Changing roles of computed tomography in diagnosing acute appendicitis in emergency rooms.

BACKGROUND: We used the Taiwan National Health Insurance Database for analysis and statistics to investigate the role of computed tomography (CT) in diagnosing acute appendicitis. MATERIALS AND METHODS: All 10 046 patients with acute appendicitis were selected and categorized into two groups based on those who did and did not receive CT 3 days before acute appendicitis diagnosis: non-CT and CT groups. A noteworthy outcome was the incidence of peritonitis within 90 days after diagnosis of acute appendicitis. RESULTS: The rate of using CT for patients with acute appendicitis increased considerably from 7.9% to 52.9% from 2000 to 2010. The peritonitis incidence rates were 3.54% and 10.7% in the non-CT and CT groups, respectively. Patients who received CT on the same day exhibited a 3.8-fold higher risk of peritonitis than did those in the non-CT group. Those who underwent CT before diagnosis of acute appendicitis exhibited no significant difference of peritonitis risk when compared with those in the non-CT group. The CT group patients were hospitalized 2.19 days longer than the non-CT group patients. Patients who received CT before and on the same day were hospitalized 1.31 and 2.43 days longer than those who did not undergo CT. CONCLUSION: Patients who underwent CT exhibited higher risks of peritonitis and longer hospital stays compared with those who did not. Moreover, patients who received CT on the same day of operation exhibited a higher risk of peritonitis than those who underwent CT 1 or 2 days before operation.

Luteinizing hormone-releasing hormone antagonists containing very hydrophobic amino acids.

In a continuation of our studies on the effects of hydrophobic substitutions in analogues of luteinizing hormone-releasing hormone (LH-RH), we have synthesized LH-RH antagonists containing the very hydrophobic amino acid 3-(2-naphthyl)-D-alanine (D-Nal(2)). The D-Nal(2) substitution was found to be effective when incorporated in positions 3 and 6. The most potent analogue containing two D-Nal(2) residues was [N-Ac-Pro,D-pF-Phe,D-Nal(2)]LH-RH (ED50 = 2.2 micrograms, rat antiovulatory assay, propylene glycol-saline vehicle). This analogue also demonstrates that the N-Ac-Pro substitution is as effective as the more costly N-Ac-delta-Pro modification. Analogues containing D-Nal(2) in combination with the hydrophilic D-Arg residue in position 6 were prepared. Neither N-Ac-Pro at position 1 nor D-Nal(2) at position 3 was effective in combination with D-Arg. N-Ac-D-Nal(2) at position 1 gave a highly potent antagonist ([N-Ac-D-Nal(2),D-pF-Phe,D-Trp,D-Arg]LH-RH; ED50 = 2.4 micrograms) that exhibited a prolonged duration of action (ED50 = 9.0 micrograms, corn oil vehicle, dosing on diestrus II).

Potent gonadotropin releasing hormone antagonists with low histamine-releasing activity.

The incorporation of Arg residues into position 6 of gonadotropin releasing hormone antagonists had resulted in compounds with increased in vivo potency but also made these analogues potent mast cell degranulators. We have focused on the substitution of position 8 by hArg(R)2 (NG,NG'-dialkylhomoarginine) substitutions, based on the hypotheses that the Arg-Pro sequence is of major importance for this side effect and that shielding of the charge may be an effective way to block degranulation. Analogues in four series were evaluated: (A) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal-(3)3,6,Arg5,hArg(R)2(8),D-+ ++Ala10]GnRH, (B) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(R)2(5,8),D-Ala10 ]-GnRH, (C) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(R)2(8),D-Ala10]G nRH, (D) [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-hArg(R)2(6),hArg(R)2( 8),D-Ala10]GnRH. Although substitution by hArg(Et)2, hArg(Bu), hArg(CH2)3, and hArg(CH2CF3)2 was tested, in each series the hArg(Et)2 residue was superior. Two compounds were considered for clinical evaluation: [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,6,hArg(Et)2(8),D-Ala10] GnRH and [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Pal(3)3,D-hArg(Et)2(6),hArg(Et) 2(8),D- Ala10]GnRH (ganirelix acetate). These compounds had high potency for ovulation suppression and low histamine-releasing potency in vitro (ED50 = 0.6, 0.29 microgram/rat and EC50 = 196, 13 micrograms/mL, respectively). Ganirelix is currently in Phase II clinical trials and appears to be the most potent GnRH antagonist tested in humans (based upon ED50 for 24-h suppression of testosterone levels).

Potent, long-acting luteinizing hormone-releasing hormone antagonists containing new synthetic amino acids: N,N'-dialkyl-D-homoarginines.

A new series of unnatural amino acids has been prepared and incorporated into antagonistic analogues of luteinizing hormone-releasing hormone (LH-RH), on the basis of the hypothesis that stabilization of a proposed phospholipid membrane interaction might yield analogues with high potency and a prolonged duration of action. Thus a series of NG,NG'-dialkyl-D-homoarginine analogues [H-D-hArg(R2)-OH; R = Me, Et, Pr, i-Pr, Bu, hexyl, cyclohexyl, (Et, Me2NPr)] was conveniently prepared by semisynthesis from D-Lys using the appropriate dialkylcarbodiimide. A number of the analogues that were prepared by using these new amino acid analogues exhibited very high potency and a prolonged duration of action. One of the most potent members of the series, [N-Ac-D-Nal(2)1,D-pCl-Phe2,D-Trp3,D-hArg(Et2)6,D-Ala10 ]LH-RH (detirelix), had an ED50 of 0.7 microgram in the rat antiovulatory assay when administered at noon on proestrus and only 2.5 micrograms when administered 24 h earlier, at noon on diestrus II. This antagonist is undergoing detailed biological and clinical evaluation.

Synthesis of a novel class of heteroaromatic amino acids and their use in the preparation of analogues of luteinizing hormone-releasing hormone.

A novel class of heterocyclic aromatic amino acids based on the 3-(2-benzimidazolyl)alanine system has been generated by chiral synthesis from D- or L-aspartic acid. The use of variously substituted o-phenylenediamines for condensation with the beta-carboxyl function of alpha-benzyl N-(benzyloxycarbonyl)-D-aspartate has led to a series of amino acids of graded hydrophobicity with a steric bulk similar to that of tryptophan. In a similar fashion, we have prepared 3-(2-benzothiazolyl)-D-alanine from o-aminothiophenol and 3-(2-benzoxazolyl)-D-alanine from o-aminophenol. Incorporation of these amino acids into the 6-position of luteinizing hormone-releasing hormone (LH-RH) led to a series of very potent agonist analogues (up to 160 times LH-RH potency), active in doses ranging from 0.1 to 0.5 microgram by twice daily injection in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds.

Synthesis and biological activity of some very hydrophobic superagonist analogues of luteinizing hormone-releasing hormone.

The effect of increased hydrophobicity at position 6 of luteinizing hormone-releasing hormone (LH-RH) has been investigated by the incorporation of a series of 15 very hydrophobic, unnatural D-amino acids at this position. The unnatural amino acids studied can be considered analogues of phenylalanine with carbocyclic aromatic side chains consisting of substituted phenyl (e.g., 2,4,6-trimethylphenyl, p-biphenyl) or polycyclic aromatic (e.g., naphthalene, anthracene) units. When enzymatic resolution (subtilisin Carlsberg) of the most hydrophobic amino acids failed, the racemic amino acids were incorporated, and the diastereomeric LH-RH analogues were resolved by preparative high-performance liquid chromatography. The analogues were synthesized by the solid-phase technique. All of the synthetic compounds were very potent LH-RH superagonists, but [6-(3-(2-naphthyl)-D-alanine)]LH-RH, [6-(3-(2-naphthyl)-D-alanine), 7-(N alpha-methylleucine)]LH-RH and [6-(3-(2,4,6-trimethylphenyl)-D-alanine)]LH-RH appear to be among the most potent LH-RH agonist analogues yet reported when tested in a rat estrus cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds [ED50 approximately 7 x 10(-8) g; twice daily in saline]. These analogues are twice as potent as [D-Trp6,ProNHEt9]LH-RH in this assay system (i.e., approximately 200 times the potency of LH-RH).

Biochemical significance of the hard and soft acids and bases principle.

The hard and soft acids and bases (HSAB) principle, which states that hard acids bind preferentially to hard bases and soft acids to soft bases, may serve to assess specific chemico-biological interactions. As living systems are composed mainly of "hard" elements, molecular events taking place within the cell are dominated by "hard-hard interactions". On this premise, it becomes likely that extraneous "soft" agents are particularly injurious to life. In the HSAB context a selected number of variegated phenomena are briefly discussed qualitatively; these include biocidal actions, heavy metal poisoning, chemical carcinogenesis, some enzymic reactions, and nucleic acid complexations. Although the HSAB principle cannot be used as a tool for mechanistic explanations of biochemical processes, it may provide clues to likely target molecules and the loci of action.

Diffusion-weighted and conventional magnetic resonance imaging in cerebral cryptococcoma.

A case of cryptococcoma involving the right cerebral hemisphere is reported. The diffusion-weighted image shows hypointensity in the central cavity of the cryptococcoma, while apparent diffusion coefficient maps show hyperintensity. The imaging features of an intracerebral cryptococcoma mimic that of a central necrotic brain tumor, rather than a pyogenic brain abscess.

Bose-Einstein condensates with large number of vortices.

We show that as the number of vortices in a three dimensional Bose-Einstein condensate increases, the system reaches a "quantum Hall" regime where the density profile is a Gaussian in the xy plane and an inverted parabolic profile along z. The angular momentum of the system increases as the vortex lattice shrinks. However, Coriolis force prevents the unit cell of the vortex lattice from shrinking beyond a minimum size. Although the recent MIT experiment is not exactly in the quantum Hall regime, it is close enough for the present results to be used as a guide. The quantum Hall regime can be easily reached by moderate changes of the current experimental parameters.

Silane/iodine-based cleavage of esters and ethers under neutral conditions.

New, efficient cleavage of carboxylic esters with iodotrimethylsilane or a mixture of phenyltrimethylsilane and iodine is described. Essentially neutral conditions can be maintained throughout the reactions. Ethers can be dealkylated by the latter method in high yields. The mechanism of the cleavage reactions is considered to include six-membered ring homopolar transition states.

Endolymphatic hydrops in animal experiments. A confirmation of mechanical and immunological methods of inducement.

The etiology underlying endolymphatic hydrops is scarcely understood. It is generally accepted, however, that the primary cause of endolymphatic hydrops is the malfunction and malabsorption of the endolymphatic sac. This has already been proven by animal experiments as well as by histopathological studies of human temporal bone. In this study, we attempted to induce endolymphatic hydrops by utilizing both mechanical and immunological methods. An obliterative procedure was performed on the endolymphatic sac and duct of 14 guinea pigs, 12 of which showed extensive endolymphatic hydrops after a variable period of time. The immunological method employed was to inject the antigen horseradish peroxidase into the endolymphatic sac of 22 guinea pigs that had been systemically sensitized to this antigen. Endolymphatic hydrops was induced in 11 of these subjects. Thus, this study lends further support to the fact that endolymphatic hydrops is caused by malfunction of the endolymphatic sac, resulting from either mechanical obliteration or immunological reaction.

Subacute mandibular and hypoglossal nerve denervation causing oedema of the masticator space and tongue.

We report the MRI of five patients with denervation oedema in the head and neck. Four had denervation oedema in one masticator space caused by a skull-base tumour invading the ipsilateral foramen ovale. Another case had denervation oedema confined to the half of the tongue ipsilateral to oral reconstruction surgery which involved mandibulectomy, free flap repair and wide excision of a buccal mucosal carcinoma. Inversion-recovery and/or T2-weighted spin-echo images showed increased signal in the affected areas. Contrast-enhanced T1-weighted images revealed enhancement of the muscles. There was no evidence of tumour or infection in the masticator space or tongue. It is important to differentiate denervation oedema from other disease processes causing high signal on T2-weighted images, such as tumour infiltration and soft-tissue infection.

Hydrophobic, aza-glycine analogues of luteinizing hormone-releasing hormone.

The effect of combination of the hydrophilic aza-Gly substitution (NHNHCO) at position 10 with hydrophobic, unnatural D-amino acids in position 6 on the potency of luteinizing hormone-releasing hormone (LH-RH) analogues has been investigated. Previously the aza-Gly residue was shown to provide protection from enzymatic cleavage and lead to potency increases in a less hydrophobic series. The compounds were prepared by coupling of the corresponding nonapeptide acids with semicarbazide hydrochloride by the N,N'-dicyclohexylcarbodiimide/1-hydroxybenzotriazole procedure. The required nonapeptide acids were prepared by the solid phase method on chloromethyl-polystyrene resin using HF/anisole deprotection. The products were purified by preparative reversed-phase high-performance liquid chromatography. The analogues were tested in a rat estrous cyclicity suppression assay designed to show the paradoxical antifertility effects of these compounds. The potencies of [6-(3-benzimidazol-2-yl)-D-alanine), 10-aza-glycine] LH-RH and [6-(3-(5,6-dimethylbenzimidazol-2-yl)-D-alanine), 10-aza-glycine] LH-RH are 40 and 190 times that of LH-RH respectively. The most active compound in this series is [6-(3-(2-naphthyl)-D-alanine), 10-aza-glycine] LH-RH with a potency 230 times that of LH-RH. This compound is 2.3 times as potent as the standard ([D-Trp6, Pro9-NHEt] LH-RH) and appears to be the most potent LH-RH agonist reported.

Clinical observations of virologically confirmed dengue fever in the 1987 outbreak in southern Taiwan.

Fifty-nine virologically confirmed cases of dengue fever were clinically studied during the 1987 outbreak in southern Taiwan. Viral isolation and serologic studies indicated that type 1 dengue was the cause. Dengue fever has not been on the island of Taiwan for 42 years and nearly all the population under 42 years of age is susceptible. Most patients under age 42 experience primary infection while those over 42 years old experience secondary infection. The majority of 59 cases studied were females in the 21-30-year age group. Classic signs and symptoms ere fever, headache, muscle pain, joint pain, nausea and vomiting, and skin rash. Approximately 80% of the patients had leukopenia (less than 5,000/mm3) and thrombocytopenia (less than 50,000/mm3) and 90% experienced mild to moderate elevation of serum glutamic oxaloacetic transaminase. Hemorrhagic manifestations occurred in 25.4% of patients. No patients under observation in this study developed hypotension or died.

Hypaque and steroids in the treatment of sudden sensorineural hearing loss.

While the origins of sudden sensorineural hearing loss remain unproven and treatment empirical, the most appropriate therapy remains a matter of controversy. In this paper we have analysed the current forms of treatment, i.e. diatrizoate meglumine, steroids and a vasodilator. The results suggest that although several related factors were shown to indicate a good prognosis regardless of the therapy, none of the currently available regimens produces consistently better results than the spontaneous recovery rate of 65% reported by Mattox & Simmons.