Clinical parameters that predict histology of postchemotherapy retroperitoneal lymph node mass in testicular cancer

BACKGROUND: Since the advent of cisplatin-based chemotherapy, the majority of metastatic testicular cancers can be cured by chemotherapy followed by retroperitoneal lymph node dissection (RPLND). However, postchemotherapy RPLND confers no therapeutic benefit if the residual mass contains no viable cells. Therefore, to determine which parameters predict a patient's likelihood of having only necrosis in the residual mass, we retrospectively analyzed clinical parameters of patients who underwent postchemotherapy RPLND. METHODS: Data from 27 patients with metastatic testicular cancer were analyzed. The histology of the primary tumor was seminoma in 11 cases and non-seminoma in 16 cases. All of the patients with non-seminoma showed a normalization of tumor markers after chemotherapy. Analysis of clinical parameters included data for the initial histology, pretreatment tumor marker levels, postchemotherapy retroperitoneal mass size, and the histology of the dissected RPLNs. RESULTS: Histological examination of dissected RPLNs showed residual tumor in 27% of seminoma patients and 38% of non-seminoma patients. In seminoma patients, no viable cells were found in all six patients with pretreatment lactate dehydrogenase (LDH) levels below 7.5 times the upper limit of normal, or in all five of the patients with postchemotherapy RPLNs less than 2.5 cm. In non-seminoma patients, no viable cells were found in nine of 10 patients with pretreatment alpha-fetoprotein (AFP) levels less than 2700 ng/mL, or in eight of nine patients with residual mass less than 2.5 cm. CONCLUSIONS: Both postchemotherapy RPLN mass size and pretreatment tumor marker levels are possible predictors for necrosis of the residual mass in testicular cancer patients.     

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, on Peroxisomes and Cell Replication

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, onPeroxisomes and Cell Replication. WADA, N., MARSMAN, D. S.,AND POPP, J. A. (1992). Fundam. Appl. Toxicol. 18, 149–154. The dose and time dependency of peroxisome proliferation andhepatocyte replication was evaluated in the liver of rats fedthe peroxisome proliferator and hepatocarcinogen, Wy-14,643.Male F344 rats were fed NIH07 diet blended with Wy-14,643 at0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegalywas induced by Wy-14,643 at all doses and at all time points.Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643as early as 1 week, as determined by the peroxisome-specificNAD⁺ reduction of palmitoyl CoA (PCO) and the peroxisome-associatedactivity of carnitine acetyltransferase (CAT) (5-and 11-foldover control, respectively). The elevations of PCO and CAT weredose-dependent from 5 to 50 ppm and then plateaued from 50 to1000 ppm throughout the treatment period. Hepatocellular replication,evaluated by nuclear histoautoradiography ([³H]thymidine labeling,6-day infusion), was increased in all Wy-14,643 dose groupsafter 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls).However, in 5 and 10 ppm groups this cell replication returnedto control levels by 3 weeks. In contrast, 50, 100, and 1000ppm groups had sustained increases in cell replication up to13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively).We have demonstrated that Wy-14,643 can induce peroxisome proliferationat 5 ppm, a dose 200 times lower than the dose shown to be highlyhepatocarcinogenic in rats (100% incidence by 60 weeks). Incontrast, 50 ppm was identified as the minimal dose which inducedsustained cell replication in rat liver. These data show thatperoxisome proliferation can be dissected from sustained cellreplication for correlating either peroxisome induction or cellreplication with tumor formation. These results provide importantinformation that can be used to design carcinogenicity experimentsto test if peroxisome proliferation and/or chronic enhancementof cell replication predictive risk factors for hepatocarcinogenieity.     

Abnormal cardiac histology in severe intrauterine growth retardation infants

Four infants with severe intrauterine growth retardation (IUGR) weighing less than 1000 g at birth developed heart failure and died in our unit, where heart failure of IUGR infants is the main reason of death in extremely low birth-weight infants. The causes of their heart failure are one of the main themes in current neonatal medicine. The subjects of this study were four small for gestational age infants; all died due to heart failure 5 to 10 days after birth. Microscopic specimens of hearts from autopsies were evaluated with respect to the following characteristics: thickness of myocardial fibers, maturation of nuclei, presence of dysgenesis or necrosis in myocardium, and amount of glycogen in the heart. Neither dysgenesis nor infarction of the heart was found but hypoplasia in myocardial fibers and decreased glycogen levels were observed. Maturation delay in myocytes' nuclei did not appear to be severe. We conclude that these infants' hearts failed to adapt to postnatal hemodynamic changes because of inadequate myocardial function and inadequate glycogen reserves.     

Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy

Hypertrophic cardiomyopathy and dilated cardiomyopathy are two major clinical phenotypes of “idiopathic” cardiomyopathy. Recent molecular genetic analyses have now revealed that “idiopathic” cardiomyopathy is caused by mutations in genes for sarcomere components. We have recently reported several mutations in titin/connectin gene found in patients with hypertrophic cardiomyopathy or dilated cardiomyopathy. A hypertrophic cardiomyopathy-associated titin/connectin mutation (Arg740Leu) was found to increase the binding to actinin, while other dilated cardiomyopathy-associated titin/connectin mutations (Ala743Val and Val54Met) decreased the binding to actinin and Tcap/telethonin, respectively. We also reported several other mutations in the N2-B region of titin/connectin found in hypertrophic cardiomyopathy and dilated cardiomyopathy. Since the N2-B region expresses only in the heart, it was speculated that functional alterations due to the mutations cause cardiomyopathies. In this study, we investigated the functional changes caused by the N2-B region mutations by using yeast-two-hybrid assays. It was revealed that a hypertrophic cardiomyopathy-associated mutation (Ser3799Tyr) increased the binding to FHL2 protein, whereas a dilated cardiomyopathy-associated mutation (Gln4053ter) decreased the binding. In addition, another TTN mutation (Arg25618Gln) at the is2 region was found in familial DCM. Because FHL2 protein is known to tether metabolic enzymes to N2-B and is2 regions of titin/connectin, these observations suggest that altered recruitment of metabolic enzymes to the sarcomere may play a role in the pathogenesis of cardiomyopathies.     

Fatal cytomegalovirus myocarditis in a seronegative ALL patient

Fatal cytomegalovirus (CMV) myocarditis occurred in a 2 year old boy with acute lymphoblastic leukemia (ALL) in remission. The patient showed mild hepatic dysfunction and a rapid progress of pancytopenia after complete remission had been achieved. At the fifth week of complete remission, he presented signs of heart failure such as tachycardia, S4 gallop on auscultation and decreased ejection fraction on echocardiography. However, no significant electrocardiographic changes were recognized. In addition to the cardiac dysfunction, the patient presented a marked tachypnea and dyspnea associated with hypoxemia. These were dramatically improved by methylprednisolone pulse therapy (30 mg/kg per day, for 3 days) and CMV high titer immunoglobulin (400 mg/kg per day, for 3 days). On the sixth day after signs of respiratory failure were improved, the patient suddenly presented a paroxysmal atrial tachycardia followed by a fatal ventricular fibrillation. Although we could detect neither a specific IgM antibody, a significant increase of IgG antibody, nor CMV genome by DNA hybridization techniques during the course of the illness, microscopic examination of necropsy specimens of the heart showed a marked disruption and disintegration of muscle bands associated with cytomegalic inclusion bodies. Polymerase chain reaction (PCR) yielded a 305 bp amplification product in the heart and lung tissues, supporting the view that myocarditis was caused by CMV.     

Certain type of chronic lung disease of newborns is associated with Ureaplasma urealyticum infection in utero

BACKGROUND: Recent studies of chronic lung disease (CLD) of newborns emphasize the contribution of antenatal infection. However, the association of Ureaplasma urealyticum infection and CLD has been controversial. The purpose of the present paper was to determine whether U. urealyticum is associated with chorioamnionitis (CAM) and a certain type of CLD. METHODS: One hundred and five infants <32 weeks of gestation who were admitted to the neonatal intensive care unit at Jichi Medical School Hospital, who underwent both histological and microbiological examinations and who survived to discharge were included. CAM was determined by histological examination. Placenta, gastric and tracheal aspirates, and nasopharyngeal swabs were cultured for Mycoplasma and other microorganisms. CLD was defined as oxygen needed at 28 days of age with symptoms of persistent respiratory distress and hazy or emphysematous and fibrous appearance upon X-ray. CLD was further divided into two subtypes according to the presence of antenatal infection. RESULTS: CAM was associated with premature rupture of membrane (odds ratio [OR], 10.19; 95% confidence interval [CI]: 3.10-33.56), placental colonization of U. urealyticum (OR 6.73, 95%CI: 1.89-23.91), neonatal colonization of other microorganisms (OR 7.33, 95%CI: 1.22-44.13) and level of IgM (OR 1.06, 95%CI: 1.01-1.11). Comparisons between CLD and non-CLD patients showed that gestational age (OR 0.43, 95%CI: 0.30-0.61) and white blood cell count (WBC) at birth (OR 1.06, 95%CI: 1.01-1.11) were risk factors for CLD, while gestational age (OR 0.38, 95%CI: 0.23-0.64), neonatal colonization of U. urealyticum (OR 5.98, 95%CI: 1.17-30.6) and WBC (OR 1.08, 95%CI: 1.01-1.15) were independent risk factors for infection-related CLD compared with non-CLD. Within CLD, infection-related CLD was associated with neonatal colonization of U. urealyticum (OR 43.7, 95%CI: 2.84-673.8) and WBC (OR 1.27, 95%CI: 1.07-1.50). CONCLUSIONS: Placental colonization of U. urealyticum was significantly related to CAM; and neonatal colonization of U. urealyticum and leukocytosis at birth were risk factors for infection-related CLD.     

Lectin-reactive alpha-fetoprotein as a marker for testicular tumor activity

BACKGROUND: Lens culinaris agglutin (LCA)-affinity electrophoresis resolves serum alpha-fetoprotein (AFP) into three isoforms, AFP-L1, -L2 and -L3. The ratio of AFP-L3 to total AFP (AFP-L3%) is frequently high in hepatocellular carcinoma (HCC) patients, and thus, it is widely used for early diagnosis of HCC. In the present study, we used the subfraction profile of LCA-binding AFP to diagnose and monitor testicular tumor activity. METHODS: Serum samples were collected from 21 testicular tumor patients, and the LCA-reactive fractions were determined by LCA-affinity electrophoresis coupled with antibody-affinity blotting. The histological diagnosis was non-seminomatous germ cell tumor (NSGCT) in 15 patients and pure seminoma in six patients. RESULTS: Serum AFP levels were abnormally elevated (>20 ng/mL) in 10 of 15 NSGCT patients. One NSGCT patient and two seminoma patients showed borderline AFP levels between 10 and 20 ng/mL. LCA-reactive AFP was detected in all 11 NSGCT patients with serum AFP levels above 10 ng/mL, but not in the two seminoma patients with serum AFP levels above 10 ng/mL. In testicular tumor patients, the broad band of AFP-L2 could not be completely separated from AFP-L3. The mean ratio of AFP-L3 plus AFP-L2 (AFP-L2 + 3%) was as high as 94% (range 80-99%) in these patients. Serial determinations of LCA-reactive fractions were performed in eight of the 11 LCA-reactive AFP-positive patients. They included five patients who received chemotherapy, and three patients who underwent orchiectomy for stage I NSGCT. In three of eight patients, LCA-reactive AFP was detected even after normalization of total AFP levels. All three patients relapsed, with elevation of serum AFP within several months. CONCLUSION: Determination of LCA-reactive AFP might be a useful marker for testicular tumor activity in patients with lower AFP levels.     

Very high doses of valsartan provide renoprotection independently of blood pressure in a type 2 diabetic nephropathy rat model

Aim:   Angiotensin II type 1 receptor blockers (ARB) retard the progression of hypertensive diabetic kidney disease. Clinical evidence suggests that the dose of ARB required to correct hypertension is suboptimal for renoprotection evaluated by proteinuria. No systematic, prospective study has yet evaluated separately the effect of increasing doses of ARB on blood pressure and proteinuria.
Methods:   Over a period of 8 weeks, the effect of seven constant doses of an ARB, valsartan (4–160 mg/kg per day), on blood pressure and proteinuria taken as a surrogate marker of nephropathy in a hypertensive, type 2 diabetic rat model, the spontaneously hypertensive/NIH-corpulent rat (SHR/NDmcr-cp), was assessed. In this spontaneously hypertensive rat strain, a genetic mutation in the leptin receptor gene is associated with hyperphagia leading to obesity with metabolic syndrome and eventually to nephropathy.
Results:   No additional blood pressure lowering was observed above 120 mg/kg per day of valsartan, suggesting that a dose of 80–120 mg/kg per day had a maximal effect. Nevertheless, higher doses of valsartan further reduced proteinuria in a dose-dependent fashion suggesting the absence of a maximal dose. Obesity, hyperglycaemia and hypercholesterolaemia were unaffected but hypertriglyceridaemia was partially corrected at various ARB doses.
Conclusion:   ARB improve renoprotection at doses above those required for a maximal effect on blood pressure. The mechanism of the renoprotection obtained at high doses of ARB is yet to be elucidated.     

Selective effector mechanisms for the expulsion of intestinal helminths

In the middle of the era of molecular biology, much less attention is paid to in vivo phenomena. However, carefully designed experimental systems in vivo still can provide valuable information as to the mechanisms underlying the establishment and maintenance of host-parasite relationships. In this review we describe the advantage of using concurrent infections with appropriately chosen combinations of different genera or different maturation stages of parasites to segregate the cellular responses of the host. By means of simple experimental approaches we have found that mucosal mast cells and goblet cells, both of which have long been considered as non-specific effectors, are in fact highly selective and specific effector cells of the host defence mechanisms capable of acting on the establishment and the expulsion of intestinal helminths.