Hopelessness and Depression Predict Sarcopenia in Advanced CKD and Dialysis: A Multicenter Cohort Study.

BACKGROUND/OBJECTIVES: Depression and hopelessness are frequently experienced in chronic kidney disease (CKD) and are generally associated with lessened physical activity. The aim of this study was to quantify the associations between sarcopenia as determined by SARC-F with both depression and hopelessness. DESIGN AND SETTING: This multicenter cohort study involving cross-sectional and longitudinal analyses was conducted in a university hospital and four general hospitals, each with a nephrology center, in Japan. PARTICIPANTS: Participants consisted of 314 CKD patients (mean age 67.6), some of whom were receiving dialysis (228, 73%). MEASUREMENTS: The main exposures were depression, measured using the Center for Epidemiologic Studies Depression (CES-D) questionnaire, and hopelessness, measured using a recently developed 18-item health-related hope scale (HR-Hope). The outcomes were sarcopenia at baseline and one year after, measured using the SARC-F questionnaire. Logistic regression models were applied. RESULTS: The cross-sectional and longitudinal analyses included 314 and 180 patients, respectively. Eighty-nine (28.3%) patients experienced sarcopenia at baseline, and 44 (24.4%) had sarcopenia at the one-year follow-up. More hopelessness (per 10-point lower, adjusted odds ratio [AOR]: 1.33, 95% confidence interval [95% CI] 1.12-1.58), depression (AOR: 1.87, 95% CI 1.003-3.49), age (per 10-year higher, AOR: 1.70, 95% CI 1.29-2.25), being female (AOR: 2.67, 95% CI 1.43-4.98), and undergoing hemodialysis (AOR, 2.92; 95% CI, 1.41-6.05) were associated with a higher likelihood of having baseline sarcopenia. More hopelessness (per 10-point lower, AOR: 1.69, 95% CI 1.14-2.51) and depression (AOR: 4.64, 95% CI: 1.33-16.2) were associated with a higher likelihood of having sarcopenia after one year. CONCLUSIONS: Among patients with different stages of CKD, both hopelessness and depression predicted sarcopenia. Provision of antidepressant therapies or goal-oriented educational programs to alleviate depression or hopelessness can be useful options to prevent sarcopenia.

Magnetic resonance spectroscopy and tissue protein concentrations together suggest lower glutamate signaling in dentate gyrus in schizophrenia.

Hippocampal dysfunction in schizophrenia is widely acknowledged, yet the mechanism of such dysfunction remains debated. In this study we investigate the excitatory and inhibitory hippocampal neurotransmission using two complementary methodologies, proton magnetic resonance spectroscopy (MRS) and tissue biochemistry, sampling individuals with schizophrenia in vivo and postmortem hippocampal tissue in vitro. The results show significantly lower glutamate concentrations in hippocampus in schizophrenia, an in vivo finding mirrored by lower GluN1 protein levels selectively in the dentate gyrus (DG) in vitro. In a mouse model with a DG knockout of the GRIN1 gene, we further confirmed that a selective decrease in DG GluN1 is sufficient to decrease the glutamate concentrations in the whole hippocampus. Gamma-aminobutyric acid (GABA) concentrations and GAD67 protein were not significantly different in hippocampus in schizophrenia. Similarly, GABA concentrations in the hippocampi of mice with a DG knockout of the GRIN1 gene were not significantly different from wild type. These findings provide strong evidence implicating the excitatory system within hippocampus in the pathophysiology of schizophrenia, particularly indicating the DG as a site of pathology.

Kv3.1-containing K(+) channels are reduced in untreated schizophrenia and normalized with antipsychotic drugs.

Neuronal firing is a fundamental element of cerebral function; and, voltage-gated potassium (K(+)) channels regulate that firing through the repolarization of action potentials. Kv3-type channels (Kv3.1-Kv3.4) represent a family of voltage-gated K(+) channels that have fast-spiking properties. Kv3.1 channel subunits are predominantly localized to cortical parvalbumin (PV)-positive, inhibitory interneurons. The firing properties of these interneurons participate in establishing the normal gamma oscillations and synchrony of cortical neuronal populations, thought to be the signature of higher information processing in human brain. Schizophrenia (SZ) is associated with abnormalities in cortical gamma synchrony and in information processing, particularly with dysfunction in working memory and executive function. Here, we report the distribution of Kv3.1b and Kv3.2 protein in normal human brain, showing that Kv3.1b is limited to neocortical areas, whereas Kv3.2 is abundantly represented in neo- and subcortical regions. In SZ cases, levels of Kv3.1b protein are decreased in the neocortex, but only in cases without antipsychotic drug (APD) treatment; Kv3.1 levels are normal in antipsychotic-treated cases. Kv3.2 is not different in distribution or in level between normal and SZ cases, nor influenced by APD, in any region tested. The apparent increase in Kv3.1b protein levels by APDs in SZ neocortex was confirmed in laboratory rodents treated with chronic APDs. These findings show a decrease in Kv3.1b channel protein in SZ neocortex, a deficit that is restored by APDs. This alteration could be fundamentally involved in the cortical manifestations of SZ and in the therapeutic response to APDs.

Association between a functional polymorphism in the renin-angiotensin system and completed suicide.

Suicide has been suggested to involve disturbances in the stress response system and to be related to genetics. The renin-angiotensin system (RAS) has been shown to affect the stress response, and several functional polymorphisms in RAS-related genes have been predicted to alter protein function. We hypothesized that the dysregulation of RAS was involved in suicide, and examined the association between completed suicides and four functional polymorphisms of RAS-related genes: the angiotensinogen M235T, angiotensin-converting enzyme (ACE) insertion(I)/deletion(D), angiotensin type-1 receptor A1166C, and G-protein-beta3 C825T gene polymorphisms. The I allele of the ACE I/D polymorphism was found to be more frequent in completed suicides than in controls (P = 0.014). The I allele was also found to be more frequent in male completed suicides (P = 0.022) than in male controls, while this was not the case in females. These results suggest that the alteration of RAS function caused by the genetic polymorphism is involved in the susceptibility to suicide in males.

Cytidinediphosphocholine (CDP-choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: CDP-choline (cytidine 5'-diphosphocholine) is a precursor essential for the synthesis of phosphatidylcholine, one of the cell membrane components that is degraded during cerebral ischaemia to free fatty acids and free radicals. Animal studies suggest that CDP-choline may protect cell membranes by accelerating resynthesis of phospholipids. CDP-choline may also attenuate the progression of ischaemic cell damage by suppressing the release of free fatty acids. CDP-choline is the endogenous compound normally produced by the organism. When the same substance is introduced as a drug it can be called citicoline.CDP-choline is mainly used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to whom the treatments were given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. Due to its effects on the adrenergic and dopaminergic activity of the CNS, CDP-choline has also been used as an adjuvant in the treatment of Parkinson's disease. OBJECTIVES: To assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 22 April 2004 using the terms CDP-choline, CDP, citicoline, cytidine diphosphate choline or diphosphocholine. The Register contains records from all major health-care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders were considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% Confidence Interval (CI)) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Fourteen studies were included in this review. Some of the included studies did not present numerical data suitable for analysis. Description of participants varied over the years and by type of disorders and severity, and ranged from aged individuals with subjective memory disorders to patients with Vascular Cognitive Impairment (mild to moderate), Vascular Dementia or Senile Dementia (mild to moderate). Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, four studies used periods extending over 2 and 3 months, one study observed continuous administration over 3 months and one study was prolonged, with 12 months of observation. The studies were heterogeneous in dose, modalities of administration, inclusion criteria for subjects, and outcome measures. Results were reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no evidence of a beneficial effect of CDP-choline on attention. There was evidence of benefit of CDP-choline on memory function and behaviour. The drug was well tolerated. AUTHORS' CONCLUSIONS: There was some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short to medium term. The evidence of benefit from global impression was stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially Vascular Mild Cognitive Impairment (VaMCI) or vascular dementia.

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: CDP-choline is used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have caused an evolution in dosage, method of administration, and selection criteria of patients to which the treatments was given. Modalities of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. OBJECTIVES: The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders in the elderly. SEARCH STRATEGY: The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 20 January 2004 using the terms CDP-choline, CDP, citicolone, cytidine diphosphate choline or diphosphocholine. This register contains records from all major health care databases and many ongoing trials databases and is updated regularly. SELECTION CRITERIA: All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to chronic cerebral disorders are considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 4 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies were heterogeneous in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of CDP-choline on attention. There are significant beneficial effects of CDP-choline on memory function and behaviour. The drug is well tolerated. REVIEWERS' CONCLUSIONS: There is some evidence that CDP Choline has a positive effect on memory and behaviour in at least the short/medium term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. Further research with CDP-choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially vascular dementia.

Mental stress-induced physiological changes in the human masseter muscle.

The effect of a long mental stress on the hemodynamics of masticatory muscles has not been investigated to date. We hypothesized some hemodynamic and electromyographic changes in jaw-closure muscles related to sympathetic nervous system activity. While healthy adult female volunteers performed a two-hour mental stress task, electromyographic activity of the temporal and masseteric muscles was recorded, and hemodynamic changes of the masseter muscle were measured non-invasively. Autonomic function was assessed by heart rate spectral analysis. Integrated electromyographic activity of the temporalis muscle, but not the masseter muscle, showed an increase that coincided with the increase in sympathetic nervous activity. In the masseter muscle, despite little change in integrated electromyographic activity, notable changes were found in hemodynamic parameters. These results suggest that hemodynamics of jaw muscles is susceptible to mental stress, implying a potential role in the etiology of jaw muscle dysfunction associated with mental stress.

Changes in masseteric hemodynamics time-related to mental stress.

Mental stress may cause a dissociation of sympathetic outflow to different regions. However, it remains unclear how the sympathetic outflow to jaw muscles is related to other sympathetic outflow under mental stress. The objective of this study was to clarify the temporal relationship between the finger sweat expulsion elicited by mental stress and the hemodynamic and electromyographic changes in the masseter muscle. Healthy adult female volunteers participated in this study. Masseteric hemodynamic changes were closely time-related to mental stress, showing a decrease in oxygen saturation of muscle blood around the onset of mental stress. In contrast, EMG activity of jaw-closing muscles was not time-related to mental stress. These results suggest that mental stress induces hemodynamic changes that are not associated with EMG activity in the masseter muscle of healthy adult females.

Auricular chondritis in young ear-tagged Crj:CD(SD)IGS rats.

Gross and histopathological features of auricular chondritis in young Crj:CD(SD)IGS rats were examined. Although the rats were identified with metallic ear tags on the right pinnae, auricular chondritis was also observed on the contralateral (left) ear in some animals. Histopathologically, the lesions were characterized by granulomatous inflammation with destruction of the normal cartilaginous plate, formation of new cartilaginous nodules and osseous metaplasia. Proliferative cell nuclear antigen (PCNA) positive cells were present predominantly in chondrocytes found in the centre of the newly-formed cartilaginous nodules. The results suggest that the newly-formed cartilaginous nodules were due to interstitial proliferation of chondrocytes.

Oxatomide for stable asthma in adults and children.

BACKGROUND: Oxatomide is a histamine H1-receptor antagonist. As an oral agent, oxatomide may be useful in managing asthma. Some guidelines recommend oxatomide for long-term prophylaxis of asthma in children. There is no clear evidence whether children or adults with asthma benefit from oxatomide. OBJECTIVES: To determine whether oxatomide alone, or in combination with other interventions, results in better disease control in people with asthma. SEARCH STRATEGY: The Collaborative Airway Group register and Collaborations trial register CENTRAL were searched using terms: oxatomide* OR Celtect OR Pinset OR KW-4354 OR Tincet. Reference lists of all relevant trials or review articles were checked. Enquiries were made of authors of included studies and relevant pharmaceutical companies. A search of 'Igaku Chuo Zasshi' and 'J-Medicine' were made using the following terms: oxatomide (also in Japanese) or Celtect (also in Japanese) or KW-4354. SELECTION CRITERIA: Studies were randomised, placebo-controlled trials and the interventions were oxatomide or matched placebo given alone or in combination with other asthma-medication for at least 4 weeks. DATA COLLECTION AND ANALYSIS: Four independent reviewers performed assessments of methodological quality and extracted relevant data. MAIN RESULTS: Six studies are included in this review. Three studies were mainly conducted in adults, two were conducted in older children (5-16 years) and one in infants (18-25 months). Trial duration was 4 to 52 weeks. Doses of oxatomide varied between studies, ranging from 1 mg/kg/day for infants to 180 mg/day for adults. Only data on adverse events was suitable for meta-analysis. Although PEF did not change significantly in any of the studies, the FVC and FEV1 improved significantly in two. There was no uniform change in symptom scores. There was no significant difference between oxatomide and placebo treatment in use of inhaled corticosteroid or bronchodilator. Two studies showed significant improvement with oxatomide as judged subjectively by physicians. Adverse events, analysed using data from 4 parallel and one cross over study, showed oxatomide to be associated with a significantly higher risk of any adverse event (OR: 2.97, 95%CI: 1.69 to 5.22) and drowsiness (OR: 5.22,95%CI: 2.53 to 10.74). REVIEWER'S CONCLUSIONS: There is no evidence to show that oxatomide has a significant effect on the control of stable asthma. Some studies reported significant benefits in subjective parameters. There was improvement in some lung function outcomes reported, but this were not consistent across measures or studies and may represent reporting bias. Adverse events, including drowsiness, were significantly greater with oxatomide than placebo.

Transfection of single-stranded hepatitis A virus RNA activates MHC class I pathway.

Although infection of single-stranded RNA viruses can enhance expression of major histocompatibility complex (MHC) class I genes, the mechanism underlying this process remains unclear. Recent studies have indicated that exposure of non-immune cells to double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) of viral origin can directly increase the expression of MHC class I and related molecules without immune cell interaction. In this report, we show that transfection of single-stranded hepatitis A virus RNA into cultured hepatocytes results in the induction of genes for MHC class I, LMP2 and transporter for antigen processing (TAP1), in addition to the generation of viral proteins. We suggest that this stimulatory effect is due to the double-stranded RNA formed during replication of single-stranded viral RNA, and involves both double-stranded, RNA-dependent protein kinase PKR and the secretion of IFNbeta.

Solitary fibroleiomyomatous hamartoma of the lung in a patient without a pre-existing smooth-muscle tumor.

A solitary well-demarcated tumor was found in the left lung of a 53-year-old man. It was located in the posterior region of the lower lobe just adjacent to, but apart from, the pleura. It was resected by video-associated thoracic surgery. Macroscopically, the tumor was a whitish solid nodule without hemorrhage or necrosis, and it was 1.5 cm in diameter. Histologically, the tumor consisted of a proliferation of fibromuscular tissue in interlacing fascicles in which many tubular or cleft-like epithelial inclusions were involved. The epithelial inclusions showed cystic changes with goblet cell metaplasia in part, but no atypical changes. Other mesenchymal components such as cartilaginous, myxomatous or adipose tissues were not seen. The patient had no history of neoplasm, including smooth-muscle tumor. Thus, we diagnosed this tumor as a "true" fibroleiomyomatous hamartoma, as distinct from so-called fibroleiomyomatous hamartoma or benign metastasizing leiomyoma, which are usually found in the lungs of women who have had hysterectomies, as multiple fibromuscular nodules. We report here this rare case and we review and discuss published reports of fibromuscular tumors of the lung.

Modified short-term guinea pig sensitization tests for detecting contact allergens as an alternative to the conventional test.

The conventional adjuvant and patch test (APT) method of guinea pig sensitization testing was modified in 2 ways, s-APT and s-APT(2), in order to shorten the test period. These short-term test methods consist of 72-h closed application of test material with intradermal injection of emulsified Freund's complete adjuvant (E-FCA) for 1st induction, 48-h closed application of test material with (s-APT) or without (s-APT(2)) intradermal injection of E-FCA on the 7th day for 2nd induction, and open application on the 14th day for challenge. They were compared with conventional APT by using 8 allergenic chemicals (formaldehyde, nickel sulfate, cobalt sulfate, ethyl-p-aminobenzoate (benzocaine), isoeugenol, 2-mercaptobenzothiazole, 2,4-dinitrochlorobenzene (DNCB) and 1-phenylazo-2-naphthol (Sudan I)). The short-term methods gave similar results to those of conventional APT in terms of mean response, sensitization rate and sensitization potency (challenge concentration that induces a mean response equal to 1.0). Thus, our short-term methods, which are capable of evaluating skin sensitization within 17 days, are sufficiently sensitive to detect potentially hazardous contact allergens.

N-Acetylglucosaminyltransferase V as a possible aid for the evaluation of tumor invasiveness in patients with hepatocellular carcinoma.

BACKGROUND: A close relationship has been shown to exist between the metastatic potential and beta1-6 branched oligosaccharides in human and rodent cells. N-acetylglucosaminyltransferase V (GnT-V) catalyzes this process. Although this phenomenon has been reported, little is known about the clinical usefulness of the determination of GnT-V in the evaluations of tumor invasiveness in hepatocellular carcinoma (HCC). In this study, we measured the GnT-V activity in serum of patients with HCC, together with its activity and gene expression in HCC tissues, and elucidated the clinical usefulness of the GnT-V level in evaluating tumor invasiveness. METHODS: Seventy-three serum samples from 38 patients with HCC, 11 with chronic hepatitis, eight with hepatic cirrhosis and 16 healthy controls were used. Twenty-one liver tissues were obtained by surgical resection from 17 patients with HCC, three with colorectal cancers and one with gallbladder cancer metastatic to the liver. The GnT-V activity was determined by using high performance liquid chromatography. The GnT-V mRNA was quantified by using competitive RT-PCR. RESULTS: There were statistically significant correlations between GnT-V activity in sera of HCC, and GnT-V activity and GnT-V mRNA expression in tumor tissue. The mean GnT-V activity in the sera of patients with HCC increased in accordance with the degree of tumor invasion. The HCC group with intrahepatic and extrahepatic metastases showed the highest serum GnT-V-value. CONCLUSIONS: The present study demonstrated that there was a close association between tumor invasiveness and GnT-V activity in sera, and that the measurement of GnT-V may improve prognostic estimates and therapeutic outcomes for patients with HCC.

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: CDP-choline has a widespread, but not exclusive use in the treatment of disorders of a cerebrovascular nature. The many years of its use have caused an evolution in dosage, method of administration, and selection of patients to which the treatment was given. Design of the clinical studies, including length of observation, severity of disease, and methodology of evaluation of the results have also varied. In spite of uncertainties about its efficacy, CDP-choline is frequently prescribed for cognitive impairment in several continental European countries, especially when the clinical picture is predominantly one of cerebrovascular disease. OBJECTIVES: The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders of older people. SEARCH STRATEGY: The CDCIG register of trials and other databases were searched in July 2000 for all relevant, non-animal randomized controlled trials using the terms CDP-choline/CDP, Citicoline, Cytidine Diphosphate choline and Diphosphocholine. The Psychlit (1974-1996), Psychiatry (1980-1996) and MEDLINE electronic databases have been searched independently by the reviewers. The reviewers have also contacted manufacturers of CDP-choline. SELECTION CRITERIA: All relevant, non-animal, unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for patients with cognitive impairment due to chronic cerebral disorders are considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 3 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies differed in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of CDP-choline on attention. There are modest, but statistically significant, beneficial effects of CDP-choline on memory function and behaviour. For the outcome of clinical global impression, the odds ratio for improvement in the subjects treated with CDP-choline as opposed to the subjects treated with placebo is 8.89 [5.19 to 15.22]. The drug is well tolerated. REVIEWER'S CONCLUSIONS: There is some evidence that CDP-choline has a positive effect on memory and behaviour in at least the short term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. There is evidence that the effect of treatment is more homogeneous for patients with cognitive impairment secondary to cerebrovascular disorder. Further studies with a more appropriate length of treatment are recommended owing to the chronic and irreversible nature of the disorders for which this treatment is indicated.

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the elderly.

BACKGROUND: The prevalent use of this compound in the treatment of disorders of a cerebrovascular nature does not mean that a homogeneous and consistent application of this therapy has been applied. Dosage, method of administration, and selection criteria of patients have varied. The modalities of the studies, including length of observation, severity of disturbance, and methodology of the evaluation of the results were also heterogeneous. In spite of uncertainties about its efficacy, CDP-choline is a frequently prescribed drug for cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease, hence the need for this review. OBJECTIVES: The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and behavioural deficits associated with chronic cerebral disorders of the elderly. SEARCH STRATEGY: The CDCIG register of trials was searched for all relevant, non-animal randomised controlled trials using the terms CDP-choline/CDP, Citicoline, Cytidine Diphosphate Choline and Diphosphocholine. The Psychlit (1974-1996), Psychiatry (1980-1996) and MEDLINE electronic databases have been searched independently by the reviewers. The reviewers have also contacted manufacturers of CDP-choline. SELECTION CRITERIA: All relevant, non-animal, unconfounded, double-blind, placebo-controlled, randomised trials of CDP-choline in cognitive impairment due to chronic cerebral disorders will be considered for inclusion in the review. DATA COLLECTION AND ANALYSIS: Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the studies included. MAIN RESULTS: Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 2 studies used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies were heterogeneous in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory testing, behavioural rating scales, global clinical impression and tolerability. There was no significant evidence of a beneficial effect of CDP-choline on attention. There were modest, but significant, beneficial effects of CDP-choline on memory function and behaviour. For the outcome of clinical global impression, the odds ratio for improvement in the subjects treated with CDP-Choline as opposed to the subjects treated with placebo was 8.89 [5.19, 15.22]. The drug was well tolerated. REVIEWER'S CONCLUSIONS: There is some evidence that CDP Choline has a positive effect on memory and behaviour in at least the short term. The evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. There is evidence that the effect of treatment is more homogeneous for patients with cognitive impairment secondary to cerebrovascular disorder. Other studies with a more appropriate length of treatment are recommended owing to the chronic and irreversible nature of the disorders for which this treatment is indicated.

Expression of thrombomodulin in squamous cell carcinoma of the lung: its relationship to lymph node metastasis and prognosis of the patients.

Thrombomodulin (TM) is a type of thrombin receptor that was identified originally on the endothelium and acts as a natural anticoagulant through converting thrombin from a procoagulant protease to an anticoagulant. We reported previously that TM was also expressed in the squamous epithelium mainly at the intercellular bridges. In this study, we examined TM expression in the primary lesions of 81 patients with squamous cell carcinomas (SCCs) of the lung and in the lymph node metastatic lesions of 39 patients using immunohistochemical methods. The carcinoma tissues expressed TM mainly at the cell-cell boundaries and also in the cytoplasm. When TM expression was compared between the primary and metastatic lesions in the 39 patients who had lymph node metastasis, 26 (67%) showed decreased TM expression, 13 (33%) showed no change, and none (0%) showed an increase in the metastatic lesions. Wilcoxon's signed-rank test indicated that tumor cells that were positive for TM expression were significantly rarer in the metastatic lesions than in the primary tumors (P < 0.0001). The present study also showed that the patients with TM-negative expression in the primary tumors showed significantly poorer survival than those with TM-positive expression, mainly due to distant metastases of poorly-differentiated SCCs with negative TM expression in the primary tumors. These results indicate that the reduction of TM expression seems to play an important role in the metastatic process of lung SCCs.