Multidimensional operando analysis of macroscopic structure evolution in lithium sulfur cells by X-ray radiography.

Lithium sulfur cells are the most promising candidate for the post lithium-ion battery era. Their major drawback is rapid capacity fading attributed to the complex electrochemical processes during charge and discharge which are not known precisely. Here we present for the first time a multidimensional operando measurement by combining X-ray radiography with impedance spectroscopy while galvanostatically charging and discharging a lithium sulfur cell. The formation of macroscopic sulfur crystals at the end of charge can be seen directly by X-ray radiography. These crystals can be assigned to stable α-sulfur (rhombic) and metastable ß-sulfur (monoclinic) by their characteristic crystal habit. These crystal structures with a length of more than 1 mm form and dissolve rapidly during cycling. Their appearance is accompanied by characteristic signals in impedance spectroscopy. Macroscopic crystals of Li2S cannot be observed in full agreement with earlier studies by operando X-ray diffraction. In addition, X-ray radiography reveals non-wetted areas on the carbon cathode. These regions grow during discharge and are reduced during charge. The area of these electrochemically inactive spots is inversely proportional to discharge capacity.

Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases.

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

Involvement of intracellular Ca2+ in the regulation of bovine leukemia virus expression.

The calcium ionophore A23187, which was used to increase the intracellular calcium concentration ([Ca2+]i), was analyzed for effects on bovine leukemia virus (BLV) expression in two BLV infected cell lines. To clarify the role of intracellular free calcium in this response, [Ca2+]i was measured during ionophore treatment with the fluorescent calcium indicator Fura-2. Elevation of intracellular calcium under these conditions caused an enhancement of BLV gp51 and p24 synthesis as well as an activation of the BLV long terminal repeat (LTR) in a dose-dependent manner. Furthermore, it was observed that elevated levels of intracellular calcium following A23187 stimulation lead to activation of NF-kappaB. Based on inhibitor studies, we hypothesize that the effect of A23187 on BLV expression appears to be mediated by PKC.

Synthesis and antitumour activity of a new series of nitrosoureido sugars.

New nitrosoureido derivatives of di- or tri-deoxy-sugars have been synthesized. Very potent antitumour activity against L1210 leukaemia was exhibited by the compounds derived from methyl 3-amino-3, 4-dideoxy-beta- and alpha- and 4-amino-2,4-dideoxy-beta- and alpha-D-arabino-hexopyranosides, 24, 26, 28 and 29, respectively. In further evaluation against B16 melanocarcinoma bearing mice, only compounds 24 and 26 displayed significant activity. Owing to its lower acute toxicity, methyl 3-[3-(2-chloroethyl)-3-nitrosoureido]-3, 4-dideoxy-beta-D-arabino-hexopyranoside 24 appeared as the best candidate for preclinical studies.

Increase of antigen production in BLV-infected cell lines via additional expression of tax.

The selection of animals infected with the bovine leukaemia virus (BLV) is performed by the immunological detection of antibodies against the virus, commonly using the antigen gp51. Furthermore, research is being carried out to develop protective vaccines against BLV that have gp51 as their main component. Taking both of these factors into account, it is clear that there will be an increasing requirement for the virus antigen gp51 for some time to come. The permanently BLV-infected foetal lamb kidney cell line FLK/BLV (and its sublines) has been proved to be the most useful culture for the mass production of the virus antigen. Stable cell lines producing higher quantities of BLV antigen have not been established, either by subcloning of the FLK/BLV or by infection of other permanent cells with BLV. Here, a report is made on efforts to increase the expression of gp51 in BLV-infected cells via the additional expression of homologous transactivating virus protein tax. Selectable tax expression vectors that integrate into the host cell genome were constructed using BL provirus DNA fragments. Highly productive FLK/BLV cells were transfected with these vectors. Following selection with G 418, gp51-producing cell lines were established and tested for their productivity for several months. Some tax-vector-containing cell lines have produced 1.5-2 times more gp51 than the highly productive parental control cell line FLK/BLV 44-1.

An effective computer-based tardive dyskinesia monitoring system.

To promote early recognition and treatment of neuroleptic-induced tardive dyskinesia we used our facility's pharmacy and appointment data bases to develop an automated reminder system that significantly improved physician monitoring of patients receiving antipsychotic drug therapy. The system prompts staff to perform regular examinations for abnormal involuntary movements and to review patients' consent to therapy with antipsychotic medication. The average prevalences in the 15 months after automated reminders began, in a population of over 800 patients, increased from 53% to 85% for an annually completed abnormal involuntary movement scale in medical records and from 38 to 74% for a statement of informed consent. Now, 45 months later, prevalences of both measures approaches 100%. The integrated design of the Department of Veterans Affairs computer system allowed linking pharmacy and appointment scheduling data and facilitated the project. The reminder system effectively promoted rapid, marked, and sustained change in physicians' documentation of antipsychotic drug therapy.

Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred.

We report the clinical and neuropathological features of chromosome 14-linked familial Alzheimer's disease (14qFAD) in affected members of the L family. Some clinical information on all 16 known affected individuals and detailed neuropathological findings in 6 family members were available for review. Common features of the phenotype of 14qFAD in the L family included onset of dementia before the age of 50, early progressive aphasia, early-appearing myoclonus and generalized seizures, paratonia, cortical atrophy, numerous and extensive senile plaques and neurofibrillary tangles, and prominent amyloid angiopathy. Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family. Comparisons also suggested several ostensible phenotypic variants in 14qFAD: (1) In two 14q-linked kindreds (SNW/FAD3, FAD1), affected individuals in some instances were noted to survive to age 70 or beyond and the mean age at onset (> 49 years) in these two kindreds was somewhat higher than in their five 14qFAD counterparts (< 48 years in each); (2) in the SNW/FAD3 kindred, seizures and myoclonus were absent in all 10 subjects examined; and (3) cerebellar amyloid plaques were variably present within and among several 14qFAD kindreds. Comparisons with phenotypic features recently detailed in three kindreds (TOR3, F19, ROM) with codon 717 amyloid precursor protein gene mutations (i.e., APP717 FAD) suggested several distinctions: Prominent progressive aphasia, myoclonus, seizures, and paratonia were all apparently less prevalent in APP717 FAD, with language function predominantly spared over the initial disease course. The extent of homogeneity and heterogeneity in the clinical and neuropathological phenotype of 14q-linked FAD and its possible meaningful distinctions from the phenotypes of APP717 FAD await further determination.

Severe withdrawal symptoms after discontinuation of alprazolam in eight patients with combat-induced posttraumatic stress disorder.

Eight patients with combat-induced chronic posttraumatic stress disorder (PTSD) receiving long-term alprazolam therapy for anxiety or depression (maximum dose of 2-9 mg/day for 1-5 years) had alprazolam therapy withdrawn. Most of the patients underwent gradual medication withdrawal. All patients had a prior history of alcohol abuse or benzodiazepine dependence. During withdrawal, all patients had severe reactions including anxiety, sleep disturbance, rage reactions, hyperalertness, increased nightmares, and intrusive thoughts; and 6 of the 8 patients had homicidal ideation. As a result of this report, the authors suggest that the potential for severe withdrawal reactions, even with gradual tapering, should be considered before prescribing alprazolam therapy for this group of patients.

Neuropathological findings in patients with clinical diagnoses of probable Alzheimer's disease.

To assess prospectively the accuracy of standard antemortem clinical diagnostic criteria for Alzheimer's disease, post-mortem examinations were performed on 25 patients who had met DSM-III criteria for primary degenerative dementia and National Institute of Neurological and Communicative Disorders and Stroke criteria for probable Alzheimer's disease. Seventeen patients (68%) met neuropathological criteria for Alzheimer's disease. Two presenile-onset patients had diffuse neocortical senile plaques of insufficient number for definite Alzheimer's disease. Six patients had non-Alzheimer's disease diagnoses. Five of these six had presenile-onset dementia. These results suggest caution in the antemortem diagnosis of Alzheimer's disease in presenile-onset dementia.

Myoclonus, seizures, and paratonia in Alzheimer disease.

Twenty-eight patients with the clinical diagnosis of probable Alzheimer disease (AD) were followed longitudinally until death. The presence of myoclonus, seizures, and paratonia was monitored as part of this process. At autopsy, 22 of the patients met pathologic criteria for AD and 6 had other degenerative neurologic diseases. Myoclonus was present in 55% of the AD patients and none of the non-AD patients. Seizures were present in 64% of the AD patients, and only 17% of the non-AD patients. Paratonia was found frequently in all patient groups. In most patients, symptoms developed late in the course of their illness. The incidence of myoclonus, seizures, and paratonia in our patients was higher than in most previous studies. The reasons for this finding are discussed.

Neuroendocrine responses to physostigmine in Alzheimer's disease.

To assess central nervous system cholinergic neuroendocrine regulation in Alzheimer's disease (AD), we measured plasma arginine vasopressin, beta-endorphin, and epinephrine responses to a cholinergic challenge elicited by intravenous administration of the acetylcholinesterase inhibitor physostigmine (0.0125 mg/kg) in male patients with AD (n = 12) and compared their responses with those of age-matched normal control subjects (n = 12). Physostigmine promptly increased plasma arginine vasopressin (tenfold), beta-endorphin (twofold to threefold) and epinephrine (threefold) levels in elderly control subjects. In contrast, patients with AD showed attenuated responses to physostigmine. When controls and patients with AD who experienced nausea (n = 2 and n = 6, respectively) were excluded, the arginine vasopressin, beta-endorphin, and epinephrine responses of patients with AD were significantly less than those of control subjects. These data suggest that the central nervous system cholinergic deterioration of AD results in decreased responsiveness of neuroendocrine systems that are regulated by central cholinergic mechanisms.

Pressor, norepinephrine, and pituitary responses to two TRH doses in Alzheimer's disease and normal older men.

Changes in blood pressure (BP), plasma norepinephrine (NE), serum prolactin (PRL), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) associated with infusions of two thyrotropin-releasing hormone (TRH) doses (0.1 mg, 0.5 mg) were examined in 10 men with early-onset Alzheimer's disease (AD) and nine normal matched controls. During the first 5 min after TRH infusion, significant increases from baseline in systolic BP (p less than 0.001), diastolic BP (p less than 0.001), and plasma NE (p less than 0.006) occurred in the study subjects. The magnitude of the BP and NE responses did not differ significantly as a function of TRH dose (p greater than 0.3). Diastolic pressor responses to TRH were substantially blunted in AD subjects relative to controls, after both the 0.1-mg (p less than 0.003) and 0.5-mg (p less than 0.02) doses. There were trends toward attenuated responses in the AD subjects for systolic BP (p less than 0.09) and plasma NE (p less than 0.07). Significant increments in serum PRL, LH, and FSH (all p less than 0.001) also occurred after TRH, but the magnitude of the hormone responses did not differ significantly between the AD and the normal subjects (p greater than 0.18). These results suggest the possibility that TRH-evoked activation of the sympathetic nervous system (SNS), as reflected by pressor and plasma NE responses, may be attenuated in men with early-onset AD.

TSH responses to two TRH doses in men with Alzheimer's disease.

TSH responses to two TRH doses (0.1 mg, 0.5 mg) were determined in 10 men with Alzheimer's disease (AD) and in nine healthy matched controls. Maximum change in TSH (delta TSH) and TSH responses over time, analyzed independently for each TRH dose, did not reveal any significant differences between the AD and the normal subjects. Blunted delta TSH responses were an uncommon finding in both groups. Analyses examining the influence of TRH dose on TSH responses revealed significant group differences. In normal subjects, delta TSH responses following the 0.5 mg TRH dose were significantly greater than delta TSH responses following the 0.1 mg TRH dose (p less than 0.01). However, in the AD group, the effects of TRH dose on delta TSH were largely attributable to the exaggerated and outlying TSH responses of one AD subject. For the remaining nine AD subjects, delta TSH responses following the 0.1 mg and 0.5 mg TRH doses were not significantly different (p greater than 0.1). In the analysis of TSH responses over time, the difference between the 0.1 mg and the 0.5 mg TRH-induced TSH responses was significantly smaller in the AD group at several timepoints after infusion compared to the normal subjects.

Laboratory evaluation for Cushing's syndrome in psychiatric patients with cortisol nonsuppression following the overnight dexamethasone suppression test.

Laboratory tests used for the differential diagnosis of Cushing's syndrome have infrequently been employed in investigations of psychiatric patients who demonstrate hypothalamic-pituitary-adrenal (HPA) overactivity, and these laboratory procedures have not previously been applied for the specific purpose of further evaluating the endocrine function of psychiatric patients with serum cortisol nonsuppression following the standard 1-mg overnight Dexamethasone Suppression Test (DST). Low-dose (4 mg/48 hr) and high-dose (16 mg/48 hr) DSTs were administered to 10 psychiatric patients who exhibited cortisol nonsuppression after the overnight DST. Patients all had normal suppression to both the low-dose and high-dose tests. HPA overactivity in these patients was thus not sufficient to meet laboratory criteria for the diagnosis of Cushing's syndrome. Study results suggest that psychiatric patients with abnormal cortisol suppression following the 1-mg overnight DST are likely to have normal responses when assessed by standard laboratory protocols used for the diagnosis of Cushing's syndrome.

Very low-dose neuroleptic treatment in two patients with agitation associated with Alzheimer's disease.

Two agitated patients with Alzheimer's disease who either failed to respond or worsened with conventional low-dose neuroleptic and other pharmacologic treatment are described. Both patients demonstrated sustained improvement with very low-dose neuroleptics, one with haloperidol 0.125 mg and the other with thioridazine 5 mg. Clinical, pharmacokinetic, and pharmacodynamic factors that may have accounted for this response are discussed.

Dementia and antipsychotic drugs.

Introduced in the 1950s, antipsychotic agents have been found to improve symptomatology and function in young and middle-aged psychotic schizophrenics. Three decades of research, however, have not made clear these agents' usefulness in demented elderly patients. A review of placebo-controlled studies suggests a definite but limited role for antipsychotic medication in behaviorally disturbed elderly dementia patients with agitated behavior. Studies also suggest that cognitive function needs careful monitoring when these drugs are prescribed to treat behavioral symptoms of dementia.

Antipsychotic drugs and the elderly.

Antipsychotic agents can be useful in the treatment of elderly patients who manifest psychotic signs and symptoms. Geropsychiatric disorders in which these drugs may be indicated include chronic schizophrenia persisting into late life, paraphrenia, dementia, and delirium. Unfortunately, antipsychotic drugs are more difficult to use in elderly patients than in younger psychotic patients. A clearly positive clinical response is less likely to occur in elderly patients, particularly in those who have an underlying dementia. In addition, the incidence of adverse effects in elderly patients is high. However, if these cautions are kept in mind, the clinician can select the appropriate antipsychotic based on a patient's particular medical status and, thus, reduce the patient's disability and enhance the patient's quality of life.

Pharmacologic treatment of agitation associated with dementia.

Pharmacotherapy of aggressive or agitated behaviors in the dementia patient has not been studied extensively, despite the prevalence of this problem. Neuroleptics have the most support for efficacy, with shorter acting benzodiazepines demonstrating benefit on occasion. However, studies done to date indicate that these drugs are effective only for a minority of patients and that side effects frequently make patients worse. Other medications, such as propranolol, carbamazepine, or lithium, may be helpful, but their efficacy in dementia patients has not been demonstrated in placebo-controlled studies. Until such studies are done, their use is most appropriate in special patient groups or in patients who have failed neuroleptic or benzodiazepine treatment. More studies are needed in elderly patients evaluating effectiveness of pharmacologic agents in specific types of dementia, particularly Alzheimer's disease. Most studies done to date have been of relatively short duration, usually two months or less. Because these medications often are given to dementia patients for prolonged periods, studies are needed to define the long-term clinical efficacy of these agents. In the clinical setting, these agents should be reduced periodically or discontinued to determine ongoing need. In addition, environmental, social, or behavioral methods of reducing agitated behaviors need to be explored as an adjunct to any medication trial.