide: Potent New “Loop” Diuretic

Bumetanide, a pharmacologically new diuretic, was evaluated in 27 subjects. Its onset of action was within 30 minutes with a peak at 90 minutes and a total duration of action of about 270 minutes. In a controlled study in oedematous patients it was equipotent with frusemide at one-fortieth the molar dosage and did not differ from frusemide with regard to its pattern of electrolyte excretion. On continuous oral administration for eight days it produced effective diuresis with minimal alteration in biochemical and haematological status. The only adverse effect was gastric discomfort in one patient.     

Reconciling competing mechanisms posited to underlie auditory verbal hallucinations

Perception is not the passive registration of incoming sensory data. Rather, it involves some analysis by synthesis, based on past experiences and context. One adaptive consequence of this arrangement is imagination—the ability to richly simulate sensory experiences, interrogate and manipulate those simulations, in service of action and decision making. In this paper, we will discuss one possible cost of this adaptation, namely hallucinations—perceptions without sensory stimulation, which characterize serious mental illnesses like schizophrenia, but which also occur in neurological illnesses, and—crucially for the present piece—are common also in the non-treatment-seeking population. We will draw upon a framework for imagination that distinguishes voluntary from non-voluntary experiences and explore the extent to which the varieties and features of hallucinations map onto this distinction, with a focus on auditory-verbal hallucinations (AVHs)—colloquially, hearing voices. We will propose that sense of agency for the act of imagining is key to meaningfully dissecting different forms and features of AVHs, and we will outline the neural, cognitive and phenomenological sequelae of this sense. We will conclude that a compelling unifying framework for action, perception and belief—predictive processing—can incorporate observations regarding sense of agency, imagination and hallucination.This article is part of the theme issue ‘Offline perception: voluntary and spontaneous perceptual experiences without matching external stimulation’.     

Metabolic Studies,Aldosterone Secretion Rate,and Plasma Renin after Carbenoxolone Sodium

A formal metabolic study of carbenoxolone sodium (Biogastrone) 300 mg./day has been performed for 17 days on a woman with gastric ulcer who in a previous 21-day trial, on a 52-mEq sodium diet, showed weight gain, retention, and rise in plasma sodium and chloride concentrations, as well as hypokalaemia without change in potassium balance. In the present trial sodium intake was restricted to 26 mEq/day; while plasma electrolyte changes of lesser degree still occurred, there was no retention of water, sodium, or chloride. Aldosterone secretion in the control period was 202 μg./24 hours, and fell to 74 μg./24 hours after carbenoxolone, but plasma renin was unchanged.These results suggest that the mineralocorticoid effects of carbenoxolone (and presumably of liquorice and its other derivatives) are due to an intrinsic aldosterone-like action, and that, with sodium deprivation, aldosterone secretion is suppressed by a mechanism which is not renin-mediated—possibly hypokalaemia.     

Variations in Sulfhydryl, Disulfide, and Protein Content during Synchronous and Asynchronous Growth of HeLa Cells

The cellular contents of protein-bound and nonprotein sulfhydry (—SH) and disulfide (—SS—) groups were measured in both asynchronous and synchronous HeLa S3 cultures. About 90% of these groups are associated with proteins, the majority in the —SH form. The content of protein-bound groups, and hence the total content of —SH and —SS— groups (28 × 10^-15 moles/cell, or 1.1 × 10^-6 moles/g protein on average), changes in parallel with the protein content (which varies between 2 and 4 × 10^-10 g/cell) as asynchronous populations pass from the lag through the exponential to the stationary phase of growth. The concentration of nonprotein —SH groups, in contrast, increases 10-fold during lag phase and decreases in stationary phase; it follows the protein concentration closely during the exponential phase, at a level of about 2.8 × 10^-15 moles/cell. In synchronous cultures the protein content doubles during the cell cycle, possibly in an exponential fashion. The total —SH and —SS— content also doubles, but the rate of increase appears to fluctuate. The concentrations of the protein-bound groups show 2- to 3-fold fluctuations per unit protein: protein-bound —SH groups and mixed —SS— linkages rise to maxima while protein-bound —SS— groups fall to a minimum at the G₁/S transition, and fluctuations in these groups occur again during G₂. In addition, the protein-bound —SH concentration falls continuously during the S phase. The nonprotein —SH concentration undergoes the largest (relative) fluctuations, dropping from 4 × 10^-15moles/cell in early G₁ to about 0.4 × 10^-15 moles/cell (of standard protein content) at the end of G₁, and then rising to 30 times this value by the end of S.     

Water Stress Enhances Ethylene-mediated Leaf Abscission in Cotton

Abscission of cotyledonary leaves from cotton (Gossypium hirsutum L. cv. Stoneville 213) seedlings occurred following relief from water stress. The amount of abscission was related to the magnitude of the plant water deficit. Leaf abscission promoted by exogenous ethylene was enhanced in seedlings subjected to water stress. Treatment with ethylene (2.0 to 3.2 microliters of ethylene per liter of air for 24 hours) raised the threshold plant water potential required to induce abscission from —17 to —7 bar, indicating that the stress caused the tissue to become predisposed to ethylene action. Based on the abscission response curve for seedlings treated with ethylene while under water stress, this apparent predisposition was developed as the plant water potentials reached the —7 to —10 bar range. The abscission-promoting effects of ethylene in combination with water stress were reversed with 15% CO₂ at plant water potentials above —12 bar, but the CO₂ reversal was lost at lower water potentials. These results are compatible with the concept that ethylene plays a regulatory role in leaf abscission induced by water stress.     

Actions of Prolactin and Frusemide on Heart Rate and Rhythm

Rat hearts with coronary circulations perfused by the Langendorff technique were studied. Recordings were made of the electrical and mechanical activity. Once the rate and rhythm of each heart and stabilized it was perfused with Ringer-Locke solution for 90 minutes; frusemide (40 μg/ml) was added to the perfusate during the last 30 minutes of this period. Eighteen experiments were performed—six controls, six in which prolactin at a concentration of 50 ng/ml was added to the perfusate for the whole 90 minutes, and six in which a prolactin concentration of 200 ng/ml was used.With the controls heart rate and rhythm remained steady, but there was a slow decline in amplitude of the contraction. With a prolactin concentration of 50 ng/ml the heart rate rose to about 40% above control during the first hour and after an initial sharp increase the contraction amplitude declined more rapidly than in the controls. The prolactin concentration of 200 ng/ml produced a decline of about 25% in heart rate over the first hour and amplitude behaved much as in the controls. Frusemide had no clear effect on the rate of beating of the controls, but it tended to reverse both the acceleration produced by 50 ng/ml prolactin and the slowing produced by the higher dose. Both the doses of prolactin consistently caused disturbances of rhythm. These effects occur at concentration of prolactin found in human plasma in various pathophysiological conditions.     

Renal Insensitivity to Frusemide Caused by Chronic Anticonvulsant Therapy

The diuretic response to 20-mg and 40-mg oral doses of frusemide was significantly smaller in a group of epileptic patients on chronic anticonvulsant therapy than in a group of normal staff members. Furthermore, the peak response was considerably delayed in the epileptic patients. The difference in the volume of diuresis was maintained after intravenous injection of 20 mg of frusemide. It is suggested that the sensitivity of the renal tubule to the diuretic action of frusemide is reduced by anticonvulsant therapy and that there may also be delayed absorption of the drug from the gastrointestinal tract.     

Clinical Evaluation of Practolol,a New Cardioselective Beta-blocking Agent in Angina Pectoris

In a controlled double-blind study practolol, a new cardioselective beta-blocking drug, was given to 15 patients with angina pectoris, and compared with propranolol 80 mg. q.d.s. The dose of practolol ranged from 200 to 600 mg.b.d. and was decided by initial open titration in individual patients. Though practolol did not influence the incidence of angina or glyceryl trinitrate consumption, it increased the duration of exercise possible in exercise tests and reduced the amount of ischaemic S—T depression in the radiocardiogram during exercise. Propranolol reduced the incidence of angina and, in the exercise tests, increased the amount and duration of exercise but did not affect the degree of S—T depression. Unlike propranolol, practolol did not produce any adverse effects on bronchial smooth muscle. Hence it is concluded that practolol is an effective drug in treating angina, and in the dosage used is of potential value in patients with asthmatic bronchitis and angina. It should, however, be used cautiously in anginal patients with heart failure.     

Differences between TNM classification and 2-[18F]FDG PET parameters of primary tumor in NSCLC patients

BackgroundThe aim of the study was to compare the TNM classification with 2-[¹⁸F]FDG PE T biological parameters of primary tumor in patients with NSCLC.Materials and methodsRetrospective analysis was performed on a group of 79 newly diagnosed NSCLC patients. PET scans were acquired on Gemini TF PET/CT scanner 60–70 min after injection of 2-[¹⁸F]FDG with the mean activity of 364 ± 75 MBq, with the area being examined from the vertex to mid-thigh. The reconstructed PET images were evaluated using MIM 7.0 Software for SUV_max, MTV and TLG values.ResultsThe analysis of the cancer stage according to TNM 8^th edition showed stage IA2 in 8 patients, stage IA3 — 6 patients, stage IB — 4 patients, IIA — 3 patients, 15 patients with stage IIB, stage IIIA — 17 patients, IIIB — 5, IIIC — 5, IVA in 7 patients and stage IVB in 9 patients. The lowest TLG values of primary tumor were observed in stage IA2 (11.31 ± 15.27) and the highest in stage IIIC (1003.20 ± 953.59). The lowest value of primary tumor in SUV_max and MTV were found in stage IA2 (6.8 ± 3.8 and 1.37 ± 0.42, respectively), while the highest SUV_max of primary tumor was found in stage IIA (13.4 ± 11.4) and MTV in stage IIIC (108.15 ± 127.24).ConclusionTNM stages are characterized by different primary tumor 2-[¹⁸F]FDG PET parameters, which might complement patient outcome.     

CARCINOMA OF THE CERVIX

Studies by eminent surgeons to reevaluate the place of radical operations in the treatment of carcinoma of the cervix—now that extensive procedures have become less hazardous—apparently have led to confusion in some minds as to choice between surgical and radiation therapy. Pending outcome of the studies, general employment of surgical treatment is unwarranted. Radiation is the treatment of choice in most cases, particularly if the lesion is in an early stage, although radical operation is indicated in certain rare early cases in which delivery of an effective dose of radiation to involved areas is technically difficult. Elsewise it appears at present that operation should be used only in cases of stages III or IV carcinoma—in which results by either means of treatment are poor.One hundred and seven patients were treated with a combination of x-ray and radium irradiation. X-ray was used first to reduce the hazard of implanting the radium. The “five-year arrest” rates were as follows: For 22 patients with stage I lesion, 70 per cent; for 31 with stage II, 55.7 per cent; 33 with stage III, 39.7 per cent; 21 with stage IV, 0. Eighteen patients with diagnosis of carcinoma of the cervix who had had subtotal hysterectomy were treated. The stage of the disease could not be determined. In this group the five-year arrest rate was 52 per cent.     

Bone Sarcoma: Treatment by Irradiation,Amputation, or a Combination of the Two

A retrospective survey of all cases of osteosarcoma of the femur and tibia treated at the major centres in the United Kingdom during 1952-9 was carried out in an attempt to assess the respective value of treatment by surgery and radiotherapy and the feasibility of a larger prospective study. Of the 192 patients available for the comparison, those treated by radiotherapy alone did least well. A combination of the two treatments—radiotherapy followed by amputation—produced better results, in terms of survival, than amputation alone; however, the comparatively small numbers involved and the inadequacy of information about the factors dictating the choice of treatment make firm conclusions impossible. A controlled clinical trial on a larger scale might provide answers to the outstanding questions.     

Indications for Treatment of Complete Atrioventricular Dissociation

For purposes of correct treatment it is important to recognize that patients with complete atrioventricular dissociation fall into three groups: Group I—established third-degree heart block with and without Stokes-Adams attacks; Group II—periodic third-degree heart block with and without Stokes-Adams attacks; Group III—established third-degree heart block with cardiac failure. Most patients in Group I present no technical problems when a pacemaker is implanted. In Group II it is advisable to insert a temporary intracardiac catheter electrode and maintain a rate of 60 to 64 during the periods of third-degree heart block. Sudden reversion, in this group, from sinus rhythm can be fatal. Group III patients will often require a pacemaker set in excess of 74 beats until they are free of cardiac failure. Fifteen of 20 patients with complete atrioventricular dissociation showed marked functional improvement after insertion of a pacemaker. The development, in our laboratory, of a 4″ portable pacemaker impulse detector has been invaluable in locating the cause of failure in an implanted pacemaker.     

Surgical stabilisation of the spine compared with a programme of intensive rehabilitation for the management of patients with chronic low back pain: cost utility analysis based on a randomised controlled trial

Objective To determine whether, from a health provider and patient perspective, surgical stabilisation of the spine is cost effective when compared with an intensive programme of rehabilitation in patients with chronic low back pain.Design Economic evaluation alongside a pragmatic randomised controlled trial.Setting Secondary care.Participants 349 patients randomised to surgery (n = 176) or to an intensive rehabilitation programme (n = 173) from 15 centres across the United Kingdom between June 1996 and February 2002.Main outcome measures Costs related to back pain and incurred by the NHS and patients up to 24 months after randomisation. Return to paid employment and total hours worked. Patient utility as estimated by using the EuroQol EQ-5D questionnaire at several time points and used to calculate quality adjusted life years (QALYs). Cost effectiveness was expressed as an incremental cost per QALY.Results At two years, 38 patients randomised to rehabilitation had received rehabilitation and surgery whereas just seven surgery patients had received both treatments. The mean total cost per patient was estimated to be £7830 (SD £5202) in the surgery group and £4526 (SD £4155) in the intensive rehabilitation arm, a significant difference of £3304 (95% confidence interval £2317 to £4291). Mean QALYs over the trial period were 1.004 (SD 0.405) in the surgery group and 0.936 (SD 0.431) in the intensive rehabilitation group, giving a non-significant difference of 0.068 (–0.020 to 0.156). The incremental cost effectiveness ratio was estimated to be £48 588 per QALY gained (–£279 883 to £372 406).Conclusion Two year follow-up data show that surgical stabilisation of the spine may not be a cost effective use of scarce healthcare resources. However, sensitivity analyses show that this could change—for example, if the proportion of rehabilitation patients requiring subsequent surgery continues to increase.     

Characterization of the Anti-HCV Activities of the New Cyclophilin Inhibitor STG-175

Shortened current direct-acting antiviral (DAA) therapies while less expensive, have not provided satisfactory efficacy in naïve cirrhotics, treatment experienced non-cirrhotics or even genotype-3 (GT3)-infected patients. Since DAA regimens consist of the same classes of inhibitors—NS5A (NS5Ai) and NS5B (NS5Bi) +/- NS3 (NS3i) inhibitors—it is likely that their costs will be high and will provide similar degrees of protection. Integrating drugs with distinct mechanisms of action (MoA) into DAA regimens could provide the solution for shortening the period of treatment. One such class of agents is the cyclophilin inhibitors (CypI), which has shown efficacy in patients. Resistance-associated variants persist for years post-treatment in patients exposed to NS5Ai or NS5Bi who fail to achieve a sustained virologic response, impairing their chance for cure on retreatment with existing DAA combinations. Because of their high barrier to resistance, CypI may be particularly useful as a rescue therapy for patients who have relapsed with DAA resistance-associated variants. In this study, we analyzed the anti-HCV properties of the novel cyclosporine A (CsA) derivate—STG-175. The non-immunosuppressive STG-175 possesses a high (EC₅₀ 11.5–38.9 nM) multi-genotypic (GT1a to 4a) anti-HCV activity. STG-175 clears cells from HCV since no viral replication rebound was observed after cessation of drug treatment. It presents a higher barrier to resistance than other CypI or selected DAAs. HCV variants, which emerged under STG-175 pressure, are only ~2-fold resistant to the drug. No cross-resistance was observed with DAAs STG-175 was efficacious against DAA-resistant HCV variants. Drug combination studies revealed that STG-175 provides additive and synergistic effects against GT1a to 4a. STG-175 inhibits the infection of HCV, HIV-1 and HBV in mono-, dual- and triple-infection settings. Altogether these results suggest that the new CypI STG-175 represents an attractive drug partner for IFN-free DAA regimens for the treatment of HCV and co-infections.     

Selective publication of antidepressant trials and its influence on apparent efficacy: Updated comparisons and meta-analyses of newer versus older trials

BackgroundValid assessment of drug efficacy and safety requires an evidence base free of reporting bias. Using trial reports in Food and Drug Administration (FDA) drug approval packages as a gold standard, we previously found that the published literature inflated the apparent efficacy of antidepressant drugs. The objective of the current study was to determine whether this has improved with recently approved drugs.Methods and findingsUsing medical and statistical reviews in FDA drug approval packages, we identified 30 Phase II/III double-blind placebo-controlled acute monotherapy trials, involving 13,747 patients, of desvenlafaxine, vilazodone, levomilnacipran, and vortioxetine; we then identified corresponding published reports. We compared the data from this newer cohort of antidepressants (approved February 2008 to September 2013) with the previously published dataset on 74 trials of 12 older antidepressants (approved December 1987 to August 2002).Using logistic regression, we examined the effects of trial outcome and trial cohort (newer versus older) on transparent reporting (whether published and FDA conclusions agreed). Among newer antidepressants, transparent publication occurred more with positive (15/15 = 100%) than negative (7/15 = 47%) trials (OR 35.1, CI_95% 1.8 to 693). Controlling for trial outcome, transparent publication occurred more with newer than older trials (OR 6.6, CI_95% 1.6 to 26.4). Within negative trials, transparent reporting increased from 11% to 47%.We also conducted and contrasted FDA- and journal-based meta-analyses. For newer antidepressants, FDA-based effect size (ES_FDA) was 0.24 (CI_95% 0.18 to 0.30), while journal-based effect size (ES_Journals) was 0.29 (CI_95% 0.23 to 0.36). Thus, effect size inflation, presumably due to reporting bias, was 0.05, less than for older antidepressants (0.10).Limitations of this study include a small number of trials and drugs—belonging to a single class—and a focus on efficacy (versus safety).ConclusionsReporting bias persists but appears to have diminished for newer, compared to older, antidepressants. Continued efforts are needed to further improve transparency in the scientific literature.     

RESULTS OF MEDICAL AND SURGICAL MANAGEMENT IN TEN CASES OF CONGENITAL MEGACOLON

Of 20 patients under 15 years of age with proven diagnoses of megacolon, ten were treated surgically with either partial colectomy or resection of the entire colon down to the rectosigmoid junction after thorough trial of medical management. Follow-up shows five of these patients as 100 per cent relieved, one as 75 per cent relieved. Three were entirely well a few months after operation but have not been heard from since. One died of peritonitis on the 16th postoperative day.In four cases in which lumbar sympathectomy was done, the result was partial, temporary or no improvement.Of the patients not operated upon, several have been lost to follow-up, some are doing well on medical treatment, one died in early infancy, and resection is being considered for two.For children with congenital megacolon the authors recommend first a thorough trial of medical treatment consisting of diet, vitamins, drugs and enemas. This should be started as soon as possible after the diagnosis is made, in an attempt to prevent the distention and hypertrophy of the bowel from progressing. If distention remains after a reasonable trial period and the child is not gaining weight adequately, requires repeated hospitalization, and is three years of age or more, then resection of the affected portion of the colon is indicated. The risk of operation has been somewhat reduced with better supportive measures and chemotherapy now available. Since infants and extremely young children do not stand operation on the colon as well as older children, decision to operate should take into consideration the age of the patient. In the reported series, the patient who died following operation was the youngest—2½ years of age.     

Clinical Evaluation of Verapamil in Angina Pectoris

A controlled double-blind study of verapamil in 16 anginal patients used two dose levels—40 mg. t.d.s. and 120 mg. t.d.s.—and was compared with propranolol 100 mg. t.d.s. At the higher dosage verapamil produced a significant improvement in frequency of angina, trinitrin consumption, and exercise tolerance, and had a favourable and significant effect on the amount and duration of ischaemic S–T depression occurring in the electrocardiogram during exercise. In the lower dose verapamil produced significant subjective improvement but no objective benefit in the electrocardiogram. No significant differences were found between the favourable results with the higher dosage of verapamil and propranolol.The action of verapamil is not fully understood, but its favourable effects in angina may be due to a direct action on the myocardium, possibly with accompanying coronary vasodilatation.     

Chromosome pairing in maize

This report summarizes our observations at pachytene on opposite-arms intercrosses between stocks of interchanges that involve chromosomes 1 and 5 in maize.—Pairing does not begin at the centromeres in these intercrosses.—We propose a model which assumes different probability values along each chromosome arm for the initial or primary site of pairing. Observations on the frequencies of the different types of configurations at pachytene were used to estimate probability values which satisfactorily fit the data.—There is a relatively low probability (of the order of.1 to.3) for the initial pairing to be in a short terminal segment (about.1 of the arm length). Initial pairing in the one or two short segments adjacent to the tip segment is much higher. Initial pairing is much lower in segments successively closer to the middles of the chromosome arms, and then zero or nearly zero in the proximal half of the arm. This means that the initial pairing may fail occasionally even in a relatively long interchanged segment and produce a T-shaped (3-armed) configuration.—After the initial pairing has occurred, the average probability that a secondary site of pairing is adjacent to the centromere in a segment.3 to.4 the length of an arm is low (.13, ranging from.02 to.29).—We can predict that in an intercross in which both breakpoints in both parental interchanges are far out on the chromosomes, "pairs" will be formed with nonhomologous ends (homologous differential segments paired). In these pairing could have begun at any point in the interstitial segments, but not likely in segments close to the centromeres.—Multiple secondary sites which vary in time or in order of pairing will explain the variation in position of the cross-shaped pachytene configuration in interchange heterozygotes.—The observed configuration in any one cell is the result of a particular combination of pairing events at the various sites. This is a very different concept of pairing from previous interpretations which described it as a result of zipper-like action, and the variation in position of the pachytene cross-configuration as the result of "shifts" in position.—Our cytogenetic results and their interpretation are in close agreement with reports on chromosome ultrastructure and molecular events in the early stages of meiosis, i.e. the attachment of chromosome ends to the nuclear membrane, the manner in which synaptonemal complexes develop, and the regions of DNA whose replication is delayed until zygonema.