Pharmacology of N-desmethylclozapine

Currently available treatments for schizophrenia have limited efficacy and are generally poorly tolerated. However, among these antipsychotic agents, clozapine stands apart in having generally superior motoric tolerability and efficacy. One intriguing possibility, based on clinical correlations, receptor activity profiles and studies with animal models predictive of antipsychotic or cognitive action is that the activity of N-desmethylclozapine (NDMC), a major metabolite of clozapine, may, at least in part, underlie the unique efficacy of clozapine. In this review we compare the pharmacological properties of NDMC to those of clozapine and consider how they may contribute to the overall clinical properties of clozapine. We also consider whether NDMC, in its own right, might be a superior antipsychotic drug.     

Diagnosis of congenital cardiac defects between 11 and 14 weeks' gestation in high-risk patients.

OBJECTIVE: To examine the feasibility of diagnosing congenital cardiac defects between 11 and 14 weeks' gestation in a high-risk population. METHODS: Fetal echocardiography was first offered at 11 to 14 weeks' gestation to all patients at risk for congenital heart defects. Echocardiography performed at 11 to 14 weeks with normal results was repeated at 14 to 16 and 20 to 24 weeks. Final diagnoses of cardiac anomalies that had been observed at 11 to 14 weeks were established at 14 to 16 weeks or later Fetal echocardiography performed at 14 to 16 weeks with normal results was repeated at 20 to 24 weeks. Ascertainment of cardiac anomalies was obtained by postnatal echocardiography or pathologic examination of the fetal heart after termination of pregnancy. Most of the examinations were performed transvaginally until 16 weeks. The transabdominal approach was used at this stage only when patients refused the transvaginal examination or because of technical difficulties. Three hundred ninety-two fetal echocardiographic examinations were performed between 11 and 14 weeks' gestation; 438 examinations were performed between 14 and 16 weeks; and 777 examinations were performed between 20 and 24 weeks. The major indications for fetal echocardiography at 11 to 14 weeks were maternal diabetes and previous pregnancy with congenital heart defects. RESULTS: Six of 7 major fetal cardiac anomalies were detected. The only major cardiac anomaly that was not detected between 11 and 14 weeks was correctly diagnosed at 22 weeks. Only 1 of 5 minor fetal cardiac anomalies was detected between 11 and 14 weeks. Another 2 minor fetal cardiac anomalies were detected at 23 weeks. Four incorrect diagnoses of minor cardiac anomalies were excluded on repeated fetal echocardiography between 20 and 24 weeks. CONCLUSIONS: The initial attempt to diagnose congenital heart defects should be offered at 11 to 14 weeks' gestation.     

Elevated Concentrations of Neurofilament Light Chain in the Cerebrospinal Fluid of Bipolar Disorder Patients

Bipolar disorder (BD) is characterized by mood swings between manic and depressive states. The etiology and pathogenesis of BD is unclear, but many of the affected cognitive domains, as well as neuroanatomical abnormalities, resemble symptoms and signs of small vessel disease. In small vessel disease, cerebrospinal fluid (CSF) markers reflecting damages in different cell types and subcellular structures of the brain have been established. Hence, we hypothesized that CSF markers related to small vessel disease may also be applicable as biomarkers for BD. To investigate this hypothesis, we sampled CSF from 133 patients with BD and 86 healthy controls. The concentrations of neurofilament light chain (NF-L), myelin basic protein (MBP), S100B, and heart-type fatty acid binding protein (H-FABP) were measured in CSF and analyzed in relation to diagnosis, clinical characteristics, and ongoing medications. Hereby we found an elevation of the marker of subcortical axonal damage, NF-L, in bipolar subjects. We also identified positive associations between NF-L and treatment with atypical antipsychotics, MBP and lamotrigine, and H-FABP and lithium. These findings indicate axonal damage as an underlying neuropathological component of bipolar disorder, although the clinical value of elevated NF-L remains to be validated in follow-up studies. The associations between current medications and CSF brain injury markers might aid in the understanding of both therapeutic and adverse effects of these drugs.     

Inhibition of estrogen-induced anterior pituitary enlargement and arteriogenesis by bromocriptine in Fischer 344 rats

The interrelationship between dopamine (DA) regulation and changes in the blood supply of the anterior pituitary lobe (AP) in the etiology of estradiol (E2)-induced proliferation of pituitary cells was studied in Fischer 344 rats. Rats were implanted with E2-filled or empty Silastic capsules for 21 days alone or in conjunction with pellets of the potent DA agonist bromocriptine (CB-154). Changes in vascularization of the AP, median eminence DA content, and responsiveness to DA of cultured AP cells were measured. Development of a direct arterial blood supply was assessed by the injection of 15-microns microspheres that can only reach the AP by newly formed arteries (arteriogenesis). APs were enzymatically dispersed and cultured for 3 days before challenges with increasing concentrations of DA for 3 h. DA content was measured by radioenzymatic assay, and serum PRL was determined by RIA. E2 treatment increased the weight of the pituitary gland, serum PRL levels, and the number of microspheres in the AP 4.5-, 173-, and 142-fold, respectively, over control values. Median eminence DA content was decreased 71% by E2 treatment, while the ability of DA to suppress PRL secretion in vitro decreased from a maximum of 70% to 40% with no change in the ED50. Simultaneous treatment with CB-154 dramatically decreased the effect of E2 on arteriogenesis, pituitary weight, serum PRL levels, and median eminence DA content. Blockade of E2-induced AP enlargement by increased dopaminergic stimulation was closely correlated with inhibition of arteriogenesis, which further suggests an important role for vascular changes in lactotroph proliferation.     

A comparative study of hepatitis B viral markers in the family members of Asian and non-Asian patients with hepatitis B surface antigen-positive hepatocellular carcinoma and with chronic hepatitis B infection.

Serologic tests for evidence of hepatitis B virus (HBV) infection were performed on family members of Asian and non-Asian patients with either hepatitis B surface antigen (HBsAg)-positive hepatocellular carcinoma or chronic HBV infection. Asian family members had a significant increase of HBsAg (34% higher) and of antibody to HBsAg or of antibody to hepatitis B core antigen (50% higher) when they were compared with non-Asian family members. In the Asian group, viral markers were detected more frequently in blood relatives than in nonblood relatives of the index cases. Within this group, birthplace did not influence the frequency of antigenemia, since HBsAg was positive in 55 (44%) of 125 Asians born in Asia and in 36 (38%) of the 94 Asians who were born in the United States. Also, HBsAg positivity frequently was seen in offspring from HBsAg-positive carrier mothers as well as from HBsAg-positive carrier fathers whose spouses were either HBsAg-negative or who had antibody. The e antigen was found more often in individuals 30 years of age or younger than in older individuals. This study indicates that intrafamilial spread of HBsAg in Asian families plays an important role in the perpetuation of HBV infection and in the eventual development of chronic liver disease in this ethnic group.     

The absolute chronology of Boker Tachtit (Israel) and implications for the Middle to Upper Paleolithic transition in the Levant

The Initial Upper Paleolithic (IUP) is a crucial lithic assemblage type in the archaeology of southwest Asia because it marks a dramatic shift in hominin populations accompanied by technological changes in material culture. This phase is conventionally divided into two chronocultural phases based on the Boker Tachtit site, central Negev, Israel. While lithic technologies at Boker Tachtit are well defined, showing continuity from one phase to another, the absolute chronology is poorly resolved because the radiocarbon method used had a large uncertainty. Nevertheless, Boker Tachtit is considered to be the origin of the succeeding Early Upper Paleolithic Ahmarian tradition that dates in the Negev to ∼42,000 y ago (42 ka). Here, we provide ¹⁴C and optically stimulated luminescence dates obtained from a recent excavation of Boker Tachtit. The new dates show that the early phase at Boker Tachtit, the Emirian, dates to 50 through 49 ka, while the late phase dates to 47.3 ka and ends by 44.3 ka. These results show that the IUP started in the Levant during the final stages of the Late Middle Paleolithic some 50,000 y ago. The later IUP phase in the Negev chronologically overlaps with the Early Upper Paleolithic Ahmarian of the Mediterranean woodland region between 47 and 44 ka. We conclude that Boker Tachtit is the earliest manifestation of the IUP in Eurasia. The study shows that distinguishing the chronology of the IUP from the Late Middle Paleolithic, as well as from the Early Upper Paleolithic, is much more complex than previously thought.

The spread of modern humans from Africa into Eurasia is certainly one of the most important events in human history (1–3). The appearance of Homo sapiens at the transition between the Middle Paleolithic (MP) and the Upper Paleolithic (UP) periods corresponds with the demise of Neanderthals in Europe and west Asia (4). This demographic process, known in the literature as the “Recent African Origin” (5), has undergone refinements since it was first introduced (6). Today, this dispersal event is thought to be a multifaceted process that involved several events and genetic admixture between H. sapiens and Neanderthals (7–12).Recognizing demographic changes in the archaeological record is not always straightforward, mainly because of a lack of human fossils. Still, transformations in material culture are often conceived as a reliable indicator for demographic change (13, 14). In the Levant, as in Europe, such changes occurred during the transition from the MP to the UP, namely, the replacement of Levallois technology by blade technologies and the introduction of systematically produced tools on bone and antler (15–18). The nature and timing of the MP to UP transition has been investigated for almost a century (18–24). While the characteristics of the material culture changes are more or less defined, the absolute chronology and the origins of the transitional industries are under debate (25–30).One of the major reasons for this uncertainty is the fact that many of the key sites with supposedly “transitional” lithic industries in the south Levant, such as Emireh and el-Wad caves, were excavated in the beginning of the 20th century and their stratigraphies are challenging (24). An important exception is the site of Boker Tachtit in the Negev Highlands, Israel, that comprises a series of intact stratigraphic layers with refitted lithic assemblages, which are separated by sterile sediments (31, 32). Here, we report the results of an excavation at Boker Tachtit and in particular the chronology based on radiocarbon and optically stimulated luminescence (OSL) dates.Boker Tachtit is located in the Wadi Zin basin in the central Negev region, Israel (Fig. 1). The site was discovered and excavated by A. Marks in the framework of the Central Negev Project (31). The excavation revealed well-preserved archaeological horizons (Levels 1 through 4 from the bottom up) composed of flint artifacts, a few hammer stones, and charcoal pieces, including the presence of a hearth feature in Level 1. Comprehensive lithic studies enabled technological reconstructions of the lithic industries at the site as well as spatial aspects of these occupations (32–34). The refitting study demonstrated a technological continuity from the lowermost Level 1 to the uppermost Level 4 and indicated on-site flint knapping. This later point is additionally supported by a study of the microflints from Marks’ excavation section D (35). Marks conceived Boker Tachtit as an MP to UP transitional site bearing two consecutive cultural phases: the Emirian (Levels 1 through 3), which he associated with the MP, and the Initial UP (IUP) (Level 4), which was predominantly UP (28). Later studies by Kuhn that included sites in the north Levant redefined the IUP and incorporated the Emirian into this phase (16). In this paper, we follow Kuhn''s definition for the IUP.Open in a separate windowFig. 1.Location of Boker Tachtit and other sites mentioned in the text.The original chronology of Boker Tachtit was based on five radiocarbon dates using the ¹⁴C decay counting method (31). Four samples (GY-3642, SMU-184, SMU-580, and SMU-259) were from Level 1 and one sample (SMU-579) from Level 4. Two samples were of infinite ages (GY-3642, >33,000 BC; SMU-184, >43,620 BC), and one (SMU-579, 33,105 ± 4,100 BC) appeared to be an outlier. Another (SMU-580, 44,330 ± 9,050 BC) had an extremely wide uncertainty range of 9,000 y. The only supposedly reliable date (SMU-259, 44,980 ± 2,420 BC) was used to set the chronology of the site to ∼47 ka BP. The latter date was perceived by Marks and many others to reflect the age of the MP to UP transition in the Levant (1, 13). The few samples analyzed and the large uncertainties are related to the methodology used and probably also to the quality of the charred material analyzed.More recent MP to UP chronological studies based on radiocarbon dating of charred material and marine shells from new and old excavations at other sites have initiated a debate about the chronology of the transition, and the age of Boker Tachtit was suggested to be too old compared with northern Levantine sites (25, 27, 29, 30, 36). The problems lie in the disparities in the documented timing of the transition. While these differences may reflect a time lag in the transition between Boker Tachtit and the northern Levantine sites, problems with the quality of dated material or their context should not be overlooked (i.e., stratigraphic provenience and/or diagenesis) (e.g., refs. 25, 29, 30).     

Oxidative stress mediates impairment of muscle function in transgenic mice with elevated level of wild-type Cu/Zn superoxide dismutase

Cases of familial amyotrophic lateral sclerosis (fALS; a neurodegenerative disorder) have been reported in which the gene for Cu/Zn superoxide dismutase (CuZnSOD) was mutated. Several studies with the fALS mutant CuZnSOD in transgenic mice and cells showed that the fALS mutations act through an as yet undefined dominant gain-of-function mechanism. Wild-type CuZnSOD catalyzes the dismutation of superoxide (O₂) but also produces hydroxyl radicals (^•OH) with H₂O₂ as substrate. Two laboratories have recently demonstrated that the ^•OH production ability was preferentially enhanced by the fALS mutant CuZnSOD, suggesting that this might be the function gained in fALS. In this study, we used transgenic CuZnSOD (Tg-CuZnSOD) mice with elevated levels of CuZnSOD to determine whether overexpression of wild-type CuZnSOD was also associated with increased ^•OH production and impaired muscle function. Enhanced formation of ^•OH was detected, by spin trapping, in brain and muscle extracts of the Tg-CuZnSOD mice. Three independently derived Tg-CuZnSOD lines showed muscle abnormalities, reflected by altered electromyography (EMG) and diminished performance in the rope grip test. After treatment with paraquat (PQ), a widely used herbicide and O₂-generating compound, muscle disability significantly deteriorated in Tg-CuZnSOD mice but not in control mice. The results indicate that elevated levels of CuZnSOD cause indigenous long-term oxidative stress leading to impairment of muscle function. These findings may provide valuable clues about the concurred role of indigenous oxidative stress and exogenous agents in the etiology of sporadic ALS and several other neurodegenerative diseases in which a specific subset of neurons is affected.