Effect of olanzapine treatment on platelet glutamine synthetase-like protein and glutamate dehydrogenase immunoreactivity in schizophrenia.

According to contemporary views, the glutamatergic system is implicated in the pathogenesis of schizophrenia, and atypical neuroleptics exert their effects (at least partially) through the glutamatergic system. Immunoreactive glutamate-metabolising enzymes, such as glutamine synthetase-like protein (GSLP) and two glutamate dehydrogenase isoenzymes (GDH), have been discovered in human platelets. The amount of GSLP in the platelets of 40 chronic patients with schizophrenia was found to be significantly higher than in 33 controls (consistent with our previous finding of increased amounts of GSLP in the prefrontal cortex of chronic schizophrenia patients). Moreover, survival analysis of the group of patients treated with olanzapine for 28 weeks showed that the larger amount of GSLP measured in platelets before treatment, the shorter the treatment time needed to achieve a positive clinical response (defined a priori as > or = 20% reduction in PANSS total score from the initial level before the treatment). Hence, GSLP level may serve as a predictor of the treatment duration to achieve a positive outcome with olanzapine. Both GSLP and GDH were found significantly changed in the course of treatment; hence, treatment with olanzapine influences the amounts of glutamate-metabolising enzymes in the platelets of chronic schizophrenia patients.     

In vivo 23Na NMR studies of myotonic dystrophy

Myotonic dystrophy is an inherited multi-system disease. Its pathophysiology leading to muscle malfunction and damage is not well understood. ²³Na NMR spectroscopy was applied here for an in vivo comparative study of the calf muscles of 7 myotonic dystrophy patients at various stages of the disease and 11 healthy volunteers. Both the total sodium content, expressed as the ratio of the ²³Na and ¹H water signals, and the fast transverse relaxation time, T₂₁, determined from the triple quantum-filtered spectra, increased in correlation with the severity of the disease. The results demonstrate that ²³Na NMR enables the quantitation of myotonic dystrophy progression.     

Candidate genes associated with ageing and life expectancy in the Jerusalem longitudinal study

In an exploratory study, 11 common polymorphisms were examined for contributing to longevity including: apolipoprotein E (apoE), methylenetetrahydrofolate reductase (MTHFR), cathepsin D (CAD), superoxide dismutase 2 (SOD2), angiotensinogen (AGT) and insulin-like growth factor 2 (IGF2), Leiden factor 7, p53 oncogene, dopamine D4 receptor (DRD4) and the serotonin transporter (SERT). Genotype and allele frequencies of these genes were compared in 224 older (75 years) Jewish Jerusalem residents of Ashkenazi ethnicity to a group of 441 younger subjects (22 years). Nominally significant results provide suggestive evidence in the Ashkenazi group that apoE, MHTFR, SOD2, IGF2 ApaI, and factor VII are risk factors for a single outcome, survival to 75. Overall, the more genetically homogenous Ashkenazi ethnic group showed evidence for association in five genes examined suggesting that future studies in this population would gainfully focus on this ethnic group.     

Neurophysiological and psychological predictors of genetic risk for schizophrenia

Mathematical genetic analyses were performed on a sample of schizophrenic families (25 probands and 58 first-degree relatives). Heritability coefficients were estimated for EEG power spectrum parameters and their topography, and also for psychological test data on thought and speech process disorder, designed to assess altered selectivity in cognitive activity. Multiple regression equations for genetic counseling regarding the prognosis of mental illness were derived from the neurophysiological and psychological measures.     

Macrophages retain hematopoietic stem cells in the spleen via VCAM-1

Splenic myelopoiesis provides a steady flow of leukocytes to inflamed tissues, and leukocytosis correlates with cardiovascular mortality. Yet regulation of hematopoietic stem cell (HSC) activity in the spleen is incompletely understood. Here, we show that red pulp vascular cell adhesion molecule 1 (VCAM-1)⁺ macrophages are essential to extramedullary myelopoiesis because these macrophages use the adhesion molecule VCAM-1 to retain HSCs in the spleen. Nanoparticle-enabled in vivo RNAi silencing of the receptor for macrophage colony stimulation factor (M-CSFR) blocked splenic macrophage maturation, reduced splenic VCAM-1 expression and compromised splenic HSC retention. Both, depleting macrophages in CD169 iDTR mice or silencing VCAM-1 in macrophages released HSCs from the spleen. When we silenced either VCAM-1 or M-CSFR in mice with myocardial infarction or in ApoE^−/− mice with atherosclerosis, nanoparticle-enabled in vivo RNAi mitigated blood leukocytosis, limited inflammation in the ischemic heart, and reduced myeloid cell numbers in atherosclerotic plaques.Leukocytosis correlates closely with cardiovascular mortality. In the steady state, blood leukocytes derive exclusively from bone marrow hematopoietic stem cells (HSCs). Supporting cells (Sugiyama et al., 2006; Ding et al., 2012; Ding and Morrison, 2013), including macrophages (Winkler et al., 2010; Chow et al., 2011), maintain the bone marrow HSC niche and regulate hematopoietic stem and progenitor cell (HSPC) activity by supplying various cytokines and retention factors. Systemic inflammation can stimulate extramedullary hematopoiesis in adult mice and humans. Splenic myelopoiesis supplies inflammatory monocytes to atherosclerotic plaques (Robbins et al., 2012) and the ischemic myocardium (Leuschner et al., 2012). In ischemic heart disease, HSPCs emigrate from the bone marrow, seed the spleen, and amplify leukocyte production (Dutta et al., 2012). Splenic HSPCs localize in the red pulp near the sinusoids in parafollicular areas (Kiel et al., 2005). Likewise, after adoptive transfer of GFP⁺ HSPCs, GFP⁺ colonies populate the splenic red pulp of atherosclerotic ApoE^−/− mice (Robbins et al., 2012). During myocardial infarction (MI), proinflammatory monocytes derived from the spleen accelerate atherosclerotic progression (Dutta et al., 2012). Collectively, these data suggest that splenic myelopoiesis has promise as a therapeutic target; however, the components of the splenic hematopoietic niche are incompletely understood, especially compared with the well-studied bone marrow niche. Understanding HSC retention factors and their regulation in the spleen was the purpose of this study.Because the spleen harbors very few HSCs in the steady state, we investigated the splenic hematopoietic niche after injecting the Toll-like receptor ligand LPS to activate extramedullary hematopoiesis. In the bone marrow, macrophages are an integral part of the HSC niche (Winkler et al., 2010; Chow et al., 2011) and differentiation depends on the receptor for macrophage colony-stimulating factor (M-CSFR, CD115; Auffray et al., 2009). We thus hypothesized that splenic hematopoietic niche assembly also requires M-CSFR signaling. In line with knockout studies (Takahashi et al., 1994; Dai et al., 2002), in vivo knockdown of M-CSFR with nanoparticle-encapsulated siRNA reduced splenic macrophage numbers substantially. Interestingly, decreased macrophage numbers were associated with a reduction of splenic HSCs. Depleting macrophages with diphtheria toxin (DT) in CD169 iDTR mice reproduced the findings obtained with M-CSF–directed siRNA treatment, thereby indicating that macrophages have a key role in splenic HSC maintenance. To investigate how splenic macrophages retain HSCs, we measured changes in splenic expression of major bone marrow retention factors after M-CSFR silencing. Silencing M-CSFR selectively reduced splenic VCAM-1, and the adhesion molecule was primarily expressed by macrophages. Inhibiting macrophage expression of VCAM-1 with siRNA targeting this adhesion molecule reduced splenic HSPC numbers. Finally, we found that M-CSFR and macrophage-directed VCAM-1 silencing in mice with atherosclerosis mitigated blood leukocytosis and dampened inflammation in atherosclerotic plaques and the infarcted myocardium. These data reveal the importance of VCAM-1 expression by splenic macrophages for extramedullary hematopoiesis and illustrate the therapeutic potential of RNAi as an antiinflammatory that mutes emergency overproduction and provision of myeloid cells.     

Expansion of the spectrum of TUBB4A-related disorders: a new phenotype associated with a novel mutation in the TUBB4A gene

Mutations in the TUBB4A gene have been identified so far in two neurodegenerative disorders with extremely different clinical features and course: whispering dysphonia, also known as dystonia type 4 (DYT4), and hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC). We describe a patient with slowly progressive spastic paraparesis, segmental dystonia, intellectual disability, behavioral problems, and evidence of permanent, incomplete myelination associated with progressive cerebellar atrophy. Whole exome sequencing revealed a novel E410K de novo heterozygous mutation in the TUBB4A gene. The clinical and radiological picture of our patient is different from the classic phenotype; thus, it expands the phenotypic variation of TUBB4A-gene-related disorders.     

Bilateral polymicrogyria associated with dystonia: A new neurogenetic syndrome?

The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.     

Bone density in axial and appendicular skeleton in patients with lactose intolerance: influence of calcium intake and vitamin D status

BACKGROUND: Lactose intolerance (LI) is a common enzymatic insufficiency, manifesting by poor tolerance of dairy products, leading to low calcium intake and poor calcium absorption from dairy products. These changes might lead to an impairment of bone metabolism [1]. OBJECTIVES: To evaluate the impact of LI on quantitative bone parameters in axial and appendicular skeletal sites. To assess the impact of calcium intake from dairy and non-dairy nutritional sources, calcium regulating hormones and bone turnover on quantitative bone parameters in LI patients. METHODS: We evaluated calcium intake and bone status in sixty-six patients with LI, 49 women and 17 men, aged 20 to 78. Bone mass was assessed at the lumbar spine (LS), total hip (TH) and femoral neck (FN) by dual-energy x-ray absorptiometry (DEXA) and at the radius, tibia, phalanx by quantitative ultrasound. Serum calcium, albumin, inorganic phosphate, calcium regulating hormones and markers of bone turnover were evaluated. RESULTS: Total daily calcium intake was below the recommended by the American Dietetic Association [2] in all study participants (mean 692 mg/day +/- 162). Elevated level of urinary deoxypyridinoline crosslinks (DPD) was observed in 63 (96%) patients and was negatively correlated with total daily calcium intake (r = -0.998, p = 0.025) and with nondairy calcium intake (r = -0.34, p = 0.015). Parathyroid hormone (PTH) level in the upper third of normal range (45-65 ng/L) was observed in 11 (17%) patients. Parathyroid hormone (PTH) was inversely correlated with total calcium intake (r = -0.4, p = 0.001), dairy calcium intake (r = -0.83, p = 0.05), non-dairy calcium intake (r = -0.29, p = 0.043), 25OHD(3) serum level (r = -0.3, p = 0.007) and positively correlated with bone turnover markers (deoxypyridinoline crosslinks [DPD], r = 0.36, p = 0.01 and bone specific alkaline phosphatase [BSAP] r = 0.36, p = 0.01). Decrease in quantitative bone parameters compared to age-matched controls was observed in the axial and in the appendicular skeleton in men and in postmenopausal women: mean z-score for LS -0.87 +/- 0.22 and -1.32 +/- 0.65, p = 0.004 and 0.015, tibia -1.15 +/- 0.53 and -0.44 +/- 0.044, p < 0.001 and 0.27, phalanx -0.98 +/- 0.22 and -0.52 +/- 0.98, p < 0.001. We observed decrease in bone mass in patients with serum PTH in the upper tertile of normal range in the FN (z-score -0.57 +/- 0.6 versus -0.03 +/- 0.9, p = 0.025), TH (-0.51 +/- 0.96 versus 0.04 +/- 0.9, p = 0.05) and radius (-1.84 +/- 0.27 versus -0.07 +/- 1.61, p = 0.025, respectively). z-scores in FN and TH positively correlated with serum 25OHD(3) level (r = 0.31, 0.29; p = 0.014, 0.019). In postmenopausal women serum 25OHD(3) level correlated also with LS z-scores (r = 0.52, p = 0.004); FN and TH z-scores negatively correlated with DPD level (r = -0.51, p = 0.02 and r = -0.55, p = 0.04). CONCLUSION: LI state may lead to increased bone turnover and decreased bone mass especially in men and postmenopausal women. Impaired vitamin D status and low calcium intake may be deleterious to bone in this condition.