Infection by CagA-Positive Helicobacter pylori Strains and Bone Fragility: A Prospective Cohort Study

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population-based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene-A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA-positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti-CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA-positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23–12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27–2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA-positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Urinary testosterone as a marker of risk of recurrence in operable breast cancer

Summary We investigated the role of urinary testosterone levels as a marker of risk of recurrent disease in 113 operable breast cancer patients (70 premenopausal, 43 postmenopausal). Twenty-four-hour urine collections for testosterone measurement were obtained before surgical treatment, between 20–40 days thereafter, and then every 6 months for 5 years. The cutoff values to separate high testosterone (A+) from normal testosterone (A–) were 8.0µg/24h in premenopause and 4.9µg/24h in postmenopause. Urinary testosterone levels were considered high when they exceeded the cutoff value in at least 2 of the first 3 measurements (pretreatment, post-treatment, 6 months) of each patient. According to the aforementioned criterion, 33 patients (29.2%) had high testosterone levels, which were associated to axillary node involvement in 16 patients. Thirteen of the latter relapsed during the 5-year follow-up period (5/7 in premenopause, 8/9 in postmenopause). Relapse-free survival (RFS) curves were drawn only for node-positive patients owning to the small number of recurrences observed in the node-negative group. In premenopausal node-positive patients, RFS was significantly different for patients presenting high and normal urinary testosterone levels (77% vs 28%, respectively; logrank test, p< 0.006). In postmenopausal node-positive patients, RFS was also different between the two groups (54% vs 11% in high and normal excretors, respectively) but the difference was not statistically significant. The present findings suggest that urinary testosterone is a prognostic indicator of early breast cancer recurrence in node-positive patients.     

Variation in smoking-related lung cancer risk factors by cell type among men in Argentina: a case-control study

A high mortality rate for lung cancer (62.7 per 100,000) is found in Rosario, Argentina. To investigate the reasons for this high rate, a case-control study was carried out among 215 male cases with histologically confirmed lung cancer and 433 hospitalized controls for conditions unrelated to tobacco consumption. Odds ratios (OR) of squamous cell (SQ), adenocarcinoma (AD), and small cell (SM) carcinoma of the lung associated with different characteristics of the smoking habit were quantified. Ninety-eight percent of the cases had smoked regularly. Smokers were significantly younger at diagnosis than ex-smokers (P<0.0001), a pattern consistent for all cell types. The ORs for the heaviest cf the lowest consumption categories were 15.3 for SQ, 11.6 for AD, and 11.6 for all lung cancer (P<0.0001). Risks associated with the use of unfiltered cigarettes were three to five times higher than those for filtered cigarettes, depending on cell types. For ex-smokers, risks after 10 years of nonsmoking were about 12 times lower than those of current smokers (P<0.001). To halt further increases in lung cancer, preventive measures in Argentina should be directed primarily towards smoking control.Ms Pezzotto and Drs Bay, Morini, and Poletto are with the Institute of Immunology, School of Medicine, National University of Rosario, Argentina. Dr Mahuad is with Hospital Italiano Rosario, Argentina. Address correspondence to Ms Pezzotto, Inst. Inmunologia, Facultad de Medicina, Santa Fe 3100, 2000 Rosario, Argentina.     

Prospective multicenter study on the clinical utility of ca-72.4 in postmenopausal patients with pelvic mass

The study objective was to evaluate the sensitivity and specificity as well as the positive predictive value and negative predictive value of CA 72.4 and CA 125 determination, separately and in combination, for diagnosing ovarian tumors in post-menopausal women with pelvic mass. The 299 patients recruited in this study underwent gynecological examination, plasma determination of CA 72.4 and CA 125, and laparotomy with histological definition of pelvic mass. CA 72.4 assay values were under 3.9 U/ml in 194 cases (70.8%); values ranged from 3.9 to 4.5 U/ml in 7 cases (2.5%) and were greater than 4.5 U/ml in 73 cases (26.6%). CA 72.4 assay was positive (>4.5 U/ml) in 56 cases (57.1%) of malignant ovarian pathology, in 4 cases (25%) of malignant extra-ovarian pathology as well as in 9 cases (7.1%) of benign ovarian pathology and in 4 cases (11.8%) of benign extra-ovarian pathology. With a cut-off at 3.9 U/ml, CA 72.4 showed a specificity of 91.3% and a sensitivity of 62.2%, whereas with a cut-off at 4.5 U/ml specificity was 92.9% and sensitivity 57.1%. Results of CA 125 assay for diagnosing a pelvic neoplasia (ovarian or extra-ovarian), showed a specificity of 85.3% and sensitivity of 68.8%. The agreement of the two markers (CA 125 and CA 72.4) as negative or positive shows a specificity of 77% and a sensitivity of 84.7% for ovarian cancer and a specificity of 73.5% and sensitivity of 75% for the diagnosis of pelvic neoplasias.     

Functional analysis of T lymphocytes infiltrating the dermis and epidermis of post-burn hypertrophic scar tissues

The cytokine profile of T cell clones (TCC) from the dermis and epidermis of burn patients with hypertrophic scars (HS) in active (AHS) and remission phases (RHS) was determined in this study. We found that AHS tissues are heavily infiltrated by Type 0-Type 1 polarized CD3+ lymphocytes producing high IFN-gamma and low IL-4 levels. Analysis of their surface marker phenotype showed that the high IFN-gamma production was shared equally between the CD4+ TCRalpha/beta and CD8+ TCRalpha/beta clones. The profile of TCC from RHS tissues revealed pronounced infiltration of Type 0-Type 1 polarized lymphocytes with an even more evident Type 1 profile. However, the levels of IFN-gamma produced by RHS-derived TCC were 4-6 times lower than those produced by AHS-derived TCC. These data show that high levels of IFN-gamma produced by Type 0-Type 1 lymphocytes infiltrating HS are a feature of AHS, whereas reduction of this ability to produce high levels of IFN-gamma, though without a shift towards a Type 0-Type 2 phenotype through an increase in IL-4, is characteristic of RHS.     

Aqueous solubility and dissolution rate does not adequately predict in vivo performance: a probe utilizing some N-acyloxymethyl phenytoin prodrugs.

Some physicochemical properties of N-acyloxyalkyl prodrugs of phenytoin were reported previously.(1,2) It was shown that despite their lower aqueous solubilities relative to phenytoin, these lower-melting prodrugs with apparently disrupted crystalline structures gave either comparable or enhanced in vitro solubility and dissolution rate in simulated intestinal media made up of bile salts and lecithin (SIBLM).(2) The current objective was to compare the in vivo behavior of two of these prodrugs to phenytoin in dogs and attempt to correlate the in vitro behavior to their in vivo behavior. The oral bioavailability of phenytoin after administration of phenytoin (1) and the selected prodrugs, 3-pentanoyloxymethyl 5, 5-diphenylhydantoin (2) and 3-octanoyloxymethyl 5, 5-diphenylhydantoin (3), in fed and fasted beagle dogs were compared to intravenously administered phenytoin. Phenytoin and its prodrugs showed improvement in fed-state phenytoin bioavailability relative to the fasted state indicating that food enhanced the delivery of phenytoin from phenytoin and its prodrugs. The increased bioavailability in the fed state may be due to stimulation of bile release by food and, for the prodrugs, possible catalysis of their dissolution by lipases.(3) In both, fasted and fed states, prodrugs 2 and 3 gave higher AUC values of phenytoin than the parent compound. The enhanced bioavailability of phenytoin after oral administration were more obvious in fed dogs. Although enhanced, AUC values of phenytoin from the prodrugs relative to phenytoin were not statistically different (at 95% confidence level) in fasted state, but were different in fed state. Although the aqueous solubilities and dissolution of both prodrugs were lower than phenytoin, dissolution of 2 and 3 was equivalent and greater, respectively, relative to phenytoin in SIBLM. As expected, the in vivo behavior correlated better with the in vitro SIBLM dissolution behavior. These results indicate that aqueous solubility per se does not adequately predict in vivo behavior.     

A novel prodrug approach for tertiary amines. 3. In vivo evaluation of two N-phosphonooxymethyl prodrugs in rats and dogs.

N-phosphonooxymethyl derivatives of tertiary amine containing drugs have been identified as a novel prodrug approach for improving aqueous solubility. The in vivo reversion of two prodrugs to the corresponding parent compounds following iv and im administration to rats and dogs was investigated. Equimolar doses of parent drugs (loxapine or cinnarizine) and the corresponding prodrugs were each administered via a rapid iv infusion to rats and dogs. Equimolar doses of loxapine and its prodrug were each administered im to rats only. Blood samples were collected over 12 h, and plasma was assayed for both parent drug and intact prodrug by HPLC. Comparison of the plasma AUC for the parent drugs following administration of the parent drugs and prodrugs allowed estimation of the apparent bioavailability of parent drug from prodrug dosing. Plasma levels of the prodrugs fell below the limit of detection 5 min after iv infusion with an approximate half-life of 1 min. The mean AUCs following iv and im dosing of parent drugs were not statistically different from the parent drug AUCs obtained after prodrug dosing. The results are consistent with rapid and quantitative prodrug to parent drug reversion following administration of the phosphonooxymethyl prodrugs to the rats and dogs. This information, together with previous studies on the synthesis and physicochemical evaluation of the prodrugs, suggests that this novel prodrug strategy is a very promising approach for overcoming solubility limitations seen with many tertiary amine containing drugs at physiological pH values.     

Cardiovascular disease and the kidney: an epidemiologic overview

Essential hypertension and congestive heart failure (CHF) are examples of cardiovascular disorders that may cause renal failure, although sometimes a primary kidney defect may lead to hypertension. Renal damage in malignant and severe hypertension is dramatic, extensive, and rapidly progressive, although nephrosclerotic damage, which develops slowly and appears late in hypertension, is a rare cause of morbidity because mild to moderate hypertension is now the most common form. However, the incidence of end-stage renal failure associated with hypertension is markedly increasing, perhaps because of underdiagnosis of renal damage in hypertension, insufficient lowering of blood pressure in clinical practice, or inability of antihypertensive drugs to lower blood pressure sufficiently to preserve the kidney, a goal that may need specific drugs that act, for example, on the renin-angiotensin system (RAS). Renal vasoconstriction and reduction of renal blood flow are early companions of cardiac insufficiency and may be involved in the development of sodium and water retention. Profound reduction of cardiac output and arterial hypotension in severe CHF may lead to acute renal failure. Chronic renal insufficiency is associated with elevated cardiovascular morbidity and mortality. Renal impairment is often caused by a disease process, such as diabetes mellitus, that involves both the cardiovascular system and the kidney. When the primary disease is renal, possible reasons for an association include renal-dependent increase in blood pressure, activation of the RAS, overproduction of other vasoactive substances of renal origin, and electrolyte imbalances leading to fatal arrhythmias.     

The Effect of Conformation on Membrane Permeability of an Acyloxyalkoxy-linked Cyclic Prodrug of a Model Hexapeptide

Purpose. To determine the different conformations of the acyloxyalkoxy-linked cyclic prodrug 1 of the model hexapeptide 2 in solution and to investigate the relationship between these solution conformations and the cellular permeability characteristics of this prodrug. Methods. Two-dimensional Homonuclear Hartmann-Hahn spectroscopy, Rotating-Frame Overhouser effect spectroscopy, circular dichroism and molecular dynamics simulations were used to find the solution conformers of cyclic prodrug 1. Results. Our spectroscopic findings suggest that cyclic prodrug 1 exhibits a major and a minor conformer in solution. The major conformer appears to have a well-defined secondary structure, which involves a -turn and 4 1 intramolecular hydrogen bond, creating a compact structure with a reduced average hydrodynamic radius compared to the model hexapeptide 2. Conclusions. The increased ability of cyclic prodrug 1 to permeate membranes compared to the model hexapeptide 2 could be due to reduction in the average hydrodynamic radius of the molecule facilitating paracellular flux and/or the reduction in the hydrogen bonding potential facilitating transcellular flux.     

Surgery for colorectal cancer guided by radiodetecting probe. Clinical evaluation using monoclonal antibody B72.3.

Radioactive antibodies that react with tumour-associated antigens to "tag" antigen-positive tumour cell deposits were given to 20 patients with primary or recurrent colorectal cancer. The tumour associated antigen TAG 72-specific monoclonal antibody B72.3 labelled with 125-Iodine was used, and the radioactivity in the tumour was sought during operation with a hand-held gamma detecting probe. Tumour was detected by the probe in 7 of 15 patients with primary cancer, with a mean tumour: normal tissue ratio of 3.9, and in 4 of 5 patients with recurrent disease, with a mean tumour: normal tissue ratio of 2.0. Immunohistochemical analysis of surgical specimens confirmed the results of the intraoperative detection. The incidence of TAG 72-positive tumours (11/20, 55%), detected by immunohistochemistry, was lower than the 80% in the other series, possibly because of sampling errors or because the cases studied were uncomplicated with small primary tumours. Results obtained with the probe were instrumental in modifying the operation in two of the four "positive" patients with recurrences, allowing the removal of tumour masses that would otherwise have been overlooked.