Effect of acid suppressant medications on the laxative action of magnesium preparations in patients with opioid-induced constipation: A pharmacovigilance analysis of the FDA Adverse Event Reporting System.

Objective: Magnesium oxide is widely used for treating opioid-induced constipation, a serious analgesic-associated problem. Opioid analgesic users are often prescribed non-steroidal anti-inflammatory drugs, which are sometimes combined with acid suppressants to prevent gastrointestinal adverse events. Magnesium preparations combined with acid suppressants may diminish magnesium preparations' laxative effect. This study was aimed at evaluating the effect of magnesium preparations combined with acid suppressants on the incidence of opioid-induced constipation by using the Food and Drug Administration Adverse Event Reporting System. Methods: Adverse events were defined per the Medical Dictionary for Regulatory Activities; the term 'constipation (preferred term code: 10010774)' was used for analysis. After adjusting for patient background factors using propensity score matching, acid suppressants' effect on constipation incidence was evaluated in opioid users prescribed magnesium preparations alone as laxatives by using a test for independence. Key Findings: The Food and Drug Administration Adverse Event Reporting System contains 14,475,614 reports for January 2004 to December 2021. Significantly increased constipation incidence was related to magnesium preparations combined with acid suppressants, especially proton pump inhibitors (P < 0.0001, McNemar's test). Conclusion: Magnesium preparations combined with acid suppressants may diminish magnesium preparations' laxative effect; healthcare professionals should pay attention to this issue.

Spin-orbital short-range order on a honeycomb-based lattice.

Frustrated magnetic materials, in which local conditions for energy minimization are incompatible because of the lattice structure, can remain disordered to the lowest temperatures. Such is the case for Ba(3)CuSb(2)O(9), which is magnetically anisotropic at the atomic scale but curiously isotropic on mesoscopic length and time scales. We find that the frustration of Wannier's Ising model on the triangular lattice is imprinted in a nanostructured honeycomb lattice of Cu(2+) ions that resists a coherent static Jahn-Teller distortion. The resulting two-dimensional random-bond spin-1/2 system on the honeycomb lattice has a broad spectrum of spin-dimer-like excitations and low-energy spin degrees of freedom that retain overall hexagonal symmetry.

Homozygosity and linkage disequilibrium mapping of autosomal recessive distal myopathy (Nonaka distal myopathy).

Autosomal recessive distal myopathy or Nonaka distal myopathy (NM) is characterized by its unique distribution of muscular weakness and wasting. The patients present with spared quadriceps muscles even in a late stage of the disease. The hamstring and tibialis anterior muscles are affected severely in early adulthood. We have localized the NM gene to the region between markers D9S319 and D9S276 on chromosome 9 by linkage analysis. To further refine the localization of the NM gene, we conducted homozygosity and linkage disequilibrium analysis for 14 patients from 11 NM families using 18 polymorphic markers. All of the patients from consanguineous NM families were found to be homozygous for six markers located within the region between markers D9S2178 and D9S1859. We also provided evidence for significant allelic associations between the NM region and five marker loci. Examination of the haplotype analysis identified a predominant ancestral haplotype comprising the associated alleles 199-160-154-109 (marker order: D9S2179-D9S2180-D9S2181-D9S1804), present in 60% of NM chromosomes and in 0% of parent chromosomes. On the basis of the data obtained in this study, the majority of NM chromosomes were derived from a single ancestral founder, and the NM gene is probably located within the 1.5-Mb region between markers D9S2178 and D9S1791.

[Successful direct thrombolysis in a patient with extensive dural sinus thrombosis induced by danazol].

A 43-year-old woman was suffered from an increasing headache with nausea and vomiting for nine days. She had received danazol 400 mg daily for endometriosis last two months. CT scan and neurological examinations revealed no evidence of abnormality. MRI showed isosignal intensity on T1-weighted images and high signal intensity on T2-weighted images in the superior sagittal, right transverse, sigmoid and straight sinuses suggesting thrombosis. With angiography, we confirmed extensive dural sinus thrombosis in the superior sagittal, straight, right transverse and sigmoid sinuses. She, then, developed progressing neurological deterioration with dysarthria and drowsy. Microcatheter was placed directly into the thrombus at dural sinus via transfemoral route. Thrombolytic therapy with urokinase was performed in right transverse, confluens sinuum, superior sagittal and straight sinuses. Successful recanalization with remarkable improvement of symptoms was achieved except right transverse sinus. We believe danazol played a role in the occurrence of dural sinus thrombosis. MRI and MRV were noninvasive and useful for diagnosis and follow-up of dural sinus thrombosis. Direct thrombolysis should be considered for dural sinus thrombosis, especially when clinical symptoms are rapidly deterioration with conventional anticoagulant therapy.

[Brain uptake ratio as an index of cerebral blood flow obtained with 99mTc-ECD].

A new index of cerebral blood flow (brain uptake ratio, BUR) using 99mTc-ECD was developed and evaluated in 66 patients (132 cerebral hemispheres). BUR was calculated from brain count in anterior planar image (60-80 sec after injection of 99mTc-ECD) divided by the summation of the count of aortic arch during first transit of radionuclide. BUR correlated well with brain perfusion index (BPI) obtained with Patlak plot method (r = 0.960, p < 0.001). In conclusion, BUR is useful as a simple and non-invasive index reflecting cerebral blood flow.

[Modifications of fractional uptake method for 123I-IMP].

We intended to improve the fractional uptake (FU) method which was developed to quantify cerebral blood flow using 123I-IMP without blood sampling. The quantification of cardiac output (CO) using first-pass data was adapted to FU method while the original FU method used CO which was estimated from the body surface area of patients. Time-radioactivity curves of the lungs and brain were separately obtained by a small-field-of-view gamma camera. In 24 cases, mean cerebral blood flow (mCBF) obtained by the modified FU method showed the better correlation (r = 0.833, P< 0.001) to mCBF measured by the Patlak plot with 99mTc-HMPAO than the original FU method (r=0.667, p<0.01). With these modifications, the reliability of FU method could be improved and the modified FU method might be performed in the other institutions.

Dissociated motor loss syndrome with cavities in the anterior horns.

A 74-year-old man developed proximal muscular weakness and wasting of the left upper extremity without sensory disturbance or myelopathic symptoms. The muscle atrophy had not progressed for a few years. Radiological examination of the spine showed cervical disc herniation. These findings and electrophysiological studies excluded motor neuron diseases, permitting the diagnosis of dissociated motor loss syndrome. Interestingly, delayed computerized tomographic myelography disclosed cavities in the anterior horns of the spinal cord, which coincided with the clinical symptoms. Previous radiological and pathological examinations showed formation of such cavities within the spinal cord resulting from chronic compression, which was followed by ischemic change. In this context, the present case supports ischemia as a cause of dissociated motor loss syndrome.

An autonomously functioning thyroid carcinoma associated with euthyroid Graves' disease.

A 39-yr-old man with an autonomously functioning thyroid carcinoma is presented. Only 17 similar cases have been reported in the literature. The patient had unilateral Graves' ophthalmopathy. He was euthyroid as reflected by normal TSH concentration, whereas the results of a T3 suppression test established the presence of autonomous thyroid function. A thyroid scan with (123)I revealed a hot nodule corresponding to the location of a papillary carcinoma and remained substantially unchanged after T3 administration. The hyperfunction of the carcinoma itself was clearly confirmed by the intense concentration of (131)I within the tumor on microautoradiograms. While a hot nodule on radioiodine scan is unlikely to be malignant, the possibility of carcinoma should not be overlooked.

Conformational modification enhances myasthenogenicity in synthetic peptide of acetylcholine receptor alpha-subunit.

The induction of myasthenia gravis depends on linked recognition of antigenic sites of acetylcholine receptor (AChR) by B-cells and T-cells. The former is conformationally restrained, and the latter is under the MHC class II restriction. We synthesized an artificially formed peptide (model peptide) by coupling the alpha 190-195 selected as B-cell site and cholinergic binding site and the alpha-107-116 selected as T-cell site and agretope with the intervening chain segment aligned as Asn-Pro-Gly-Gly (NPGG) to adopt beta-turn conformation. This model peptide, alpha 107-116-NPGG-alpha 190-195, was potently immunogenic in Lewis rats to provoke anti-peptide antibody reactive with native AChR and to induce the animal model of immunopharmacologic blockade of acetylcholine (ACh)-binding site. Low immunogenicity compared with this was found when using natural peptides predicted as sequences of B-cell site or T-cell site and the peptide synthesized by linking both without intervention of NPGG. The alpha 190-195 had no function of cholinergic binding either as a single segment or as part of the conformation-modified peptides; results suggest that the conformation modified for high immunogenicity does not assume the bioactive conformation for ACh-binding.

Chemical modification of erythropoietin: an increase in in vitro activity by guanidination.

Human recombinant erythropoietin (rHuEPO) was chemically modified with several group-specific reagents in order to study the role of each kind of amino-acid residue in its biological activity. Guanidination of the amino groups of the lysine residues yielded derivatives that showed higher activities in vitro than native rHuEPO, whereas amidination had no effect on the activity. By contrast, modification of the positive charges of the lysine residues to neutral or negative charges, such as in carbamylation, trinitrophenylation, acetylation or succinylation, caused a significant loss of rHuEPO activity. Chemical modification of other amino-acid residues, such as arginine and tyrosine residues or carboxyl groups, also led to loss of activity.

Promotion of cell-substratum adhesion of clonal rat pheochromocytoma cells (PC12) by factors contained in glioma-conditioned medium (GCM): separation of two active factors contained in GCM.

Culture medium conditioned over C6 glioma cells (GCM) contains factors which induce neurite outgrowth from clonal rat pheochromocytoma (PC12) cells. The effects of GCM on the cell-substratum adhesion of PC12 cells, which is an early event required for the neurite outgrowth, were investigated. The results obtained are as follows. Addition of GCM promoted the adhesion of PC12 cells specifically to collagen-coated tissue culture dish. The GCM-promoted adhesion of PC12 cells was prevented by the treatment of the cells with cytochalasin B, concanavalin A and glycosidase mixture suggesting the contribution of microfilaments and cell surface carbohydrates in the cell adhesion. GCM did not increase significantly the intracellular content of cAMP and the extent of cell adhesion promoted by cAMP or dibutyryl-cAMP was much less than that by GCM. Two active factors contained in GCM were separated by either gel filtration or chromatofocusing using the cell adhesion assay as an index. The first factor with an apparent mol. wt. around 40,000 had the abilities to induce the neurite outgrowth and to enhance the choline acetyltransferase activity in addition to the ability to promote the adhesion of PC12 cells. The second factor with an apparent mol. wt. around 10,000 was devoid of the ability to induce the neurite outgrowth, but had the abilities to enhance the choline acetyltransferase activity and to promote the adhesion of PC12 cells. Both factors were sensitive to trypsin digestion and relatively heat stable. The significance of these factors in the neuronal differentiation was discussed.

Cholinergic differentiation of clonal rat pheochromocytoma cells (PC12) induced by factors contained in glioma-conditioned medium: enhancement of high-affinity choline uptake system and reduction of norepinephrine uptake system.

The effects of glioma-conditioned medium (GCM) and factors contained in GCM on the neurochemical differentiation of the PC12 clone of rat pheochromocytoma cells were investigated. The results obtained are as follows. The accumulation of choline into PC12 cells proceeded through two uptake systems with high (Km = 3.20 microM) and low (Km = 65.2 muM) affinities as revealed by least-squares iterative fitting of a substrate-velocity curve to the data. Culturing of PC12 cells in the presence of GCM led to a 5-fold increase in the Vmax value of the high-affinity uptake system without affecting the Km of the high-affinity uptake system. Both Km and Vmax of the low-affinity uptake system were unaffected by the GCM treatment. The high-affinity choline uptake system in both GCM-treated and untreated PC12 cells was devoid of Na+ dependency and showed low sensitivity to hemicholinium-3. The ratio of [3H]acetylcholine converted from [3H]choline taken up by PC12 cells at 1 muM choline for 1 h was two-fold higher than that by untreated cells. PC12 possess a high-affinity norepinephrine uptake system. Culturing of PC12 cells in the presence of GCM led to a decrease in the rate of uptake of 3 muM norepinephrine to 43% of that in control cells. The 40-K and 10-K fractions isolated by gel filtration of GCM had both abilities to enhance the high-affinity choline uptake system and to suppress the high-affinity norepinephrine uptake system. From these observations it was concluded that GCM contains factors which induce the cholinergic neuronal differentiation of PC12 cells.

Transient infantile hyperthyrotropinaemia. Report of a case.

A case of transient hyperthyrotropinaemia was found by mass screening for neonatal hypothyroidism using the paired TSH assay method. The patient was a baby boy born at term after a normal pregnancy who grew without any abnormal signs or symptoms. For the first 7 months after birth, his serum TSH was abnormally high while his total serum T4, T3, and free T4, T3 were within normal limits, exept for slightly low free T4 level at 7 months. The raised serum TSH decreased spontaneously to within normal limits after he was 9 months old.