phoenixin(smim20), a gene coding for a novel reproductive ligand, is expressed in the brain of adult zebrafish.

Gonadotropin-releasing hormone (GnRH) is a highly conserved neuroendocrine decapeptide that is essential for the onset of puberty and the maintenance of the reproductive state. In addition to its role as hypothalamic releasing hormone, GnRH has multiple functions including modulator of neural activity within the nervous system and of resulting behaviors. These multiple functions are reflected by the existence of multiple isoforms. Despite its importance as a critical hypothalamic releasing hormone, the gnrh1 gene has been lost in zebrafish, and its reproductive function is not compensated for by other GnRH isoforms (GnRH2 and GnRH3), suggesting that, surprisingly, zebrafish do not use any of the GnRH peptides to control reproduction and fertility. Previously we proposed that Phoenixin/SMIM20, a novel peptide identified in mammals and the ligand for the orphan GPR173, is a potential candidate to control the initiation of sexual development and fertility in the zebrafish. Here we confirm the sequence of the zebrafish phoenixin/smim20 gene and by RT-PCR show that it is expressed early in development through adulthood. Subsequently we show that phoenixin/smim20 is expressed in the adult brain including the regions of the hypothalamus important in the control of fertility and reproduction.

Enzymatic scarification of Anacamptis morio (Orchidaceae) seed facilitates lignin degradation, water uptake and germination.

The seed coat of many species contains hydrophobic lignins, and in soil the action of microbial ligninases may contribute to release from dormancy. Laboratory use of ligninases to stimulate germination is promising because of the specific action on the seed coat, whereas chemical scarification agents may also corrode the embryo. We hypothesised that exposure of Anacamptis morio (Orchidaceae) seeds to fungal laccase would stimulate germination, and that the mechanism involves lignin degradation and increased imbibition. Germination capacity in vitro was quantified with 1 U filter-sterilised laccase added to agar medium following autoclaving, compared to a 10% bleach solution (standard bleach surface sterilisation/scarification method used in orchid seed sowing). Lignin degradation was quantified using an optical method (phloroglucinol-HCl staining) combined with image analysis, following experimental pre-treatments involving immersion in laccase solution, distilled water (negative control) or bleach (positive control). Water uptake after experimental treatments was quantified as the proportion of seeds exhibiting visible uptake of an aqueous fluorochrome under UV excitation. Laccase stimulated a doubling of germination in vitro with respect to bleach surface sterilisation/scarification alone, from 23.7 to 49.8% (P = 0.007). Laccase and bleach methods both significantly decreased the optical signal of phloroglucinol (for laccase, to 79.9 ± 1.3% of controls; anova: F = 10.333, P = 0.002). Laccase resulted in a modest but highly significant (P < 0.0001) increase in water uptake with respect to the control (11.7%; cf 99.4% for bleach). Laccase scarification can stimulate germination of A. morio through a mechanism of targeted seed coat degradation. The results demonstrate the potential of this relatively non-invasive enzymatic scarification technique.

Low glomerular filtration rate is a risk factor for ribavirin-associated anaemia in old patients with chronic hepatitis C.

Elderly patients with chronic hepatitis C have a reduced responsiveness to antiviral therapy with Peg-interferon and ribavirin. The dose reduction or the discontinuation of ribavirin due to the occurrence of anaemia is one of the most important causes for the low sustained viral response observed in older patients. We aimed to evaluate the relationship between baseline renal function and the early onset of ribavirin-associated anaemia in older (≥60 years) patients. Using data from 348 patients with chronic hepatitis C consecutively treated with peg-interferon plus ribavirin, we investigated which factors were associated with the occurrence of anaemia in elderly patients (≥60 years). Ribavirin-induced anaemia occurred in 40.5% of patients. Older patients showed a rate of anaemia significantly higher than younger patients (51.5% vs 36.3%; P = 0.009). Consequently, the rate of ribavirin dose reduction or discontinuation due to anaemia was 35.1% in older patients and 23.5% in younger patients (P = 0.029). A significantly higher proportion of older patients had a low baseline glomerular filtration rate (GFR) compared with younger patients (56.7% vs 27.1%; P < 0.001). At the multivariate regression analysis, low baseline GFR (<70 mL/min) was associated with an increased risk of ribavirin-associated anaemia only in the older patients (OR: 3.526; 95% CI: 1.385-8.979; P = 0.008). In this subset, baseline GFR was significantly correlated with both absolute (r = -0.320; P < 0.001) and relative (r = -0.324; P < 0.001) haemoglobin decrease within the first 8 weeks of treatment. In patients aged >60 years, a low pre-treatment GFR was strongly associated with the risk to develop ribavirin-related anaemia with consequent reduction in ribavirin doses.

Sorafenib in patients with Child-Pugh class A and B advanced hepatocellular carcinoma: a prospective feasibility analysis.

BACKGROUND: Sorafenib has shown survival benefits in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh (CP) class A liver function. There are few prospective data on sorafenib in patients with HCC and CP class B. PATIENTS AND METHODS: A consecutive prospective series of 300 patients with CP class A or B HCC were enrolled in a dual-phase trial to determine survival and safety data according to liver function (class A or B) in patients receiving oral sorafenib 800 mg daily. [Results of this study were presented in part at the ASCO 2012 Gastrointestinal Cancers Symposium, 19-21 January 2012. J Clin Oncol 2012; 30 (Suppl 4): abstract 306.] RESULTS: Overall progression-free survival (PFS), time to progression (TTP) and overall survival (OS) were 3.9, 4.1 and 9.1 months, respectively. For patients with CP class A versus B status, PFS was 4.3 versus 2.1 months, TTP was 4.2 versus 3.8 months and OS was 10.0 versus 3. 8 months. Extrahepatic spread was associated with worse outcomes but taken together with CP class, liver function played a greater role in reducing survival. Adverse events for the two CP groups were similar. CONCLUSION: Although patients with HCC and CP class B liver function have poorer outcomes than those with CP class A function, data suggest that patients with CP class B liver function can tolerate treatment and may still benefit from sorafenib.

Complete response in 5 out of 38 patients with advanced hepatocellular carcinoma treated with stem cell differentiation stage factors: case reports from a single centre.

Hepatocellular carcinoma (HCC) represents the third cause of cancer-related death. Because HCC is multi-centric with time, excluding the few transplanted patients, sooner or later it becomes untreatable with loco-regional therapies and, until some years ago, it was not responsive to systemic therapies. In 2005 a randomized trial indicated the efficacy of a product containing stem cell differentiation stage factors (SCDSF) taken from zebra fish embryos during the stage in which the totipotent stem cells are differentiating into the pluripotent adult stem cells. In such a trial the patients, with "intermediate" and "advanced" HCC according to BCLC/AASLD guidelines, presented benefit in terms of performance status (PS) and objective tumoral response, with some cases (2.4%) of complete response (CR). The aim of this cohort study is to report the experience of a tertiary referral center on the evidence of cases of CR in patients with "advanced" stage HCC treated with SCDSF as supportive care. CR was regarded as sustained disappearance of the neoplastic areas or blood supply therein, accompanied by normalization of AFP levels. Out of 49 patients consecutively recruited and retrospectively evaluated, 38 had "advanced" stage and 11 "terminal" stage. In 5 patients with "advanced" stage a sustained CR was reported (13.1%). Improvement on PS was obtained in 17 patients (34.6%). No side effects occurred. SCDSF treatment confirmed its efficacy in patients with "advanced" HCC, in terms of PS and tumoral response.

Effectiveness of pegylated interferon/ribavirin combination in 'real world' patients with chronic hepatitis C virus infection.

BACKGROUND: Clinical trials have shown that the combination of pegylated interferon/ribavirin induces a sustained virological response in 54-63% of patients with chronic hepatitis C virus infection, but its effectiveness in day-to-day clinical practice is less clear. AIM: To verify if the efficacy of pegylated interferon/ribavirin combination in 'real world' patients is comparable to that observed in trials. Methods The medical records of 397 consecutive naïve patients with chronic hepatitis C virus infection treated with pegylated interferon/ribavirin combination in nontertiary hospital settings were reviewed in order to assess the response to anti-viral treatment. RESULTS: The sustained virological response rate achieved in this population was similar to that recorded in registration trials (total population: 64%; genotype 1: 46%; genotypes 2-3: 84%). Also, the premature discontinuation rate (15%) was similar to that observed in registration trials, but there were fewer dose reductions in one or both medications (26%). We confirmed the association between adherence and sustained virological response among the patients infected with hepatitis C virus genotype 1 who were treated for > or =80% of the planned duration of treatment. CONCLUSION: The effectiveness of pegylated interferon/ribavirin therapy and factors predicting an sustained virological response in everyday clinical practice mirror those reported in randomized-controlled studies.

Comparison of simple tests for the non-invasive diagnosis of clinically silent cirrhosis in chronic hepatitis C.

BACKGROUND: Biopsy is the gold standard for assessing cirrhosis in patients with chronic hepatitis C virus infection, but it is expensive and at risk of complications. Alternative non-invasive methods have been developed but their usefulness remains uncertain. AIM: To compare the accuracy of five non-invasive scores in detecting cirrhosis. METHODS: We reviewed the charts and liver biopsies of 228 consecutive, treatment-naïve, hepatitis C virus-positive patients, 13.2% of whom with histological diagnosis of cirrhosis. The five alternative scores were age-platelet index, cirrhosis discriminant score, aspartate transaminases to platelet ratio index, Pohl's index, and aspartate transaminases/alanine transaminases ratio. RESULTS: The specificities of the scores were good (87-100%), but not so their sensitivities (17-67%). Accordingly positive likelihood ratios were generally good but negative likelihood ratios were suboptimal. Combinations of the scores independently related to cirrhosis only slightly change this diagnostic accuracy. Using double cut-offs to exclude/diagnoses cirrhosis, cirrhosis discriminant score classified 21% of patients without misdiagnoses and aspartate transaminases to platelet ratio index classified 85% of case with 9% of misdiagnoses. CONCLUSIONS: The five scores showed variable sensitivities and specificities in detecting liver cirrhosis, both individually and in combination. The use of double cut-off points may make the cirrhosis discriminant score and aspartate transaminases to platelet ratio index useful to reduce the number of patients submitted to liver biopsy.

Iatrogenic Kaposi's sarcoma and HCV infection.

Iatrogenic Kaposi's sarcoma develops in patients undergoing immunosuppressive treatment and is considered to be induced by activation of latent HHV8. In most cases the first manifestation of Kaposi's sarcoma develops after 1 year from when the drug was first administered. In a recent study from Italy on HHV8 positivity in patients with Kaposi's sarcoma, it was found that 52% of the control group were positive (Masini C., et al. G Ital Dermatol Venereol 1999; 134: 315-320). For this reason we could expect a larger number of cases of iatrogenic Kaposi's sarcoma given the number of patients who undergo immunosuppressive treatment for one reason or another. Thus, we have to look to a contemporaneous presence of other factors that co-operate with the HHV8. We present a case of a 49-year-old woman, HHV8 and HCV positive, who develops a Kaposi's sarcoma after 9 months of steroid therapy (methylprednisolone 16 mg/die). The low dose of steroids prescribed to our patient and the fact that the first skin manifestation developed after a shorter period than average from the start of therapy do not explain the acute onset of an extensive Kaposi's sarcoma even taking into account the HHV8 positive status. Both HHV8 and HCV produce proteins, such as IL6 and IL8 which are able to control cell growth. It can be supposed that the contemporaneus presence of the two viruses created a sinergy for the onset of the Kaposi's sarcoma.

Hepatocyte proliferation and risk of hepatocellular carcinoma in cirrhotic patients.

OBJECTIVES: High hepatocyte proliferation has been recently proposed as a risk factor for the development of hepatocellular carcinoma (HCC). The aim of this study was to assess whether hepatocyte proliferation is an independent risk factor for HCC when considered together with clinical and demographic characteristics. METHODS: We retrospectively evaluated 97 consecutive patients with a histological diagnosis of cirrhosis and preserved liver function, enrolled in a surveillance program for early diagnosis of HCC. Hepatocyte proliferation was evaluated by flow-cytometric analysis in liver samples collected at the time of histological diagnosis of cirrhosis. All patients were followed with abdominal US and serum alpha-fetoprotein (AFP) assays every 6 months. RESULTS: During a mean follow-up of 53 months (range, 12-120 months), 12 patients developed HCC, giving an annual incidence of 2.8%. The mean S-phase fraction was 2.5%+/-1.6 in patients who developed HCC and 0.9%+/-0.6 in those who did not (p < 0.0001). By univariate analysis, S-phase fraction 1.8% or higher and AFP higher than 20 ng/ml were the only two variables significantly correlated with the development of HCC (p < 0.0001, p < 0.0001). Multivariate analysis found that both variables were independently associated with HCC development (p < 0.003 and p < 0.005, respectively), with hazard ratios of 8.0 and 7.3 (confidence intervals, 2.1-31.2 and 1.8-29.2). Among patients with high AFP and/or high S-phase fraction, 11 (39%) developed HCC, compared with only one (1%) with a low S-phase fraction and normal AFP, corresponding to HCC yearly incidences of 9.5% and 0.3% (p < 0.00009). CONCLUSIONS: Patients with high S-phase fraction and/or above-normal serum AFP are at higher risk of developing HCC and should be offered a close surveillance program.

Radiosensitization of tumor-targeted radioimmunotherapy with prolonged topotecan infusion in human breast cancer xenografts.

Clinical radioimmunotherapy (RIT) of solid tumors holds great promise, but as yet has been unable to deliver tumoricidal radiation doses without unacceptable toxicity. Our experimental approach aims to potentiate the therapeutic action of radioimmunoconjugates at the tumor site and thus improve the efficacy of RIT by combination with other treatment modalities. The topoisomerase I inhibitors are a unique class of chemotherapeutic agents that interfere with DNA breakage-reunion by inhibiting the action of topoisomerase I. Preclinical studies suggest that prolonged infusion of topoisomerase I inhibitors enhances cell toxicity due to ionizing radiation. We evaluated the efficacy of combined treatment with continuous administration of topotecan and 90Y-MX-DPTA BrE3 monoclonal antibody (which recognizes an epitope of breast epithelial mucin expressed in most breast cancers) on human mammary carcinoma xenografts in nude mice. Topotecan or 90Y-BrE3 treatment alone delayed overall tumor growth rate transiently but did not affect survival. The combination of RIT with topotecan substantially reduced growth of relatively large established tumors and caused complete tumor regressions and prolonged tumor-free survival in a substantial proportion of treated animals. In vitro studies demonstrated an increase in apoptotic rate and a decrease in cell proliferation of tumor cell lines treated with this combination. We combined the radiosensitization property of topotecan and the specificity of systemic RIT to establish a novel therapy for solid tumors in an experimental tumor xenograft model.

Structural and functional aspects of three major glycoproteins of the human milk fat globule membrane.

The MUC1 mucin, lactadherin, and butyrophilin are 3 major components of the human milk fat globule membrane. The mucin inhibits binding of S-fimbriated Escherichia coli to buccal epithelial cells, and lactadherin prevents symptomatic rotavirus infection in breast-fed infants. Butyrophilin has been suggested to be a structural component of the human milk fat globule (HMFG) membrane and to have receptor functions, but has no known anti-infective activity. These HMFG glycoproteins also are present in skimmed milk, possibly associated with phospholipid micelles, while mucin is also in a soluble form. Mucin and lactadherin resist digestion in the stomach of milk-fed infants, while butyrophilin is rapidly degraded. The MUC1 mucin is an extended rod-like structure forming part of the glycocalyx on the surface of many epithelial cells and membranes of milk, and may act as a decoy for binding of infective agents. The extracellular segment of butyrophilin has homology to Ig superfamily receptors and an intracellular domain with homology to developmentally regulated proteins. Lactadherin is a laterally mobile cell adhesion molecule that interacts with integrins and has a novel means of membrane-association involving specific binding to phosphatidylserine. The structural and functional aspects of these glycoproteins are discussed with regard to their role in human milk for breast-fed infants.

Cardiogenic shock due to acute left main coronary artery occlusion: successful treatment with primary angioplasty.

A 56-year-old patient was admitted with cardiogenic shock due to an acute anterior myocardial infarction. Cardiac catheterization with coronary angiography disclosed a thrombotic occlusion of the left main coronary artery. Prompt mechanical recanalization of the infarct-related artery with multiple stent implantations associated with prolonged circulatory and respiratory supports allowed for a partial recovery of the left ventricular function and the discharge of the patient.

Protective function of human milk: the milk fat globule.

Human milk contains many components that protect the newborn against infection at a time when the infant's own defense mechanisms are poorly developed. Fat is one of the major nutrients in human milk. The fat is contained within milk fat globules composed of a core of triglyceride and a membrane consisting of phospholipids, cholesterol, proteins, and glycoproteins. Both the membrane and the core components can provide protection against microorganisms. The major protective membrane glycoproteins, mucin, and lactadherin are resistant to conditions in the newborn's stomach and maintain their structure and function even at low pH and in the presence of the proteolytic enzyme pepsin. The core triglycerides upon hydrolysis by digestive lipases (especially gastric lipase, which is well developed in the newborn) produce free fatty acids and monoglycerides, amphiphylic substances able to lyse enveloped viruses, bacteria, and protozoa. Therefore, in addition to its nutritional value, the fat in human milk has a major protective function.

Construction and characterization of a chimeric fusion protein consisting of an anti-idiotype antibody mimicking a breast cancer-associated antigen and the cytokine GM-CSF.

Anti-idiotype antibody, 11D10 mimics biologically and antigenically a distinct and specific epitope of the high molecular weight human milk fat globule (HMFG), a cancer-associated antigen present in over 90% of breast tumor samples. To augment the immunogenicity of 11D10 without the aid of a carrier protein or adjuvant, we made a chimeric 11D10-GM-CSF fusion protein for use as a vaccine. An expression plasmid for 11D10 was made by ligation of the DNA sequences of the 11D10 light-chain variable region upstream of the human kappa constant region. The heavy-chain plasmid carrying GM-CSF was made by ligation of the heavy-chain variable region sequences upstream of the human gamma1 constant region CH1 fused to the DNA fragment encoding the mature GM-CSF peptide 3' to the CH3 exon. NS1 plasmacytoma cells were transfected with the light and heavy-chain vectors by electroporation. Fusion protein secreted in the culture medium was purified and was characterized by gel electrophoresis as well as by determination of the biological activity of the fused GM-CSF. In nonreducing SDS-polyacrylamide gels, a single band approximately 200 Kd reacted with anti-human kappa, anti-human lambda1 and anti-GM-CSF antibodies. In reducing polyacrylamide gels, a approximately 74 kd protein reacted with anti-human lambda1 and anti-GM-CSF antibodies. The fusion protein induced proliferation of GM-CSF dependent NFS-60 cells. These results suggest that the protein is a chimeric anti-idiotype antibody consisting of 11D10 variable domains, human kappa and lambda1 constant domains and that the GM-CSF moiety fused to the constant region lambda1 is biologically active.

[Percutaneous drainage of abdominal abscess. A clinical case and issues of operative ultrasonography in urology]. / Drenaggio percutaneo di ascesso addominale. Caso clinico e argomenti di ecografia operativa in urologia.

Percutaneous drainage of intrabdominal abscesses currently is a well established technique. The use of ultrasound, ever more frequently utilized in urology department, made urologists autonomous in ultrasound diagnosis and operative stage. We report on a patient admitted to emergency department in whom acute prostatitis was diagnosed. Urological consultation was obtained. The ultrasound examination performed, permitted to reveal the real syntomatology origin and to make an evaluation about the possible application of ultrasound in diagnosis and treatment of abdominal abscesses. This was also an occasion to re-examine some not urological ultrasound cases and their treatment. We believe that, also for the urologists, morphological knowledge of most frequent abdominal pathologies, visible by ultrasound, is useful to avoid diagnostic mistakes and useless and hazardous treatments. In our experience we confirm that percutaneous and non invasive techniques, if well utilized, have a good cost/benefit ratio. The percutaneous treatment is also useful to convert an urgent surgical operation into a well established and programmed one.

HCV genotypes in Northern Italy: a survey of 1368 histologically proven chronic hepatitis C patients.

BACKGROUND/AIMS: Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotype 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. METHODS: We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors. RESULTS: Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusions were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. CONCLUSION: The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes.

Ritodrine-related liver injury. Case reports and review of the literature.

beta-sympathicomimetic ritodrine chloridrate is a commonly used tocolytic agent for the treatment of preterm labour. Previous reports have described the occurrence of liver test abnormalities during ritodrine administration but the clinical significance and incidence of this side effect are still unclear. We report on two cases including one with a positive rechallenge of liver injury during oral ritodrine administration and a review of the literature.

Milk fat globule glycoproteins in human milk and in gastric aspirates of mother's milk-fed preterm infants.

Human milk fat globule (HMFG) glycoproteins can prevent infections by microorganisms in breast-fed infants; the MUC-1 mucin inhibits binding of S-fimbriated Escherichia coli to buccal mucosa, and lactadherin may prevent symptomatic rotavirus infections. In this study, the survival of these HMFG glycoproteins in the stomach of human milk-fed preterm infants (gestational age = 27.5 +/- 0.4 wk) was assessed, and levels in their mothers' milk determined, using specific RIAs. Butyrophilin, a major component of HMFG membrane that has no demonstrated antimicrobial activity, was studied for comparison. The levels of mucin, lactadherin, and butyrophilin in 41 milk samples of 20 mothers were 729 +/- 75, 93 +/- 10, and 41 +/- 3 microg/mL, respectively. Mucin and lactadherin were significantly higher in early milk samples (<15 d postpartum) than in later milk samples (15-90 d postpartum), whereas butyrophilin showed no such difference. Significant amounts of mucin and lactadherin were found in almost all gastric aspirates of human milk-fed infants, even 4 h after feeding (mucin, 270 +/- 30 microg/mL; lactadherin, 23.2 +/- 4.4 microg/mL), whereas butyrophilin was rapidly degraded in the majority of aspirates. Western blot analysis demonstrated that the immunoreactive mucin, lactadherin, and butyrophilin in the milk-fed gastric aspirates had the expected native molecular weights. Mucin and lactadherin survived at all gastric pH values, whereas butyrophilin was found only at pH > 4. Neither lactadherin nor butyrophilin were detected in gastric aspirates of formula-fed infants (gestational age = 27.8 +/- 0.5 wk), whereas the very low level of mucin (9.1 +/- 1.1 microg/mL) in this group is presumably cross-reacting gastric mucin. These results demonstrate that two HMFG glycoproteins implicated in prevention of infection, MUC-1 mucin and lactadherin, survive and maintain their integrity in the stomachs of human milk-fed preterm infants.

Initial clinical evaluation of radiolabeled MX-DTPA humanized BrE-3 antibody in patients with advanced breast cancer.

To evaluate radiometal-labeled humanized BrE-3 (huBrE-3) monoclonal antibody as a radioimmunolocalization and therapeutic agent in breast cancer patients, tumor localization, pharmacokinetics, radiation dosimetry, and immunogenicity of (111)In-labeled combined 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyldiethylenetriamine pentaacetic acid (MX-DTPA) huBrE-3 were studied. Seven women with BrE-3 antigen-positive, metastatic breast carcinoma underwent (111)In huBrE-3 infusion (5 mCi; 50 mg), followed by serial gamma camera imaging and plasma sampling. Region of interest analysis of images was used to make radiation absorbed dose estimates for (111)In huBrE-3. Data were extrapolated to 90Y huBrE-3. Human anti-human antibody (HAHA) response was measured in serum samples obtained up to 3 months after infusion. Patients tolerated infusions well. Seventy-six percent of 105 known sites of disease were identified on planar and single-photon emission computed tomography scans. For six of seven patients, a biexponential model fit the plasma time-activity curve best with an average T1/2alpha=10.6+/-8.5 (SD) h and average T1/2beta=114.2+/-39.2 h. Radiation absorbed dose estimates for (111)In huBrE-3 for whole body averaged 0.53+/-.08 rads/mCi. Dose estimates for 90Y huBrE-3 for marrow averaged 8.4+/-11.9 rads/mCi, and for tumors, 70+/-31.5 rads/mCi. Liver radioactivity uptake averaged 19.7+/-8.8% injected dose at 24 h after infusion, translating into an average radiation absorbed dose 21.1+/-12 rads/90Y mCi administered. Only one of seven patients demonstrated a low level of HAHA response. Although the plasma half-lives are longer and marrow dose higher for radiolabeled huBrE-3 compared with the murine construct, the excellent tumor localization, good tumor dosimetry, and low immunogenicity support the use of 90Y-huBrE-3 antibody for radioimmunotherapy of breast cancer.

Role of human-milk lactadherin in protection against symptomatic rotavirus infection.

BACKGROUND: Human milk contains a 46 kDa mucin-associated glycoprotein, lactadherin, which binds specifically to rotavirus and inhibits its replication. This study tested the hypothesis that lactadherin protects against symptoms of rotavirus infection. METHODS: 200 infants in Mexico City were recruited at birth and monitored by regular stool EIA for rotavirus, serology, and recording of feeding and stool patterns. Milk samples were obtained from the mothers weekly until 4 weeks post partum then monthly. The sample taken immediately before an infant's episode of rotavirus infection was assayed for lactadherin, butyrophilin, mucin, and secretory IgA. An infection was defined as symptomatic if diarrhoea occurred in the 5 days before or after detection of the virus. FINDINGS: 31 infants developed rotavirus infection; 15 were symptomatic and 16 had no symptoms. The median concentration of lactadherin in the milk samples (obtained 4-41 days [median 13] before the infection) was 48.4 (range 5.6-180) microg/mL in the asymptomatic group and 29-2 (6.2-103-4) microg/mL in the symptomatic group. Although these medians did not differ significantly, in logistic regression analysis adjusted for age at infection and secretory IgA concentration there was a significant difference between the groups (p=0O01). No association between symptom status and concentrations of butyrophilin, mucin, or secretory IgA was found. INTERPRETATION: Protection against rotavirus by human milk is associated with the glycoprotein lactadherin. This association is independent of products of the secretory immune system.