A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Do children with focal cerebellar lesions show deficits in shifting attention?

More recent findings suggest a possible role of the cerebellum in nonmotor functions. Disability of individuals with cerebellar damage in rapidly shifting attention is one frequently used example to support cerebellar involvement in mental skills. The original proposal was based on findings in five children with chronic surgical lesions of the cerebellum and a young adult with a degenerative disorder. The aim of the present study was to repeat Akshoomoff and Courchesne's initial findings in a larger group of children with focal cerebellar lesions. Ten children with cerebellar lesions and 10 age- and sex-matched controls were tested. Neocerebellar areas were affected in all children with cerebellar damage except one based on detailed analysis of MRI scans. Subjects had to perform a focus and a shift attention task. Two visual and two auditory stimuli were presented in a pseudorandom order. An ellipse and a high-pitched tone were presented less frequently than a circle and a low-pitched tone. Rare stimuli were presented at five different time intervals. In the focus tasks, subjects had to react to the same rare stimulus of one of the two modalities. In the shift task, subjects had to switch between the two rare stimuli. Motor deficits based on reaction times were small in cerebellar children compared with controls. The ability of target detection did not significantly differ in the children with cerebellar lesions compared with the control children in both the focus and the shift attention task. In particular, children with cerebellar damage showed no significant impairment in rapid (<2 s) shifts of attention. The present findings indicate that the cerebellum may be less critical in attention related processes than suggested previously.     

Increased circulating CSF-1 (M-CSF) in myeloproliferative disease: association with myeloid metaplasia and peripheral bone marrow extension

Myeloproliferative disease (MPD) is heterogeneous in phenotypic expression and may display features consistent with expansion and activation of the monocyte/macrophage population during its course. The role of colony-stimulating factor-1 (CSF-1) in the pathophysiology of MPD was investigated by measuring circulating CSF-1 levels and examining their relationship to disease phenotype. Serum CSF-1 concentrations, measured by radioimmunoassay, were elevated in all MPD phenotypes. CSF-1 levels differed significantly between groups of patients with essential thrombocythemia, polycythemia vera, and postpolycythemic or agnogenic myeloid metaplasia (in ascending order). CSF-1 serum levels were positively correlated with spleen size and the degree of peripheral bone marrow extension, determined by scintigraphy using a macrophage-seeking isotope. There was no correlation between CSF-1 concentration and circulating levels of erythrocytes, neutrophils or platelets, or the presence of bone marrow fibrosis. Elevated serum CSF-1 levels appear to be associated with an expanded monocyte/macrophage population in MPD. In view of the known cooperativity between CSF-1 and other growth factors in regulating hematopoiesis, the finding of increased serum CSF-1 concentrations and its association with myeloid metaplasia and bone marrow extension may indicate a pathophysiologic role for CSF-1 in determining the phenotypic expression of MPD.     

22例皮质醇增多症的临床研究

目的：探讨皮质醇增多症的临床表现和内分泌检查等辅助检查的意义.方法：从年龄、性别、病程及实验室检查等方面,观察22例不同原因所致皮质醇增多症患者不同的临床表现和测定实验室检查指标.结果：22例中诊断库欣病（增生型）14例[63.6％,其中13例（92.9％）得到MRI检查证实],肾上腺腺瘤6例[27.3％,均得到MRI检查证实（100％）],另有肾上腺结节样增生1例（4.5％）,异位ACTH综合征1例（4.5％）.临床表现：按出现的频率前4位依次为,库欣病：高血压（100％）、满月脸（92.9％）、向心性肥胖（85.7％）、多血质（85.7％）,肾上腺腺瘤：高血压（100％）、满月脸（100％）、向心性肥胖（100％）、多血质（83.3％）.实验室检查：小剂量地塞米松不能抑制：库欣病与肾上腺腺瘤均为100％.结论：根据高血压、满月脸、向心性肥胖,小剂量地塞米松抑制试验和MRI检查可诊断绝大多数皮质醇增多症.     

Patient‐reported convenience of once‐daily versus three‐times‐daily dosing during long‐term studies of pramipexole in early and advanced Parkinson’s disease

Background and purpose: In chronic diseases including Parkinson’s disease (PD), complex pharmacotherapy dosing schedules are reported to reduce adherence, perhaps leading to less‐effective symptom control and, in PD, more erratic stimulation of dopamine receptors. However, blinded clinical‐trial designs preclude direct comparisons of adherence to various schedules. Methods: In two double‐blind (DB) studies of early PD and one of advanced PD, subjects received three‐times‐daily (t.i.d.) pramipexole or placebo. In open‐label (OL) extensions, subjects took extended‐release, once‐daily (q.d.) pramipexole. At 24 or 32 OL weeks, q.d. versus t.i.d. dosing preference was surveyed by questionnaire. Results: Of 590 DB‐trial completers with early PD, 511 entered the OL extension. Of 374 survey respondents, 94.4% preferred q.d. dosing (72.2% of them found it ‘very much more convenient’ and 27.8%‘more convenient’), 2.7% preferred t.i.d., and 2.9% chose ‘no difference’. Of 465 DB‐trial completers with advanced PD, 391 entered its OL extension. Of 334 survey respondents, 88.9% preferred q.d. dosing (59.9% of them found it ‘very much more convenient’ and 40.1%‘more convenient’), 5.7% preferred t.i.d., and 5.4% chose ‘no difference’. Results excluding DB‐placebo recipients were highly similar. Conclusions: In this first direct comparison of patient preference for q.d. versus t.i.d. dopamine‐agonist dosing, patients with early or advanced PD had a strong preference for q.d. rather than t.i.d. pramipexole. The high proportion of advanced‐PD patients declaring this preference indicates that it does not depend on whether a patient is taking concomitant PD medications dosed more frequently than q.d.     

Cerebellar agenesis II: Motor and language functions

In a former study of a patient with cerebellar agenesis (HK) mild motor deficits, problems in delay eyeblink conditioning and mild to moderate deficits in IQ, planning behavior, visuospatial abilities, visual memory, and attention were found. The present study reports additional findings in the same patient. In the motor domain, impairments in fine motor manipulations, trace eyeblink conditioning and motor imagination in a functional magnetic resonance (fMRI) study were found. Based on fMRI findings; however, cortical areas involved in a tapping task did not significantly differ from a healthy control group. In the cognitive domain, deficits in speech comprehension as well as verbal learning and declarative memory were present. No significant affective symptoms were observed. Although problems in executive, visuospatial and language tasks are in agreement with the so-called cerebellar cognitive affective syndrome—other possibilities remain. Non-motor impairments in HK might also be a consequence of lacking motor abilities in development and motor deficits may interfere with the performance of parts of the cognitive tasks. In addition, lack of promotion and learning opportunities in childhood may contribute and mental retardation based on extracerebellar dysfunction cannot be excluded.     

Structural Brain Alterations Associated With Schizophrenia Preceded by Conduct Disorder: A Common and Distinct Subtype of Schizophrenia?

Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ–CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ–CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ–CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.Key words: conduct problems, antisocial behavior, violence, structural brain alterationsMany years ago, Lee Robins found that conduct disorder (CD) was a precursor of schizophrenia ¹ and later confirmed this finding. ^{2 , 3} Subsequent evidence concurs. For example, a prospective investigation that followed a birth cohort to age 26 determined that 40% of the cohort members who developed schizophreniform disorders had displayed CD prior to age 15. ⁴ The CD modules of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental (DSM) disorders (fourth edition, DSM-IV), SCID in short, were designed to diagnose CD prior to age 15 among adults. ⁵ Several studies have used this interview protocol, some supplementing self-reports with information from family members, school, social service, and justice files, to diagnose CD among adults with schizophrenia. Among men and women with schizophrenia in general psychiatric services, the prevalence of CD prior to age 15 ranged from 20% to 45%, ^{6 , 7} with higher rates in samples recruited from forensic hospitals and correctional facilities. ⁶ CD is a precursor of schizophrenia, and it is more common among people with schizophrenia than in the general population. ⁶ Among people with schizophrenia, CD prior to age 15 continues to be associated with antisocial and violent behavior through adult life after taking account of past and current substance misuse. ^6–12 Among people with schizophrenia, ^{10 , 13–17} as in the general population, ^18–20 those who present CD in childhood commit a disproportionate number of violent crimes. While some studies show that positive symptoms are associated with aggressive behavior even after taking account of CD, ²¹ those with CD are not distinguished from other patients with schizophrenia by profiles of positive and negative symptoms. ²² Prospective investigations show that adults with schizophrenia and prior CD (SZ+CD) displayed aggressive behavior, psychotic-like experiences as children, ²³ and poor academic achievement. ²⁴ Retrospective studies report that adults with SZ+CD, as compared to those with SZ–CD, obtained lower-than-average marks in elementary school, failed to graduate from secondary school, abused substances in adolescence, and experienced physical abuse. ^{6 , 24–27} Criminality and substance misuse are elevated among fathers and brothers of men with SZ+CD, whereas rates of mental illness are similar to that found among patients with SZ–CD. ^{6 , 27 , 28} Among the non–mentally ill men, a small group present CD from an early age, persistent antisocial and aggressive behavior through adulthood, and abnormalities in brain structure relative to healthy men. ^29–37 Results of structural magnetic resonance imaging studies (sMRI) measuring gray matter (GM) volumes are inconsistent regarding the type (larger or smaller) and regions of abnormality. ^{32 , 35–37} Among men with SZ+CD, however, there no studies. ^{38 , 39} A few studies of brain structure have been conducted among men with schizophrenia who display different ages of onset and patterns of aggressive behavior, including persistent aggressive behavior and poor response to antipsychotic medication, no previous aggressive behavior and 1 violent offence, no aggressive behavior prior to onset followed by persistent aggression, and finally the largest group comprising those who show conduct problems from childhood that persist across their life span. The extant literature is limited and difficult to aggregate, but it does suggest differences specific to each pattern of violent behavior. ^38–43 Two studies examined male offenders with schizophrenia: one compared those with and without comorbid antisocial personality disorder (ASPD), which requires, by definition, CD prior to age 15; ⁴⁴ and another compared those with and without high psychopathy scores. ⁴⁵ Both included small samples and reported fewer neuropsychological deficits among the antisocial participants in tests tapping the dorsolateral prefrontal and the orbital frontal cortex (OFC) functions. ³⁸ A recent meta-analysis reported that among persons with schizophrenia, those defined very broadly as antisocial, as compared to the nonantisocial, were characterized by lower intelligence quotients (IQs) and memory dysfunction, whereas compared to non–mentally ill antisocial participants, they exhibited deficits in IQ, attention, executive function, and memory. ⁴⁶ Among patients with schizophrenia, scores on the Life History of Aggression (LHA) measure were associated with increased diffusivity in the inferior frontal white matter and lower functional connectivity between the amygdala and the ventral prefrontal cortex. ³⁹ Diffusivity has been associated with increased cerebrospinal fluid (CSF). ⁴⁷ Functional MRI (fMRI) studies of violent offenders with schizophrenia observed decreased frontal basal activation during a Go/NoGo task, increased activity in the motor, premotor, and anterior cingulate regions among those with ASPD, ⁴⁸ and attenuated amygdala activation to fearful faces among those with high psychopathy scores. ⁴⁹ Thus, among men with schizophrenia, at least one in five people presents CD prior to age 15 and persistent antisocial and aggressive behavior. Identifying distinctive subtypes of schizophrenia may facilitate etiological research ⁵⁰ and inform the development of effective treatments for both the illness and the antisocial and aggressive behavior. ⁵¹ Both schizophrenia ⁵² and CD ^{53 , 54} are neurodevelopmental disorders. In both disorders, from conception onwards, combinations of genes, in addition and in interaction with environmental events, are thought to modify brain structure and function. Thus, we reasoned that when schizophrenia develops in parallel with CD, neurodevelopment would be distinct from both that associated with schizophrenia and that associated with CD. We hypothesized that in adulthood, men with SZ+CD would show cognitive and structural brain abnormalities relative to healthy men, and both similarities and differences relative to men with SZ–CD and those with CD and no mental illness.Almost all persons with childhood onset of CD and persistence of antisocial and aggressive behavior in adulthood also display childhood onset and persistent pattern of substance misuse. ^55–57 This is true among those with and without schizophrenia. ^{22 , 26–28} Although substance misuse is an integral part of a heritable pattern of lifelong antisocial behavior, ⁵⁸ disentangling the cognitive and structural abnormalities consequent to substance use from those associated with persistent antisocial and aggressive behavior is necessary to understand the mechanisms underlying these behaviors. However, neither statistical controls nor studying groups of antisocial persons without substance misuse provide an ideal solution to this problem. ⁵⁹ Further, prospective studies indicate that heavy cannabis use in adolescence may play a causal role in schizophrenia ^{60 , 61} by altering brain development, ^{62 , 63} and 1 study has shown that among persons experiencing a first episode of psychosis, CD increased the likelihood of cannabis use before age 14. ⁶⁴ In addition, histories of substance misuse that can be obtained from middle-aged adults are imprecise measures of different phenomena—past and current use by type, combinations, and doses of substances. This led us to obtain careful histories of use of substances and to statistically control for group differences in use.Four groups of men, with SZ+CD, SZ–CD, CD, and no schizophrenia or history of CD (H), were compared on sociodemographic, clinical, and forensic characteristics, and their GM brain volumes were assessed using sMRI.     

Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Experimental human endotoxemia enhances brain activity during social cognition

Acute peripheral inflammation with corresponding increases in peripheral cytokines affects neuropsychological functions and induces depression-like symptoms. However, possible effects of increased immune responses on social cognition remain unknown. Therefore, this study investigated the effects of experimentally induced acute inflammation on performance and neural responses during a social cognition task assessing Theory of Mind (ToM) ability. In this double-blind randomized crossover functional magnetic resonance imaging study, 18 healthy right-handed male volunteers received an injection of bacterial lipopolysaccharide (LPS; 0.4 ng/kg) or saline, respectively. Plasma levels of pro- and anti-inflammatory cytokines as well as mood ratings were analyzed together with brain activation during a validated ToM task (i.e. Reading the Mind in the Eyes Test). LPS administration induced pronounced transient increases in pro- (IL-6, TNF-α) and anti-inflammatory (IL-10, IL-1ra) cytokines as well as decreases in mood. Social cognition performance was not affected by acute inflammation. However, altered neural activity was observed during the ToM task after LPS administration, reflected by increased responses in the fusiform gyrus, temporo-parietal junction, superior temporal gyrus and precuneus. The increased task-related neural responses in the LPS condition may reflect a compensatory strategy or a greater social cognitive processing as a function of sickness.