Hirayama disease.

PURPOSE: Hirayama disease is an initially progressive disease caused by cervical neck flexion compressing the anterior horns of the lower cervical spinal cord. It is primarily seen in young males of Indian or Asian descent. With increasing dispersion of these populations this condition is increasingly being encountered internationally. This grand round reviews this rare but increasingly recognized condition. MATERIALS AND METHODS: We present a classic case of a young Indian male with progressive hand and forearm weakness. We discuss the typical clinical presentation, appropriate investigations and management of this condition. RESULTS: Our patient presented with oblique amyotrophy and underwent a diagnostic flexion MRI scan which revealed anterior translation of the posterior dura with compression of the anterior horns of the lower cervical cord. He has been successfully treated in a cervical collar. CONCLUSIONS: This case illustrates the typical presentation, diagnostic investigations and treatment of Hirayama syndrome. It is hoped that this review will alert clinicians of this condition and optimize the management of affected individuals.

The discovery of a potent Nav1.3 inhibitor with good oral pharmacokinetics.

In this article, we describe the discovery of an aryl ether series of potent and selective Nav1.3 inhibitors. Based on structural analogy to a similar series of compounds we have previously shown bind to the domain IV voltage sensor region of Nav channels, we propose this series binds in the same location. We describe the development of this series from a published starting point, highlighting key selectivity and potency data, and several studies designed to validate Nav1.3 as a target for pain.

Constrained total hip arthroplasty in a paediatric patient with cerebral palsy and painful dislocation of the hip. A case report.

We describe a patient with cerebral palsy, of normal intelligence, who could not walk but who by the age of 16 had been successfully managed with a staged bilateral total hip arthroplasty using a constrained liner.

The enzymatic basis of the selective action of cyclophosphamide.

The initial metabolic products of cyclophosphamide (4-hydroxy-cyclophosphamide and aldophosphamide) were prepared biologically in unpurified form. Their toxicity to tumor cells were tested by bioassay techniques and in cell culture, and the deactivation abilities of various tissue-soluble fractions were quantitated. Liver and kidney cytosol effectively deactivated the primary metabolites, whereas cytosols from gastrointestinal tract mucosa, Walker ascites tumor, and spleen were less efficient. When [14C]cyclophosphamide was activated and incubated with liver cytosol, 34% of all radioactivity was identified as carboxyphosphamide, by mass spectrometry of the methyl ester. Measurement of alcohol dehydrogenase (EC 1.1.1.1) and aldehyde dehydrogenase (EC 1.2.1.3) activities by reduced nicotinamide adenine dinucleotide production revealed a qualitative correspondence between aldehyde dehydrogenase activity and deactivation ability. Unpurified aldophosphamide and the analogs prepared from 6-methyl- and 5,5-dimethylcyclophosphamides were substrates for nicotinamide adenine dinucleotide-requiring enzymes, whereas incubation of 4-hydroxy-4-methylcyclophosphamide in an unfractionated incubation mixture with liver soluble enzymes did not cause reduced nicotinamide adenine dinucleotide production.

The unexpected formation of biologically active Cu(II) Schiff mono-base complexes with 2-thiophene-carboxaldehyde and dipropylenetriamine: crystal and molecular structure of CudptaSCl2.

Two novel mononuclear Cu(II) coordination compounds of the type [Cu(dptaS)Cl(2)] and [Cu(dptaS)Br(2)] (dptaS=1,3-propanediamine, N(1)-[3-aminopropyl]-N(3)-[2-thienylmethylidene] or Schiff mono-base of dipropylenetriamine with 2-thiophene-carboxaldehyde) were prepared by the hydrolysis of the di-bases, [Cu(dptaSS)Cl(2)] and [Cu(dptaSS)Br(2)] (dptaSS=1,3-propanediamine, N(1)-[2-thienylmethylidene]-N(3)-[[2-thienylmethylidene]aminopropyl] or Schiff di-base of dipropylenetriamine with 2-thiophenecarboxaldehyde) to mono-bases with the release of one aldehyde molecule and freeing of the -NH(2) group of the coordinated dpta ligand. The X-ray determined structure of the compound [Cu(dptaS)Cl(2)] was confirmed by spectroscopic methods, magnetic and molar conductivity measurements. The Cu(II) atom is a five-coordinated CuN(3)Cl(2) chromophore with three nitrogen atoms coming up from the (dptaS) ligand and two chlorine atoms completing the square pyramidal geometry. Antiproliferative activity of both novel compounds was examined against a panel of different normal and cancer cell lines (MRC5, HeLa, MCF7, HT-29 and T47D) and showed that the Cu(II) Schiff mono-bases exhibit increased activity as compared to the starting materials. In vitro studies of plasmid DNA (pDNA) and double stranded DNA (dsDNA) interaction with the compounds under study support this difference. Some of the important factors contributing to the antiproliferative activity of the compounds under study, such as ionic character and dipole moment were also discussed in terms of the density functional theory calculated electronic structures of the ligands and their Cu(II) compounds.

Alloreactivity. I. Effects of age and thymic hormone treatment on cell-mediated immunity in C57B1/6NNia mice.

C57B1/6NNia mice 1, 12, and 24 months old showed loss of cellular-mediated cytotoxicity with aging. Treatment of the three age groups with different thymic hormone preparations effected their cellular mediated cytotoxicity differently. When cytotoxicity of the thymic hormone treated groups was compared to that of the physiological saline treated group, 1-month-old mice treated with serum thymic factor (FTS) at 1 microgram/mouse and 10 ng/mouse had significantly higher activity, and lower to similar activities at 12 and 24 months; TP5 (active fragment of thymopoietin) at 1 microgram and 10 ng caused significantly higher activity in 1-month-old mice, and lower to higher and significantly lower to similar activity at 12 and 24 months, respectively; TM4 (an analogue of TP5) at 1 ng showed significantly depressed activity in 1-month-old mice, and significantly enhanced activity in 12- and 24-month-old mice; thymosin at 10 micrograms and 1 microgram had slightly lower, but not significant, depression at 1 month, similar activities at 12 months and significantly depressed to higher activity at 24 months. Unimmunized control mice showed significant protection in the 12-month-old mice in comparison to 1- and 24-month-old mice. Different hormone preparations showed age- and dose-dependent effects on the ability of spleen cells to kill P815 mastocytoma. Partial restoration of cytotoxicity was observed in 24-month-old mice treated with FTS, TP5 and thymosin fraction V.

Synthesis and antitumor activity of 6-trifluoromethylcyclophosphamide and related compounds.

In an attempt to increase the combined toxicity of the metabolic end-products [acrolein (4) and phosphoramide mustard (3)] from cyclophosphamide (1), the analog 2-[bis(2-chloroethyl)amino]tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide (2, 6-trifluoromethylcyclophosphamide) was synthesized and its metabolism and antitumor activity studied. Following metabolism of 2 by rat liver microsomes the predicted formation of 4,4,4-trifluorocrotonaldehyde (5) was confirmed by isolation and identification, by mass spectrometry, of its dinitrophenylhydrazone. The therapeutic indices (LD50-/ID90) for 2 against the ADJ/PC6 mouse tumor and the Walker 256 tumor in the rat were 28.6 and 7.7, respectively, and were lower than the corresponding values for 1 (91.8 and 33.2, respectively) although the toxicities toward Walker cells in a bioassay system of 1 and 2 following microsomal metabolism were similar. In order to study the toxicities of 4 and 5 released under drug metabolizing conditions independently of the production of a toxic mustard the analogs 18 [2-(diethylamino)tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide] and 6 [2-(diethylamino)tetrahydro-6-trifluoromethyl-2H-1,3,2-oxazaphosphorine 2-oxide] were also synthesized. The release of 5 from 6 following metabolism was confirmed and shown by use of the bioassay system to be an event of similar toxicity to release of 4 from 18; in vivo, however, 6 (LD50 330 mg/kg) was more toxic to mice than 18 (LD50 greater than 500 mg/kg).

Tumor inhibitory triazenes. 3. Dealkylation within an homologous series and its relation to antitumor activity.

The in vivo antitumor activity and in vitro metabolic dealkylation have been measured for an homologous series of 3-alkyl-1-(4-carbamoylphenyl)-3-methyltriazenes and have been compared with their partition coefficients. This investigation has shown that the extent of oxidative metabolism in vitro and the antitumor activity in vivo of these compounds are dependent upon hydrophobicity. These findings provide confirmation for the relationship between metabolism and antitumor activity for aryldialkyltriazenes.

Information processing in the cerebral hemispheres: selective hemispheric activation and capacity limitations.

Several previous experiments have found that concurrently maintaining verbal information in memory influences visual laterality patterns (e.g., Hellige & Cox, 1976; Kinsbourne, 1975). The present article critically reviews existing experiments and reports five additional experiments designed to identify the mechanisms responsible for such effects. Experiment 1 demonstrates that laterality patterns are not influenced by a concurrent memory task that does not require verbal processing. (The verbal nature of the concurrent task was an important aspect of previous experiments.) Experiments 2 and 3 were designed to determined whether concurrent verbal memory primarily influences very early visuospatial processes or later processes such as those involved in visuospatial memory. In Experiment 2, observers indicated whether two simulteneously presented nonsense forms had the same shape. Observers held 0, 2, 4, or 6 words in memory during each shape judgment trial. Responses were faster when the forms were presented to the left visual field--right hemisphere (LVF-RH) than to the right visual field--left hemisphere (RVF-LH). This effect did not interact with memory set size. In Experiment 3, observers indicated whether either of two simultaneously presented forms was identical to a target form held in memory. Observers held 0, 2, or 6 words in memory on each trial. On same-as-target trials, responses were faster on LVF-RH trials than on RVF-LH trials in the no-word memory condition; this difference was reversed in the two-word and six-word conditions. The combined results of Experiments 2 and 3 suggest that concurrent verbal memory influences stages of processing beyond the initial registration of visuospatial information. Experiments 4 and 5 examined the influence of concurrent verbal memory on verbal laterality tasks. Observers indicated whether two simultaneously presented letters of different cases had the same name. In Experiment 4, different groups of observers held 0, 2, 4, or 6 words in memory on each letter-pair trial. In Experiment 5, memory set size was manipulated within subjects. On the same-pair trials of Experiment 4 and the first session of Experiment 5, responses in the no-memory condition were faster on RVF-LH trials than on LVF-RH trials; this difference was reversed in all of the work memory conditions. This shift is opposite to that found when the laterality task does not require verbal processing and further indicates that concurrent verbal memory influences processing stages beyond those that are common to the form-pair and letter-pair tasks. Neither directness-of-pathway nor attention-gradient laterality models can explain the entire pattern of results from the present experiments. Rather, the results suggest that the left hemisphere functions as a typical limited-capacity information processing system that can be influenced somewhat separately from the right hemisphere system.

Effects of concurrent verbal memory on recognition of stimuli from the left and right visual fields.

Two experiments examined the effect of concurrently holding 0, 2, 4, or 6 nouns in memory on the recognition of visual stimuli briefly presented to the left or right visual fields. When stimuli to be visually recognized were complex visuospatial forms it was found that a relatively easy memroy load of 2 or 4 nouns improved visual recognition accuracy on right visual field (left-hemisphere) trials relative to the no-memory condition; however, a more difficult memory load of 6 nouns decreased visual recognition accuracy to a level slightly below the no-memory condition. There were no effects of concurrent verbal memroy on visual form recognition on left visual field (right-hemisphere) trials. When the stimuli to be visually recognized were words it was found that a relatively easy memroy load of 2 or 4 nouns improved visual recognition accuracy and a more difficult load of 6 nouns decreased visual recognition accuracy on both left and right visual field trials. The complete pattern of results indicates that several factors including cerebral hemisphere specialization, stimulus codability, selective perceptual orientation, and selective cerebral hemisphere interference interact in systematic ways to produce overall visual laterality effects.

Copper(II) Schiff base coordination compounds of dien with heterocyclic aldehydes and 2-amino-5-methyl-thiazole: synthesis, characterization, antiproliferative and antibacterial studies. Crystal structure of CudienOOCl2.

A new series of coordination compounds of the starting materials [Cu(dienX(2)Y(2))] and their adducts [Cu(dienXXY(2))(2a-5mt)] (where dien=diethylenetriamine, dienXX=Schiff bases of diethylenetriamine with 2-furaldehyde or 2-thiophene-carboxaldehyde, X=O, S, Y=Cl, Br, NO(3) and 2a-5mt=2-amino-5-methylthiazole) were synthesized by stepwise reactions and their structures were established by C, H, N, Cu analysis, spectroscopic, magnetic and molar conductivity measurements. The isolated compounds are monomers, paramagnetic and electrolytic compounds of the type 1:1. In all cases, the pentadentate Schiff base (dienXX) is bonded in a tridentate fashion through the 3 N atoms. In the CudienXXY(2) compounds the coordination sphere is completed by two Cl or Br or NO(3) groups in a square pyramidal arrangement. The proposed structure for this type of compound was further supported by X-ray diffraction analysis of the compound [Cu(dienOO)Cl(2)]. Its basal plane consists of three Cu-N contacts [2.017(2), 2.025(2) and 2.012(2) A] from dienOO, and the Cl(1) atom, while the Cl(2) atom possesses the apical position, the relevant distances being 2.2732(7) A for Cu-Cl(1) and 2.6051(7) A Cu-Cl(2). In the CudienX(2)Y(2).2a-5mt adducts the coordination sphere of copper is further completed by the nitrogen ring atom of the 2a-5mt, forming an octahedral configuration. The study of the biological activity of the compounds synthesized against a panel of different normal and cancer cell lines (MRC5, HeLa, MCF7, HT-29, OAW42, T47D) and bacteria (E. coli, B. cereus, B. subtilis) showed that the adducts of the type [Cu(dienXXY(2))(2a-5mt)] exhibit increased activity both in cancer cells and in bacteria, compared to the starting material of type [Cu(dienXXY(2))].

The effect of plasma on the reaction of cyclophosphamide with 4(-p-nitrobenzyl)-pyridine.

Cyclophosphamide is not structurally modified by blood plasma and may be recovered quantitatively from it. The apparent loss of alkylating ability of cyclophosphamide, as measured by its ability to react with 4-(p-nitrobenzyl)-pyridine (NBP), following treatement with plasma is not, as has been reported, due to metabolism of the drug but rather to an inhibition of the colorimetric reaction by a constituent of the plasma. This inhibition is strongly pH dependent, reaching 100% when the pH of the solution of cyclophosphamide in plasma is above 8, and falling to less than 20% when the pH is below 6, but extraction with chloroform at pH 7 separates cyclophosphamide from the inhibitor. Although the nature of the inhibitor has not been elucidated, its presence in plasma is of great importance in the quantitative determination of cyclophosphamide, and may also be of significance in the biological effects of cyclophosphamide and other alkylating agents in vivo.

Metabolism of N-nitrosomorpholine by the rat in vivo and by rat liver microsomes and its oxidation by the Fenton system.

N-Nitrosomorpholine is converted into N-nitroso-2-hydroxymorpholine by rat liver microsomes and by the Fenton oxidation system. The hydroxy derivative was also synthesised by the oxidation of N-nitrosodiethanolamine with permanganate and characterized as the methoxime and the 2,4-dinitrophenylhydrazone. The Fenton system also afforded products believed to be N-nitroso-2-morpholone, and the 2-hydroperoxy- and 2-peroxy-derivatives of N-nitrosomorpholine. The only urinary metabolite definitely identified was N-nitrosodiethanolamine. The significance of metabolic 2-hydroxylation in relation to the carcinogenic action of N-nitrosomorpholine is discussed.

Clinical characterization of Dicea a new cellulose membrane for haemodialysis.

A prospective randomised clinical study comparing the functional performance and biocompatibility of a new cellulose diacetate variant (Dicea) in which the degree of hydroxyl group substitution differs, with cellulose diacetate and low flux polysulfone incorporated into commercially produced hollow fiber hemodialysers with a surface area 1.5-1.6 m2 has been undertaken. All dialysers studied demonstrated clinically acceptable performance in terms of their small molecular removal characteristics, with minor statistical but not clinical differences. Use of both cellulose diacetate membranes but not low flux polysulfone resulted in a reduction in plasma beta(2) microglobulin levels. The membranes were impermeable to albumin, but showed some permeability to low molecular weight proteins. The average protein recovery from the dialysis fluid was 3105 mg for Dicea, 2913 mg for cellulose diacetate and 2842 mg for low flux polysulfone. For Dicea the white cell count by 15 minutes had declined to 68% of pre treatment value, compared with 59% and 86% for cellulose diacetate and low flux polysulfone. The differences between Dicea and cellulose diacetate were not significant, but both cellulose based membranes differed from low flux polysulfone (p = 0.0015). There was a strong evidence of differences between the membranes in respect of C5a and C5b-9 generation (p = 0.0001) but not for C3a (p = 0.16) furthermore the levels of C5b-9 generated during dialysis also showed a significant positive correlation compared to C5a for all membranes. (Pearson's correlation coefficient = 0.856, p = 0.0001). It is concluded that the two cellulose diacetate membranes are not identical, with the differences observed being a consequence of the degree of acetyl substitution, resulting in alteration of membrane structure and the method of sterilization. The clinical significance of these differences are difficult to characterize but the modification of the cellulose structure appears to be a promising method to improve the biocompatibility of cellulose membranes. The improved biocompatibility offered by this method still falls short of that achieved with low flux synthetic membranes such as Fresenius Polysulfone.

Evaluation of biodegradable rifampicin-bearing microsphere formulations using a stability-indicating high-performance liquid chromatographic assay.

The validation of a rapid and selective stability-indicating high-performance liquid chromatographic procedure for the determination of rifampicin (RIF) and its decomposition products in aqueous solution is described. Direct injection and column switching HPLC procedures have been compared and, owing to the increased sensitivity and precision, the latter has been applied to the study of RIF stability in the presence of isoascorbic acid at pH 7.4. The time-dependent hydrolytic decomposition of RIF to 3-formyl rifamycin SV (RSV) was found to be biexponential. Log concentration versus time plots of RIF and RSV decomposition were found to be parallel, indicating a pseudo equilibrium decomposition process. This feature allowed corrections for the amounts lost to secondary reactions to be calculated when the assay was applied to the determination of release characteristics of RIF from biodegradable poly-d, l-lactide-co-glycolide microspheres.

Relationship between swelling, erosion and drug release in hydrophillic natural gum mini-matrix formulations.

The swelling, erosion and solvent front penetration properties of mini-matrices containing xanthan (X), locust bean (LB) and karaya (K) gums were examined, analysed and related to the overall in vitro release kinetics of diclofenac sodium, used as a model drug. Mini-matrices were produced with drug:gum ratios of 1:1 as well as formulations of drug and X in combinations of 2:1, 2:3 and 1:2. The rank order of decreasing swelling index (SI) in both axial and radial dimensions was X?K?LB and each gum showed almost Fickian swelling behaviour. The solvent front penetration rates were consistent with the rates of swelling. However, the order of decreasing drug release and erosion rates was LB>X>K and all formulations demonstrated anomalous (non-Fickian) drug release kinetics. Therefore Fickian drug diffusion and polymer erosion were both occurring simultaneously. The dominant mechanism depended on the nature and content of the gum, as well as the stage in the dissolution time period. There was a loss of matrix integrity in formulations containing a high drug:gum ratio.

Studies of polymorphism in three compounds by single crystal X-ray diffraction.

The role of single crystal diffraction in the quantitative determination of polymorphism is demonstrated by the examination of three compounds. Two polymorphs were found for each of the compounds bis(2-nitrophenyl) trisulphide (1), 2-amino-5-nitrobenzophenone (2) and bis(2-nitrophenyl) sulphide (3). Only in one polymorph of (1) does molecular symmetry correspond with crystallographic symmetry. In (2) the polymorphs arise in the same crystal class and in the same crystallographic space group whereas in (3) the two polymorphs exist in different crystal classes and hence in different space groups. Crystallographic space group transformation is also discussed.

Compressed xanthan and karaya gum matrices: hydration, erosion and drug release mechanisms.

Directly compressed matrices were produced containing either xanthan gum or karaya gum as a release-controlling agent. These swellable hydrophilic natural gums were used to control the release of varying proportions of two model drugs, caffeine and diclofenac sodium, which have different solubilities in aqueous medium. Gum erosion, hydration and drug release studies were carried out using a dissolution apparatus (basket method) at two agitation speeds. Xanthan gum displayed a high degree of swelling due to water uptake and a small degree of erosion due to polymer relaxation. Neither agitation speed nor drug solubility had any significant effect on water uptake, but matrices with the lower proportion of gum produced a lesser degree of hydration. In contrast, karaya gum displayed a much lower hydration capacity and a higher rate of erosion, both markedly affected by agitation speed. Drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of drug. Both xanthan and karaya gums produced near zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices.

Hydrogen bonding in salicylsalicylic acid (salsalate) crystals.

An X-ray crystallographic study of the drug salsalicylic acid (salsalate) has been performed. Crystal formation of the drug is influenced by both inter- and intra-molecular hydrogen bonding. In addition an OH group in salsalate can occupy alternate ortho positions resulting in two hydrogen bonding motifs within a single crystal.

Development and evaluation of a multiple-unit oral sustained release dosage form for S(+)-ibuprofen: preparation and release kinetics.

Mini-matrix tablets containing S(+)-ibuprofen have been prepared by the wet granulation method. The hydrophilic matrix was formed with either xanthan gum, karaya gum or hydroxymethylcellulose (HPMC) together with a choice of additives from lactose, Encompress(R), Avicel(R) PH101, talc and Lubritab(R). Multiple unit dosage forms (MUDFs) were subsequently obtained by encapsulating the mini-matrix tablets into hard gelatin capsules. Preparation, in vitro release profiles and release kinetics are presented.