Lactobacillus johnsonii La1 attenuates Helicobacter pylori-associated gastritis and reduces levels of proinflammatory chemokines in C57BL/6 mice

In clinical settings, Lactobacillus johnsonii La1 administration has been reported to have a favorable effect on Helicobacter pylori-associated gastritis, although the mechanism remains unclear. We administered, continuously through the water supply, live La1 to H. pylori-infected C57BL/6 mice and followed colonization, the development of H. pylori-associated gastritis in the lamina propria, and the levels of proinflammatory chemokines macrophage inflammatory protein 2 (MIP-2) and keratinocyte-derived cytokine (KC) in the serum and gastric tissue over a period of 3 months. We documented a significant attenuation in both lymphocytic (P=0.038) and neutrophilic (P=0.003) inflammatory infiltration in the lamina propria as well as in the circulating levels of anti-H. pylori immunoglobulin G antibodies (P=0.003), although we did not observe a suppressive effect of La1 on H. pylori colonizing numbers. Other lactobacilli, such as L. amylovorus DCE 471 and L. acidophilus IBB 801, did not attenuate H. pylori-associated gastritis to the same extent. MIP-2 serum levels were distinctly reduced during the early stages of H. pylori infection in the La1-treated animals, as were gastric mucosal levels of MIP-2 and KC. Finally, we also observed a significant reduction (P=0.046) in H. pylori-induced interleukin-8 secretion by human adenocarcinoma AGS cells in vitro in the presence of neutralized (pH 6.8) La1 spent culture supernatants, without concomitant loss of H. pylori viability. These observations suggest that during the early infection stages, administration of La1 can attenuate H. pylori-induced gastritis in vivo, possibly by reducing proinflammatory chemotactic signals responsible for the recruitment of lymphocytes and neutrophils in the lamina propria.     

Weekly Cisplatin induction chemotherapy in high-risk cervical-cancer patients with bulky tumor - a phase-ii study

In this study we evaluated efficacy and toxicity of a neoadjuvant chemotherapy regimen before radiation therapy or surgery in high-risk cevical cancer patients. Between January 1988 and July 1993, 37 out of 40 consecutive patients with bulky cervical carcinoma (>40 mm) received chemotherapy consisting of six (range 4-9) weekly courses of cisplatin (1 mg/kg), followed by radical surgery and/or radiotherapy. Thirty-six patients completed the planned sequence of treatment. Overall response rate was 65% after induction chemotherapy (complete 0% and partial 65%) and 73% (complete 57% and partial 16%) after definitive treatment. After a median follow-up of 23 (range 4-61) months the median duration of response was 29, 19 and 11 months for complete partial and non-responders respectively. Toxicities from induction chemotherapy were mild to moderate, reversible and tolerable and did not affect the subsequent application of the definitive treatment. The proposed cisplatin neoadjuvant chemotherapy regimen gave positive results in a good number of cases with low toxicity and without interfering with the definitive radio-surgical treatment of this group of high-risk patients. The number of cisplatin courses for best effect remains to be established.     

Indications for free soft-tissue flap transfer to the upper limb and the role of alternative procedures.

The aim of soft-tissue replacement to the upper limb is twofold. The first is to restore as much functional tissue as possible, and the second is to achieve this in the shortest possible time. Of lesser consideration is the desire to achieve a good cosmetic result. In any given clinical situation, no single reconstructive procedure will maximally satisfy these aims. The personal philosophy expounded in this article exposes disadvantages as well as advantages of the many operations available to the upper limb surgeon. Each clinical problem is different from any other, so no blueprint or computer program is available to help the surgeon select an operation. It takes judgment based on knowledge and experience on the part of the surgeon to make the most appropriate selection. During the last two decades, free vascularized transfers have superseded some of the conventional pedicled flap operations, and this has been acclaimed quite rightly as a significant advance. By the same token, indications for the "older" techniques should remain in the armamentarium of the surgeon because in certain situations these may yet offer the best solution. A spin-off of the microsurgical era is the reverse forearm island flap, and in my view, this has become a new "star" in the recent era. It is fitting that it should have prominence in the reconstructive arena because it straddles the border between microsurgical and nonmicrosurgical techniques. It is a modern reminder that there are many ways to treat defects of the upper limb and that the responsibility of the surgeon is to be both imaginative and wise in securing the best possible result for the patient.     

Human kallikrein 6 (hK6): a new potential serum biomarker for diagnosis and prognosis of ovarian carcinoma.

PURPOSE: The discovery of new ovarian cancer biomarkers that are suitable for early disease diagnosis and prognosis may ultimately lead to improved patient management and outcomes. PATIENTS AND METHODS: We measured, by immunoassay, human kallikrein 6 (hK6) concentration in serum of 97 apparently healthy women, 141 women with benign abdominal diseases, and 146 women with histologically proven primary ovarian carcinoma. We then calculated the diagnostic sensitivity and specificity of this test and examined the association of serum hK6 concentration with various clinicopathologic variables and patient survival. RESULTS: Serum hK6 concentration between normal and benign disease patients was not different (mean, 2.9 and 3.1 micro g/L, respectively). However, hK6 in presurgical serum of ovarian cancer patients was highly elevated (mean, 6.8 micro g/L; P <.001). Serum hK6 decreased after surgery (to a mean of 3.9 micro g/L) in 68% of patients. The diagnostic sensitivity of serum hK6 at 90% and 95% specificity is 52% and 47%, respectively, in the whole patient population. For early stage disease (stage I or II), sensitivity is approximately 21% to 26%. When combined with CA-125, at 90% specificity, sensitivity increases to 72% (for all patients) and to 42% in stage I or II disease. Serum hK6 concentration correlates moderately with CA-125 and is higher in patients with late-stage, higher-grade disease and in patients with serous histotype. Preoperative serum hK6 concentration is a powerful predictor of disease-free and overall survival in both univariate and multivariate analyses. CONCLUSIONS: Serum hK6 concentration seems to be a new biomarker for ovarian carcinoma and may have value for disease diagnosis and prognosis.     

Downregulation of human kallikrein 10 (KLK10/NES1) by CpG island hypermethylation in breast, ovarian and prostate cancers.

OBJECTIVE: The human kallikrein 10 (KLK10)/normal epithelial cell-specific-1 (NES1) gene is highly expressed in normal mammary, ovary and prostate cells, but its expression is dramatically decreased in cancer cell lines. Recently, it has been shown that CpG island hypermethylation of the KLK10 gene is responsible for the tumor-specific loss of KLK10 gene expression in certain breast cancer cell lines. METHOD: We examined the role of CpG island hypermethylation in the tumor-specific loss of KLK10 expression in breast, ovarian and prostate cancers. We treated cells with the demethylating agent 5-aza-2'-deoxycytidine (dC) and monitored changes in KLK10 mRNA by RT-PCR and secreted hK10 protein expression by ELISA. The following cell lines were used: MDA-MB-231, MDA-MB-468, MCF-7, ZR-75-1, T-47D and BT-474 (breast); BG-1, MDAH-2774, HTB-75, HTB-161, PA-1 and ES-2 (ovary), and LNCaP and PC-3 (prostate). RESULTS: Upregulation of KLK10 mRNA levels, which was accompanied by an increase in secreted hK10 protein concentration, was observed for a subset of breast, ovarian, and prostate tumor cell lines after 5-aza-2'-dC. Genomic sequencing of sodium-bisulfite-treated DNA demonstrated that CpG sites within the KLK10 gene exon 3 were highly methylated. Hypermethylation of exon 3 CpG regions was also detected in primary ovarian cancers. CONCLUSION: These data suggest that CpG island hypermethylation plays an important role in the downregulation of kallikrein 10 mRNA and protein expression, but it cannot explain the pattern of expression of this gene in all cell lines or tissue tested.     

Coronary and peripheral blood flow changes following biventricular pacing and their relation to heart failure improvement.

AIMS: To study the effect of cardiac resynchronization therapy (CRT) on coronary and peripheral arterial circulation and to assess whether their changes are related to the improvement in patients' functional capacity and prognostically important biochemical markers. METHODS AND RESULTS: Twenty-five patients were studied (New York Heart Association classes III and IV, left ventricular ejection fraction <35%, QRS>120 ms, mean age 66 +/- 2.1 years). Coronary blood flow (CBF), forearm blood flow (FBF), and their reserve were measured by transoesophageal echocardiography (in cm/s) and venous occlusion plethysmography (in mL/100 mL/min) at baseline and following 3 months of CRT. N-terminal-pro-brain natriuretic peptide (Nt-pro-BNP) and serum adhesion molecules, sICAM-1 and sVCAM-1 levels were also assessed. CRT induced a non-significant increase in resting CBF (baseline vs. CRT: 52.1 +/- 5.5 vs. 58.2 +/- 3.6, P: NS), whereas hyperaemic CBF was increased by CRT (baseline vs. CRT: 67.8 +/- 6.8 vs. 79.8 +/- 6.2, P < 0.05). Significant increases were observed in resting FBF (baseline vs. CRT: 1.6 +/- 0.2 vs. 2.6 +/- 0.2, P < 0.05) and hyperaemic FBF (baseline vs. CRT: 2.1 +/- 0.2 vs. 3.2 +/- 0.3, P < 0.05). The per cent difference in hyperaemic FBF was related to the per cent change in Nt-pro-BNP (r = -0.71, P < 0.05) and the per cent improvement in exercise duration (r = 0.80, P < 0.05). CONCLUSION: CRT induces favourable changes in coronary and peripheral arterial function. Changes in peripheral blood flow are related to patients' improvement and may be prognostically significant.