Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

Therapeutic effects of topical 0.03% Tacrolimus ointment in children with refractory vernal keratoconjunctivitis in Middle East

ObjectiveThe purpose of this paper is to review the efficacy and safety profile in children treated with topical 0.03% Tacrolimus ointment for vernal keratoconjunctivitis in Middle East and to propose a treatment posology. According to recent studies, a complex non-IgE dependent mechanism plays a relevant role in the pathogenesis of vernal keratoconjunctivitis. Numerous cells and mediators have been found in the serum, conjunctiva and tears of patients with Vernal keratoconjunctivitis.DesignThis case series included 10 patients from a single centre, pediatric department of a tertiary hospital with active symptomatic vernal keratoconjunctivitis. All the patients had proliferative lesions and corneal involvement despite conventional medications, including topical steroids. All other medications, systemic and topical: steroids, antihistamines and cyclosporine, were unsuccessful. Patients were treated with topical 0.03% Tacrolimus ointment twice daily for 8 weeks and then once a day for the next two month followed by thrice a week for two months. The changes in symptoms and signs after treatment were evaluated, also the development of possible complications was assessed.ResultsThe results showed a significant reduction in signs and symptoms after 4 weeks of the treatment. Clinical resolution of giant papillae and corneal lesions were seen within eight weeks and no additional drug was required during that period, except tear substitutes. Treatment was continued for period of two months and then slowly reduced.ConclusionThe use of 0.03% Tacrolimus ointment is safe and effective in children refractory to conventional treatment of vernal keratoconjunctivitis even in high temperature climate as Middle East. Due to the effectiveness of the treatment, the dosage used may be proposed for conventional use.     

针刺京骨穴联合推拿治疗背肌筋膜炎临床研究

目的探讨针刺京骨穴联合推拿治疗背肌筋膜炎的临床疗效。方法将2016年10月—2018年10月收治的背肌筋膜炎患者86例纳入研究,采用随机数字表法分组。对照组43例予以推拿治疗,观察组43例予以针刺京骨穴联合推拿治疗。比较2组患者的治疗总有效率、VAS评分及Oswestry功能障碍指数、痊愈所用时间。结果观察组治疗总有效率为95.3%,而对照组仅为81.4%,差异有统计学意义(P<0.05);2组治疗后VAS评分、Oswestry功能障碍指数均有下降,观察组上述指标低于对照组,差异有统计学意义(P<0.05);观察组痊愈所用时间短于对照组,差异有统计学意义(P<0.05)。结论针刺京骨穴联合推拿治疗背肌筋膜炎的临床疗效突出,可缓解背部疼痛、恢复功能活动,并缩短了愈合时间,提高了生活质量,值得一定的临床推广。     

L’expert judiciaire et l’irresponsabilité pénale. Débats et controverses au cours du temps et questions contemporaines

IntroductionSince the creation of the Société Médico-Psychologique, an accumulation of discussions at the national level has resulted in legislative changes, which concern people with mental disorders. Public opinion has now become a stakeholder, prompting us, as judicial experts, to address criminal irresponsibility. The authors wish to give an account of the evolution of the ideas and professional practices in alienism and forensic psychiatry regarding criminal liability, irresponsibility, and the evolution of legislative measures in this realm.MethodsTo do so, they rely on the use of their forensic psychiatric and medico-psychological expertise, which has been effective for many years and remains relevant today, as well as on their clinical and theoretical research activities. The methodology is based on the analysis of language and the critical approach of historical and clinical epistemology.Forensic IssuesThey are examined taking into account the cultural and scientific context from the middle of the 19th century to the beginning of the 21st century. Criminal responsibility and irresponsibility are ancient principles codified in Roman law by Marcus Aurelius and which evolved with the political, social and religious conjunctions of each epoch. Whether the reason given for the recognition of criminal irresponsibility is referred to as madness, degeneration, insanity, dementia, psychic abnormality or discernment, it has always been the subject of research by physicians, alienists, and then psychiatrists. The authors analyze the role of the dissemination of the debates from the creation of the Annales Médico-Psychologiques (in 1843) and of the Société Médico-Psychologique (in 1852), illustrating them with some famous cases in specialized literature. The importance of forensic discussions at the Société Médico-Psychologique animated the end of the nineteenth century and the first part of the twentieth century, contributing to the enrichment of psychiatric semiology and to the opening up of new research, notably methodological. This will lead to an evolution of the conceptions relative to what induces the criminal act and will no longer limit irresponsibility to a diagnosis of insanity or dementia ; the study of psychic functioning will be put forward with the notion of discernment and those of self-control of one's actions. If numerous theoretical debates within the profession have fueled “expert disputes” sometimes disqualifying the role of experts, they remained, however, in the medical and judicial field. Over the past decade, these issues have been broadened to include societal debates around issues related to dangerousness and recidivism. This has become a dominant theme in scientific gatherings, before the eruption into the criminal field, of the increasing role played by victims and victims’ associations. Law No. 92-683 of 22 July 1992 introduced into the Penal Code Article 122-1 (1994 Penal Code) replacing Article 64, by inserting the notions of alteration or abolition of discernment. This distinction has given rise to new difficulties and tensions in expert practice ; the law came into force in 1994. During the 2000s, a series of high-profile homicides involving people with serious mental disorders, sometimes carried out in a recidivist situation, hit the headlines in France. This resulted in a shift in public opinion that led to the law of 25 February 2008 on criminal irresponsibility. The law put an end to the judicial dismissal of cases on the grounds of criminal irresponsibility, by introducing other provisions in the form of security measures (judicial supervision and detention of security). This law creates new interferences between legal procedural issues and psychiatric practice ; it also emphasized the importance of the role of experts by creating new missions, including the expertise of dangerousness. The movement linked to the consideration of the place of victims has been accentuated, both by the objective of obtaining a judgment for the perpetrator of the acts, and by the solicitation of their participation in the successive phases of the procedure. We have recently moved on to questions and controversies about the lack of accountability leading to the law of 24 January 2022. The current article 122 did not specify the origin of the psychic disorder causing the abrogation of discernment, which was interpreted by the Minister of Justice as “a legal void”, which must be “filled with urgency”. Title I states: “Provisions limiting criminal irresponsibility in cases of mental disorder resulting from self-induced psychoactive substances”. All these new provisions, as well as the creation of new incriminations and qualifications, certainly engender debates between magistrates and experts, but they are above all part of a concern of the public authorities about the necessity of setting up “provisions limiting criminal liability in the case of mental disorder”. The interpretation of the contribution of the law to a criminal act remains complex, according to the authors, in terms of psychopathological and etiopathogenic research. Within the context of expert practice, this new law will make it necessary to add new questions for the current missions, and it can only result in an increase in the complexity of these missions and in a risk of confusion in the answers.ConclusionThe authors show that the question of criminal liability does not solicit the same questions and problems in the judicial field (the point of view of the forensic psychiatrist, during the expert examination) or in the societal field with the confrontation with all the representations that are attached both to madness and to the passage to the criminal act, which since the beginning of the twentieth century involves other emerging disciplines. From their point of view, the assertion that a psychic disorder can be of such severity so as to affect the free will and discernment of the perpetrator of a criminal act at the time of the offence, must remain within the domain of psychiatry, even if the new law of 24 January 2022, through several of its provisions, would attempt to eliminate this necessity.     

Delayed expression of NADPH-diaphorase in rat brain after administration of the cholinotoxin AF64A

Administration of cholinotoxin etylcholine aziridinium (AF64A) into the brain selectively induces nonrever-sible cholinergic deficit. Wistar rats were injected intracerebroventricularly bilaterally with AF64A at doses of 1–3 nmol/ventricle. 28 days later the number of neurons survived was counted in dorsolateral, intermediate and medial groups of cells of the medial septum. AF64A induced a decrease in neuronal density and expression of cholineacetyl transferase at all doses used as well as in all regions studied. Brain sections were also stained for NADPH-diaphorase representing neuronal NO-synthase. Effects of AF64A on NADPH-diaphorase expression depended on the region studied. The number of NADPH-diaphorase-positive cells increased in the medial cellular group where more cholineacetly transferase-positive cells survived. In contrast, decrease in NADPH-diaphorase expression in the dorsolateral group of cells coincided with low level of cholineacetyltransferase-po-sitive neurons. The data presented suggest that in the AF64A-dependent model of neurodegeneration NO may play a neuroprotective function.     

Chronic lithium treatment increases the phosphorylation of a 64-kDa protein in rat brains

Despite the wide clinical use of lithium in the treatment of manic depressive illness there is no adequate explanation for its mechanism of action. In the light of lithium's suggestive effects on the second messenger system in the brain, we studied the effects of chronic dietary lithium treatment (achieving blood levels in the therapeutic range) on protein phosphorylation in different areas of rat brain. An increase in the phosphorylation of a 64-kDa membrane-associated protein was evident in the lithium-treated rats compared to controls. This increase was observed only under basal phosphorylating conditions and was abolished when the phosphorylation was performed in the presence of Ca²⁺ or Ca²⁺ and calmodulin. The possibility that this 64-kDa protein affected by lithium is the beta-subunit of the calmodulin-dependent protein kinase or a different protein which co-migrates with it is discussed.     

Interaction of sensory and cognitive processes during visual recognition: The role of the associative areas of the cerebral cortex

The first part of the present study used a model of Alzheimers disease in two groups of animals (three monkeys in each), given injections of neurotoxins (monkeys of group I) and physiological saline (monkeys of group II). Before injections, all monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids and geometrical figures of different colors and with different spatial relationships between objects) and to perform spatial selection. The dynamics of impairments in the characteristics of working memory were identified using delayed differentiation tasks in monkeys of both groups before injections and every two months after injections. Quantitative measures of impairments were made using the entropy of visual recognition, which characterizes uncertainty in decision-taking. The development of Alzheimers disease in rhesus macaques was characterized by a deficit of working memory, resulting from lesions to the two component processes of memory. Impairments of the first of these in monkeys of group I were manifest as a significant increase in entropy, which is associated with correct decision-taking. The magnitude of the increase depended on the type of visual information. Impairments of the second component were characterized by increases in entropy associated with refusals to take decisions and were independent of the delay duration and the type of visual information. Monkeys given injections of physiological saline showed no significant changes in these characteristics. The features of working memory were also studied in the second part of the investigation, using four groups of Rhesus macaques: intact, those with bilateral extirpation of the sulcus principalis or field 7 or both: degradation again identified two components. Entropy associated with this was increased significantly for most of the stimuli tested on monkeys of all extirpation groups as compared with intact animals. Significant differences were found in these characteristics for a number of stimuli, which depended on the location of the structures removed. The characteristics of impairments of the components of working memory resulting in the development of Alzheimers disease showed that the cholinergic mechanisms responsible for sensory processing differ from those involved in decision-taking. The structural-functional organization of the interaction of sensory and cognitive processes controlled by the motivation and attention systems is discussed, as is the role of the associative areas of the cortex.Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 89, No. 10, pp. 1226–1239, October, 2003.     

Factors that affect genetic interaction during mixed infection with temperature-sensitive mutants of simian rotavirus SA11

A number of factors that affect genetic interaction during mixed infection with temperature-sensitive mutants of simian rotavirus SA11 have been examined. (1) Statistical analyses of recombination frequency (RF) indicated that (a) the variability noted in RF was not related to variations in experimental conditions and (b) a linear map of the mutations could not be drawn. (2) The wild phenotype of recombinant progeny was stable on passage. (3) Aggregates of progeny virus or heterozygous progeny virus particles did not contribute significantly to the observed RF. (4) RF increased in parallel with multiplicity of infection. (5) A maximal, or near maximal, RF was obtained at the earliest time significant recombinants could be detected. (6) Recombination was efficient at nonpermissive temperature. (7) Complementation did not occur or was inefficient. (8) Mutants from all recombination groups interfered with the growth of wild-type virus at both permissive and nonpermissive temperatures.     

Dimebon improves learning in animals with experimental Alzheimer's disease

Systemic administration of antihistamine drug dimebon improves active avoidance conditioning in rats with chronic partial deprivation of cerebral cholinergic functions caused by intracerebroventricular injections of AF64A. The effects of dimebon on learning are similar to those of tacrine used in the treatment of Alzheimer's disease. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 129, No. 6, pp 640–642, June, 2000