Maternal pre-pregnancy obesity and child neurodevelopmental outcomes: a meta-analysis.

This review examined evidence of the association between maternal pre-pregnancy overweight/obesity status and child neurodevelopmental outcomes. PubMed and PsycINFO databases were systematically searched for empirical studies published before April 2017 using keywords related to prenatal obesity and children's neurodevelopment. Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta-analysis. Findings indicated that compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes (overweight: OR = 1.17, 95% CI [1.11, 1.24], I2  = 65.51; obese: OR = 1.51; 95% CI [1.35, 1.69], I2  = 79.63). Pre-pregnancy obesity increased the risk of attention deficit-hyperactivity disorder (OR = 1.62; 95% CI [1.23, 2.14], I2  = 70.15), autism spectrum disorder (OR = 1.36; 95% CI [1.08, 1.70], I2  = 60.52), developmental delay (OR = 1.58; 95% CI [1.39, 1.79], I2  = 75.77) and emotional/behavioural problems (OR = 1.42; 95% CI [1.26, 1.59], I2  = 87.74). Given the current obesity prevalence among young adults and women of childbearing age, this association between maternal obesity during pregnancy and atypical child neurodevelopment represents a potentially high public health burden.

Phosphorous metabolite and cell cycle kinetic response of two human squamous cell carcinomas to radiation.

Phosphorous metabolism and cell cycle phase kinetics in response to radiation of two perfused human squamous cell carcinoma cell lines, SQ20B (radioresistant) and SQ38 (relatively radiosensitive), embedded in both basement membrane (Matrigel) and agarose gel threads were studied. The findings for these human cancer cells in response to 2- and 50-Gy irradiation are as follows. (a) Well perfused pure cancer cells (both SQ20B and SQ38) in both proliferative (cells embedded in Matrigel) and static (cells embedded in agarose threads) states did not show significant alteration in either phosphorous bioenergetics or membrane metabolites at 24 and 48 h after irradiation, although a large fraction of the population was clonogenically impaired. Previously reported, sensitively detected, metabolite alterations in response to radiation in rodent and human tumors in situ were not seen in these homogeneous cancer cell populations. (b) The radiosensitive squamous cell carcinoma cell lines SQ38 exhibited G1 block (from 54.38 +/- 1.40% in control to 73.93 +/- 1.01% after irradiation; mean +/ SD) in response to low-dose 2-Gy irradiation and G2 block (from 12.98 +/- 2.15% in control to 25.6 +/- 3.15% after irradiation) in response to high-dose 50-Gy irradiation, while the radioresistant cell line SQ20B showed only conventional G2 block in response to both doses. The differential cell cycle phase response may indicate the difference in radioresistance. (c) The membrane metabolites (including phosphomonoesters and phosphodiesters) and phosphocreatine gradually increased from the early passages to late passages, suggesting that cell proliferation rates were increasing as the cells adapted to tissue culture. The results suggest that the radiation-induced metabolite changes observed in solid tumors in situ may not be a direct response to interim changes within the cancer cells but, rather, a consequence of radiation damage either to the vasculature or to other host-mediated factors.

Interleukin-2-induces development of denditric cells from cord blood CD34+ cells.

Dendritic cells (DC) have been shown to develop along a myeloid or lymphoid lineage of differentiation propagated from bone marrow or early thymic precursor cells with hematopoietic cytokines. In our study, we have induced growth and differentiation of DC from cord blood CD34+ cells initiated in interleukin-2 (IL-2) alone or in IL-2 + stem cell factor (SCF) + tumor necrosis factor alpha (TNF-alpha)-supplemented medium and cultured with IL-2 or IL-2 + SCF for 28-35 days. Dendritic morphology and antigenic phenotype of DC grown with IL-2 were characteristic for DC cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Growth and differentiation of DC was followed by an increase in expression of MHC II and co-stimulating molecules CD80 and CD86. We have also shown the expression of the IL-2 receptor (IL-2R) gamma-chain in CD34+ cells after 2-3 days of culture with IL-2 alone. The co-expression of the IL-2R alpha, beta, and gamma subunits in both DC cultured with IL-2- or GM-CSF-containing cocktail of cytokines was also shown. The time curve for induction of IL-2R demonstrated low levels of subunit expression at the beginning of culture. The number of CD1a cells co-expressing CD25, CD122, and CDgamma increased to about 24-68 and to 78-95% after 21 and 28-35 days, respectively. Development of natural killer cells was shown along with DC. The proportion of CD56+ cells and cytotoxicity increased in a time-dependent manner.

1H-MRS evidence of neurodegeneration and excess glutamate + glutamine in ALS medulla.

OBJECTIVE: To determine whether short echo-time (TE) proton magnetic resonance spectroscopic imaging (1H-MRSI) can detect in vivo differences in signal intensities of specific metabolites in the medulla of patients with ALS compared with healthy individuals and whether these metabolites could be useful surrogate markers of disease. BACKGROUND: 1H-MRSI can detect N-acetylaspartate + N-acetylaspartylglutamate (abbreviated NAx), which is localized to neurons, and glutamate (Glu) + glutamine (Gln), abbreviated Glx, which may be important in ALS pathogenesis. The medulla is an ideal region to study ALS because of its high density of nuclei and fiber tracts that frequently undergo degeneration, even when more rostral brain regions show minimal pathology. METHODS: Ten patients with ALS and seven healthy control subjects underwent short TE 1H-MRSI on a 1.5 T clinical imaging system. Signal intensities of NAx and Glx were normalized to creatine-phosphocreatine and compared between groups. RESULTS: Compared with normal subjects, the medulla of patients with ALS had 17% lower NAx (p = 0.03) and 55% higher Glx (p = 0.02) signals. Bulbar symptoms, represented by the ALS Functional Rating Scale, correlated with Glx (r = -0.68, p = 0.03) but not NAx (r = 0.22, p = 0.53). CONCLUSION: There is in vivo 1H-MRSI evidence of neuronal degeneration or loss and excess Glu + Gln in the medulla of patients with ALS. Although this cross-sectional study cannot identify which change occurred first, the higher Glx signal in the medulla of patients with more dysarthria and dysphagia is consistent with the hypothesis of Glu excitotoxicity in ALS pathogenesis. Longitudinal 1H-MRSI studies of the medulla (and other brain regions) in more patients with ALS are required to confirm these findings and to determine whether such metabolite changes will be useful in monitoring disease progression, in clinical diagnosis, and in understanding the pathogenesis of ALS.

Response of a non-Hodgkin lymphoma to 60Co therapy monitored by 31P MRS in situ.

High quality 31P MR spectra (signal to noise ratio (S/N) approximately 18, 15 min acquisition for each spectrum) were consistently obtained with surface coils over a period of 6-week RT. Both transient and steady state alterations in metabolites in response to RT were found in this case. The transient changes occurred during the first 3 hr immediately after the 3rd fractionated RT, these changes include the transient elevation of the PCr resonance, a decrease in PDE and an increase in intracellular pH. The monitoring showed that the metabolites approached steady state approximately 2 hr after the fractionated radiation intervention, suggesting that in vivo MRS can be useful for studying the dynamics of tumor response to RT such as repair of potential lethal damage, growth delay, and reoxygenation etc. The steady-state MR spectra showed the net response to each intervention and can clinically be useful for predicting and measuring the result of the fractionated RT. In this case study, the PDE peak which contains the phospholipid metabolites GPC and GPE, is the most sensitive resonance in response to RT. After the 3rd RT, prior to tumor size reduction, the PDE to ATP ratio decreased 33% and intracellular pH increased to 7.34 +/- 0.05 from 7.27 +/- 0.05. In the subsequent RT interventions, both the tumor size and PDE/ATP ratio continually decreased whereas the pH values remained alkaline and fluctuated around 7.34 to 7.65. The data suggest that the phospholipid metabolite PDE may signal important alterations in membrane metabolism that eventually lead to cell death.

Pretransplant assessment of renal viability by phosphorus-31 magnetic resonance spectroscopy. Clinical experience in 40 recipient patients.

A group of 40 cadaveric kidneys was studied just prior to planned transplantation to further assess the applicability of 31P-MRS in the analysis of clinical renal transplant viability. Renal intracellular high-energy phosphorus metabolites (ATP [or NADP], phosphomonoester [PME] and inorganic phosphate [Pi]) and pH were measured noninvasively with MRS surface coils external to cold storage containers. Pretransplant MRS parameters were correlated with subsequent renal function in recipient patients (measured one week postoperatively by the need of dialysis, drop in serum creatinine, urine output, and 123I or 131I Hippuran assessed renal tubular function). ATP and NADP was detected in eleven kidneys and was significantly (P less than 0.001) associated with the best renal function posttransplantation. These kidneys also had the highest PME/Pi ratios (1.66-0.54), while lower ratios (0.36-0.10) were associated with prolonged acute tubular necrosis. The PME/Pi ratios significantly (P less than 0.0001) correlated with subsequent clinical renal function, whereas cold storage times (37 +/- 10 hr) or intracellular renal pH (6.53-7.91) did not. These preliminary data suggest that MRS is a noninvasive, nondestructive and sterile method for assessing clinical viability during hypothermic storage of human cadaver kidneys and the subsequent recovery of renal function postrenal transplantation.

Characterization of human bone marrow stromal cells with respect to osteoblastic differentiation.

Human bone marrow was harvested by means of iliac crest aspiration and cultured under conditions that promote an osteoblastic phenotype. Human bone marrow aspirates from 30 normal subjects, ages 8-80 years, with no systemic illness, yielded a mean of 92 +/- 65 x 10(6) nucleated cells per 2 ml of aspirate. The prevalence of potential osteoblastic progenitors was estimated by counting the number of alkaline phosphatase-positive colonies. This assay demonstrated a mean of 43 +/- 28 alkaline phosphatase-positive colonies per 10(6) nucleated cells, which was about one per 23,000 nucleated cells. The prevalence of these colonies was positively correlated with the concentration of nucleated cells in the original aspirate (p = 0.014) and was negatively correlated with donor age (p = 0.020). The population of alkaline phosphatase-positive colonies in this model sequentially exhibited markers of the osteoblastic phenotype; essentially all colonies (more than 99%) stained positively for alkaline phosphatase on day 9. Matrix mineralization, which was associated with the synthesis of bone sialoprotein, was demonstrated on day 17 with alizarin red S staining. On day 45, cells that were stimulated with 1,25-dihydroxyvitamin D3 synthesized and secreted osteocalcin at concentrations consistent with known osteoblastic cell lines. This model provides a useful method for the assay of progenitors of connective tissue from human subjects, examination of the effects of aging and selected disease states on this progenitor population, and investigation into the regulation of human osteoblastic differentiation.

Conformations of 1,3,3,5,7,7-Hexamethyl-1,5-diazacyclooctane and Its Bis-BH(3) Adduct. Mono- and Bis-BH(3) Adducts of Di-Tertiary Amines.

A variable-temperature (1)H- and (13)C-NMR study revealed a conformational equilibrium for 1,3,3,5,7,7-hexamethyl-1,5-diazacyclooctane (4) having DeltaG() = 8.8 +/- 0.6 kcal/mol at 184 K. This activation barrier connects a major and a minor form of 4. Molecular mechanics calculations on 4 led to the conclusion that the major form is a set of twist-chair-chairs interconverting rapidly via the chair-chair and that the minor form is most likely a set of twist-boat-boats interconverting rapidly via the boat-boat. The proximity of the two nitrogen lone pairs in the major form of 4 made plausible the expectation that 4, as well as a related diamine with apposed nitrogens, 3,7-dimethyl-3,7-diazabicyclo[3.3.1]nonane (3), might bind a Lewis acid, namely BH(3), using both lone pairs simultaneously and equally. This proved not to be the case: for 3 only the bis-BH(3) adduct was found and for 4 the mono-BH(3) adduct utilized only one nitrogen lone pair. The structure of the bis-BH(3) adduct of 4 (12) was determined by X-ray crystallography to be a twist-boat-boat with BH(3)s cis. Molecular mechanics calculations on 12 were consistent with the solid state conformation found.

Short echo time proton spectroscopy of human brain using a gradient head coil.

Short echo time, single voxel localized proton spectroscopy was accomplished using a stimulated echo (STEAM) sequence running on a Siemens 1.5-T system with a head coil incorporating the Z and Y gradients. Spectra from the temporal lobe, the cerebellum and mid brain were acquired from a group of normal volunteers using the following parameters: voxel size = 8 ml, TE = 22 msec, 512 signal averages and TR = 1.7 sec. STEAM spectra acquired with the small diameter gradients showed significantly fewer artifacts at short TE, allowing the observation of glutamate/glutamine, GABA, taurine, and inositol in addition to the prominent resonance of choline, creatine/phosphocreatine and N-acetylaspartate (NAA). The levels of chlorine, creatine and NAA were found to be significantly different in the three regions of the brain examined.

Cell density and proliferation modulate collagen synthesis and procollagen mRNA levels in arterial smooth muscle cells.

Collagen synthesis and procollagen mRNA levels were determined and compared in (1) sparse, rapidly proliferating smooth muscle cells (SMC); (2) postconfluent, density-arrested SMC; and (3) sparse, nonproliferating (mitogen-deprived) rabbit arterial SMC. Collagen synthesis per SMC was decreased by 70% in postconfluent versus proliferating cells. However, relative collagen synthesis, expressed as the percentage of total protein synthesis, increased from 3.7% in sparse cultures to approximately 7% in postconfluent cultures. Slot blot analyses demonstrated that the relative steady state alpha 1(I) and alpha 1(III) procollagen mRNA levels were also increased in postconfluent cultures when compared to sparse cultures. As with collagen synthesis per cell, the mRNA levels per cell for types I and III procollagen in postconfluent cells, determined by densitometry of blots, were likewise approximately half that found in sparse, proliferating cells. In a separate study to determine if cell-cell contact was necessary for eliciting these changes in collagen synthesis, we determined collagen synthesis in mitogen-deprived and proliferating SMC cultures at low density. Mitogen-deprived cultures synthesized only 10% the amount of collagen produced (per cell) by proliferating cultures in 10% fetal bovine serum. Relative collagen synthesis in proliferating and nonproliferating cultures was 5.0 and 8.3%, respectively. These results demonstrate elevated collagen synthesis, per cell, by proliferating cultures compared with nonproliferating cultures, regardless of whether cells were rendered quiescent by density arrest or by mitogen deprivation. Results also suggest a pretranslational mechanism for the regulation of collagen synthesis in rabbit aortic smooth muscle cells.

A deficiency of cysteine impairs fibrillin-1 deposition: implications for the pathogenesis of cystathionine beta-synthase deficiency.

Cystathionine beta-synthase (CBS) deficiency is an inborn error of amino acid metabolism that has pleiotropic manifestations and is commonly called "homocystinuria." The features include skeletal, ocular, and vascular defects, some of which are reminiscent of those found in Marfan syndrome (MFS). Because of the spectrum of clinical effects, the pathogenesis of homocystinuria has long been thought to involve the extracellular matrix (ECM), and the condition has been classified as a heritable disorder of connective tissue. Because of the superficial similarities with MFS, we and others (Pyeritz, in McKusicks Heritable Disorders of Connective Tissue, St. Louis, Mosby-Year Book Inc., 5th ed., pp 137-178, 1993; Pyeritz, in Principles and Practice of Medical Genetics, New York, Churchill Livingstone, 3rd ed., pp 1027-1066, 1997; Mudd, Levy, and Skovby, in The Metabolic and Molecular Bases of Inherited Disease, New York, McGraw-Hill Publishing Co., 7th ed., pp 1279-1327, 1995) have speculated how CBS deficiency might affect fibrillin-1, the protein altered in MFS. For example, the altered plasma concentrations of homocysteine and/or cysteine in patients with CBS deficiency may hinder fibrillin-1 synthesis, deposition, or both. When arterial smooth muscle cells were cultured under conditions of cysteine deficiency, fibrillin-1 deposition into the ECM was greatly diminished as revealed by immunocytochemistry. Excessive homocysteine, in contrast, had little, if any, effect on fibrillin-1 deposition. When cysteine concentrations were returned to normal, the smooth muscle cells began to accumulate a matrix rich in fibrillin-1. Type I collagen, the major matrix component synthesized by these smooth muscle cells, was not reduced by low cysteine concentrations nor high homocysteine concentrations. These results demonstrate that a deficiency of cysteine and subsequent inhibition of fibrillin-1 accumulation in CBS deficient patients may be at least partly responsible for their phenotype, and suggest that maintenance of normal plasma cyst(e)ine levels may be an important therapeutic goal.

Basic fibroblast growth factor in the extracellular matrix suppresses collagen synthesis and type III procollagen mRNA levels in arterial smooth muscle cell cultures.

To determine the effects of an intact extracellular matrix on collagen synthesis, arterial smooth muscle cells (SMCs) were plated sparsely on a cell-free, SMC-derived matrix and examined the following day. Collagen synthesis during a 5-hour incubation by cells on the matrix was reduced to 67% of the control values obtained from cultures on plastic. Total protein synthesis was unaffected. Treatment of the matrix with heparitinase to remove basic fibroblast growth factor (bFGF) before seeding the SMCs abolished the inhibitory effect of the matrix on collagen synthesis. The inhibitory effect was also eliminated by treating the matrix with a neutralizing polyclonal antibody directed against bFGF. Collagen synthesis by SMC cultures grown in wells coated with purified bFGF was only 61% that of control cultures, whereas total protein synthesis remained unchanged. Slot-blot analysis revealed that the relative message level for alpha 1(III) procollagen was reduced in cultures grown on the preexisting matrix or on plastic precoated with bFGF, whereas the alpha 1(I) procollagen message was unaffected. These results demonstrate the ability of the extracellular matrix to modulate the synthesis of collagen by arterial SMCs and indicate that bFGF in the matrix is responsible for these effects.

Spectral editing of tumor 13C MRS in situ.

The editing pulse sequence DEPT (D.T. Pegg, D.M. Doddrell, and M.R. Bendall, J. Chem. Phys. 77, 2745 (1982)) was modified using a scheme of various composite pulses and a 16-step phase cycling to obtain proton-decoupled natural-abundance 13C edited subspectra of solid tumors. A solenoidal probe including a Faraday shield and an orthogonal saddle decoupling coil was built for this purpose.

Homocysteine as a risk factor for vascular disease. Enhanced collagen production and accumulation by smooth muscle cells.

An increased plasma homocysteine level is an independent risk factor for vascular disease. However, the pathological mechanisms by which homocysteine promotes atherosclerosis are not yet clearly defined. Arterial smooth muscle cells cultured in the presence of homocysteine grew to a higher density and produced and accumulated collagen at levels significantly above control values. Homocysteine concentrations as low as 50 mumol/L significantly increased both cell density and collagen production. Cell density increased by as much as 43% in homocysteine-treated cultures. Homocysteine increased collagen production in a dose-dependent manner. Smooth muscle cells treated with homocysteine at concentrations observed in patients with hyperhomocysteinemia had collagen synthesis rates as high as 214% of control values. Likewise, collagen accumulation in the cell layer was nearly doubled in homocysteine-treated cultures. Addition of aquacobalamin to homocysteine-treated cultures controlled the increase in smooth muscle cell proliferation and collagen production. These results indicate a cellular mechanism for the atherogenicity of homocysteine and provide insight into a potential preventive treatment.

In vivo MR spectroscopy of human subjects with a 1.4-T whole-body MR imager.

A 1.4-T magnetic resonance (MR) imager was modified to perform MR spectroscopy measurements. The implementation involved only a few additions in hardware and practically no change in software. Procedures for acquiring the MR spectra are similar to those for MR images. Both sensitivity and homogeneity were found to be adequate over a region 12 cm in diameter. Typical scanning times are 4.5 minutes for human brain, 2.8 minutes for muscle, and 20-35 minutes for solid tumors. Preliminary spectral studies of the metabolism of human brains, tumors, and a muscle of the forearm during exercise obtained with the modified system are presented.

Monitoring therapeutic response of human superficial tumors using phase-encoded spectroscopy.

A one-dimensional phase-encoded spectroscopy sequence was implemented on a GE 1.5-T Signa imager and the feasibility of its application to monitor the 31P metabolites of superficial tumors was demonstrated. Serial 31P spectra of 1-cm slices with adequate signal-to-noise ratio and insignificant T2 weighting can be obtained in 28 min. The degree of "bleeding" effect was reduced with increased phase-encoding steps.

Growth and magnetic resonance characteristics of human squamous cell carcinoma xenografts implanted with cells suspended in Matrigel.

Growth and magnetic resonance characteristics of a human squamous cell carcinoma SQ20B were studied in vivo as xenografts in nu/nu nude mice. Tumor cells injected subcutaneously in the flank using either Matrigel (MTG, an extract of basement membrane proteins) or growth medium (GM) as a vehicle were compared. Much higher tumor growth rates and cell density were observed with Matrigel than with GM implantation. Histology also showed that MTG implanted cells grew as vascularized solid tumors compared to GM tumors which formed cysts. As a result of increased cell density with the improved method, tumors as small as 0.3 cm3 provide high S/N magnetic resonance spectra which yield smaller standard deviations with fewer experiments.

Oblique proton chemical shift imaging for the presurgical localization of mesial temporal epilepsy.

Precise localization of the epileptogenic zone in patients suffering from mesial temporal lobe epilepsies is a prerequisite for surgery. For this purpose, a scheme for selecting the volume of interest in an oblique plane covering the head, body, and tail of the hippocampal formation (HF) was implemented in a water-suppressed proton chemical shift imaging (CSI) acquisition. This approach, evaluated by consecutively acquired CSI spectra of both temporal lobes, demonstrates that it can potentially be a routine technique for clinical diagnosis. Since the method produces localized spectral detail of the HF, it facilitates a convenient comparison of CSI lateralization to that assessed by HF atrophy (due to sclerosis) using the MRI-volumetry technique.