An assessment of the developmental toxicity of inorganic arsenic

A critical analysis of the literature base regarding the reproductive and developmental toxicity of arsenic compounds, with emphasis on inorganic arsenicals, was conducted. The analysis was stimulated by the great number of papers that have purported to have shown an association between exposure of pregnant laboratory animals to arsenic compounds and the occurrence of offspring with cranial neural tube defects, particularly exencephaly. For the most part, the literature reports of arsenic developmental toxicity in experimental animals are inadequate for human risk assessment purposes. Despite the shortcomings of the experimental database, several conclusions are readily apparent when the animal studies are viewed collectively. First, cranial neural tube defects are induced in rodents only when arsenic exposure has occurred early in gestation (on Days 7 [hamster, mouse], 8 [mouse], or 9 [rat]). Second, arsenic exposures that cause cranial neural tube defects are single doses that are so high as to be lethal (or nearly so) to the pregnant animal. Third, the effective routes of exposure are by injection directly into the venous system or the peritoneal cavity; even massive oral exposures do not cause increases in the incidence of total gross malformations. Fourth, repetition of similar study designs employing exaggerated parenteral doses is the source of the large number of papers reporting neural tube defects associated with prenatal arsenic exposure. Fifth, in five repeated dose studies carried out following EPA Guidelines for assessing developmental toxicity, arsenic was not teratogenic in rats (AsIII, 101 micromol/kg/d, oral gavage; 101 micromol/m3, inhalation), mice (AsV, 338 micromol/kg/d, oral gavage; est. 402 micromol/kg/d, diet), or rabbits (AsV, 21 micromol/kg/d, oral gavage). Data regarding arsenic exposure and adverse outcomes of pregnancy in humans are limited to several ecologic epidemiology studies of drinking water, airborne dusts, and smelter environs. These studies failed to (1) obtain accurate measurements of maternal exposure during the critical period of organogenesis and (2) control for recognized confounders. The lone study that examined maternal arsenic exposure during pregnancy and the presence of neural tube defects in progeny failed to confirm a relationship between the two. It is concluded that under environmentally relevant exposure scenarios (e.g., 100 ppm in soil), inorganic arsenic is unlikely to pose a risk to pregnant women and their offspring.     

Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages

Nitric oxide (NO) plays an important role in resistance to Mycobacterium tuberculosis infection. Our aim was to determine whether inducible NO synthase (iNOS) expression and generation of reactive nitrogen intermediates (RNI) by alveolar macrophages (AM) are increased in patients infected with M. tuberculosis. NO levels in the exhaled air of 19 active pulmonary tuberculosis (TB) and 14 control subjects were measured using a chemiluminescence NO analyser. The expression of iNOS on AM was studied by labelling AM with anti-mac iNOS polyclonal antibody analysed with a flow cytometer. The spontaneous generation of RNI by cultured AM was also measured. Data are presented as mean+/-SEM. The level of NO in exhaled air was higher in patients with active TB (16.2+/-1.2 parts per billion (ppb)) compared to control subjects (6.5+/-0.9 ppb), p<0.0001. Exhaled NO decreased with anti-TB treatment. Compared to control subjects (29.0+/-4.5 fluorescence intensity (FI)), iNOS expression on AM was upregulated in TB patients (86.3+/-12.5 FI) p<0.001 and the capacity for spontaneous generation of nitrite was enhanced. Nitrite production was inhibited by N(G)-monomethyl-L-arginine (L-NMMA), a competitive inhibitor of iNOS. The expression of iNOS on AM was related to the concentration of exhaled NO (r=0.66, p<0.001) and the nitrite generation capacity of AM (r(s)=0.77, p<0.001). We conclude that the increase in exhaled nitric oxide observed in patients with active pulmonary tuberculosis is due to an upregulation of inhaled NO synthase expression in alveolar macrophages which have an enhanced capacity for nitric oxide production.     

Predictors of systemic embolism in patients with mitral stenosis. A prospective study

BACKGROUND: Most studies of the predictors of systemic embolism in patients with mitral stenosis have been retrospective. OBJECTIVE: To prospectively study factors associated with systemic embolism in mitral stenosis. DESIGN: Prospective cohort study. SETTING: University-affiliated medical institution with 3000 beds. PATIENTS: 534 consecutive patients with a mitral valve area of 2.0 cm2 or less; 132 patients were in sinus rhythm, and 402 were in atrial fibrillation. MEASUREMENTS: Nine clinical and 10 echocardiographic variables were assessed for prediction of systemic embolism over a mean (+/- SD) follow-up of 36.9 +/- 22.5 months. Diagnosis of systemic embolism was based on symptoms and signs (sudden onset of peripheral arterial ischemic or neurologic manifestations without prodromes) and on findings on computed tomography, angiography, and surgery. RESULTS: For patients in sinus rhythm, age (relative risk [RR], 1.12 [95% CI, 1.04 to 1.21]), the presence of a left atrial thrombus (RR, 37.1 [CI, 2.82 to 487.8]), mitral valve area (RR, 16.9 [CI, 1.53 to 187.0]), and the presence of significant aortic regurgitation (RR, 22.4 [CI, 2.72 to 184.8]) were positively associated with embolism. For patients in atrial fibrillation, previous embolism (RR, 3.11 [CI, 1.66 to 5.85]) was positively associated with embolism; percutaneous balloon mitral commissurotomy (RR, 0.37 [CI, 0.18 to 0.79]) was a negative predictor. CONCLUSIONS: It may be prudent to give anticoagulants not only to patients in atrial fibrillation and patients with previous systemic embolism but also to those showing a left atrial thrombus or significant aortic regurgitation on echocardiography. Early percutaneous balloon mitral commissurotomy may also help prevent systemic embolism in patients with mitral stenosis.     

Influence of antithyroid antibodies in euthyroid women on in vitro fertilization-embryo transfer outcome

The direct synthesis and subsequent rapid characterisation of multiple antigen peptides (MAPs) for use as immunogens has presented difficulties, partly because of the formation of incomplete or truncated peptide sequences during the synthetic procedure. Therefore, many researchers have resorted to ligation procedures for the synthesis of MAP constructs. This article describes a method to improve the yield of MAP constructs by direct synthesis methods, as well as a general procedure that enables easier characterisation of the synthetic products. In particular, during the synthesis of MAP constructs, a capping procedure was introduced after each amino acid coupling step, thus improving significantly the yield of the desired multi-dendritic peptidic immunogens. Through the use of this capping procedure, problems arising from the incomplete amino acid residue coupling at the point of synthesis were minimised, and any deletion peptides which formed could be eliminated more readily during the subsequent purification procedures. In addition, previous difficulties in purification and characterisation of MAP construct by, e.g. electrospray mass spectroscopy (ES-MS), often led to the multi-dendritic peptidic immunogens being used without full characterisation after dialysis and recovery of the product(s). This article describes an enzymatic (tryptic) digestion method with the MAP construct, followed by characterisation of the enzymatic digest by reversed phase high-performance liquid chromatography-ES-MS. With this method, fragments of the MAP construct cleaved at specific amino acid residue sites (e.g. lysine or arginine) within the sequence of the parent peptide can be readily determined and the kinetics of the digestion easily followed. This enzymatic digestion procedure thus provides a facile approach to confirm that all of the multi-dendritic arms of the purified MAP construct have been equivalently elongated during the peptide synthesis and that consequently the purified construct structure contains the correct peptide sequence.     

Prostate target volume variations during a course of radiotherapy

PURPOSE: The purpose of this study was to measure the mobility of the clinical target volume (CTV) in prostate radiotherapy with respect to the pelvic anatomy during a course of therapy. These data are needed to properly design the planning target volume (PTV). METHODS AND MATERIALS: Seventeen patients were studied. Each patient underwent computed tomography (CT) scanning for treatment planning purposes. Subsequently, three CT scans were obtained at approximately 2-week intervals during treatment. The prostate, seminal vesicles, bladder, and rectum were outlined on each CT study. The second through the fourth CT studies were aligned with the first study using a rigid body transformation based on the bony anatomy. The transformation was used to compute the center of mass position and bounding box of each organ in the subsequent studies relative to the first study. Differences in the bounding box limits and center of mass positions between the first and subsequent studies were tabulated and correlated with bladder and rectal volume and positional parameters. RESULTS: The mobility of the CTV was characterized by standard deviations of 0.09 cm (left-right), 0.36 cm (cranial-caudal), and 0.41cm (anterior-posterior). Prostate mobility was not significantly correlated with bladder volume. However, the mobility of both the prostate and seminal vesicles was very significantly correlated with rectal volume. Bladder and rectal volumes decreased between the pretreatment CT scan and the first on-treatment CT scan, but were constant for all on-treatment CT scans. CONCLUSION: Margins between the CTV and PTV based on the simple geometric requirement that a point on the edge of the CTV is enclosed by the PTV 95% of the time are 0.7 cm in the lateral and cranial-caudal directions, and 1.1 cm in the anterior-posterior direction. However, minimum dose to the CTV and avoidance of organs at risk are more important considerations when drawing beam apertures. More consistent methods for reproducing prostate position (e.g., empty rectum) and more sophisticated beam aperture optimization are needed to guarantee consistent coverage of the CTV while avoiding organs at risk.     

Survival of patients with advanced urothelial cancer treated with cisplatin-based chemotherapy

The aim of the present retrospective study was to assess long-term survival after cisplatin-based chemotherapy in 398 patients with advanced urothelial transitional cell carcinoma (TCC) treated at seven international oncological units. Various combinations of cisplatin, methotrexate, vinblastine (or vincristine) and doxorubicin were used. The complete response rate according to the WHO criteria was 17%. Partial responses were obtained in 42% of the patients. The overall cancer-related 2 year and 5 year survival rates were 21% and 11% respectively. Based on multivariate analyses, a good prognosis group could be identified comprising patients with a good performance status with disease confined to lymph nodes (14%) or patients with T4b disease only. These patients had a 28% 5 year survival rate, which, in part, has to be related to post-chemotherapy consolidation treatment in patients with pelvis-confined disease (radiotherapy, 26%; total cystectomy, 11%). Fifteen patients died of chemotherapy-related complications and in 16% of the patients toxicity led to discontinuation of treatment. Modern cisplatin-based chemotherapy leads to long-term survival and cure of selected patients with advanced urothelial transitional cancer. In routine clinical practice, chemotherapy should be offered to good prognosis patients; those presenting with a good performance status and a non-metastasising T4b tumour or with metastases confined to lymph nodes. Post-chemotherapy consolidation treatment by surgery or radiotherapy should always be considered. Such chemotherapy requires oncological expertise in order to avoid unnecessary toxicity.     

Use of gabapentin in pain management

There have been many proposed uses for gabapentin, including midscapular pain secondary to radiation myelopathy, RSD, neuropathic pain, postherpetic neuralgia, and migraine prophylaxis. However, the published reports consist of a small number of patients and limited data. Limited data provided in published case reports do not allow adequate evaluation of expected adverse effects or efficacy. It is unclear whether gabapentin is more effective for a specific type of pain and how gabapentin may compare with placebo or other therapeutic alternatives. Therefore, randomized, double-blind, placebo-controlled, prospective studies are warranted to further elucidate gabapentin uses beyond what is recommended by the Food and Drug Administration. Gabapentin should only be considered for pain management after well-established therapies have failed to produce desired outcomes.     

Basal cell adenocarcinoma of the salivary gland--a case report

A phenylene moiety in the chain of fatty acids was expected to impair metabolic degradation. Three phenoxy-containing [11C]carboxyl-labelled fatty acids were synthesized and evaluated in mice and an in vivo tissue distribution study. Of these three, 1[11C]-3-(p-dodecyloxyphenyl)propionic acid (C12C3) showed the most favourable uptake in the myocardium: 1.2% of the injected dose at 30 min p.i., vs. 0.6% for [11C]palmitate. The metabolic stability of C12C3 and [11C]palmitate was assessed by determining the amount of exhaled [11C]CO2 during a 30-min interval after injection. It was found that the phenoxy moiety in the gamma-position did not prevent the metabolic degradation of C12C3: After 30 min 20.7% of the injected dose was exhaled as [11C]CO2 vs. 12.7% for [11C]palmitate.     

Synthesis and inhibitory properties of a thiomethylmercuric sialic acid with application to the X-ray structure determination of 9-O-acetylsialic acid esterase from influenza C virus

2-alpha-Thiomethylmercuryl 9-acetamido-9-deoxy-sialoside was prepared and found to inhibit the 9-O-acetylsialic acid esterase from influenza C virus in a competitive manner with a Ki of 4.2 +/- 0.5 mM. The inhibitor is being used in the X-ray determination of the crystal structure of the esterase.