[Efficacy and safety of neoadjuvant chemotherapy combined with PD-1 antibody for esophageal squamous cell carcinoma in the real world].

Objective: To evaluate the efficacy and safety of neoadjuvant chemotherapy combined with programmed death-1 (PD-1) antibody in operable, borderline or potentially resectable locally advanced esophageal squamous cell carcinoma(ESCC) in the real world. Methods: The study retrospectively analyzed 28 patients with operable or potentially resectable locally advanced ESCC patients treated with preoperative chemotherapy combined with PD-1 inhibitor in Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School from April 2020 to March 2021. According to the clinical TNM staging system of the 8th edition of the American Joint Committee on Cancer, there were 1, 15, 10, 1 and 1 case of stage Ⅱ, Ⅲ, ⅣA, ⅣB and unknown stage respectively. The treatment was two cycle of dual drug chemotherapy regimen including taxane plus platinum or fluorouracil combined with PD-1 antibody followed by tumor response assessment and surgery if the patient was eligible for resection. Results: Of the 28 patients, 1, 2, 3 and 4 cycles of chemotherapy combined with PD-1 antibody treatment completed in 1, 21, 5, and 1 patient, respectively. Objective response rate (ORR) was 71.4% (20/28), and disease control rate (DCR) was 100% (28/28). The incidence of adverse events exceeding grade 3 levels was 21.4% (6/28), including 3 neutropenia, 1 leukopenia, 1 thrombocytopenia and 1 immune hepatitis. There was no treatment-related death. Of the 23 patients underwent surgery, R0 resection rate was 87.0% (20/23), 13 patients had down staged to the T1-2N0M0 I stage, the pCR rate was 17.3% (4/23), and the pCR rate of primary tumor was 21.7% (5/23). Four patients received definitive chemoradiotherapy. One patient rejected surgery and other treatment after achieved PR response. Conclusion: Neoadjuvant chemotherapy combined PD-1 inhibitor is safe and has high efficacy in operable, borderline or potentially resectable locally advanced ESCC, and it is a promising regimen.

[Effects and mechanism of digoxin on atrium electrical remodeling and susceptibility of atrial fibrillation in aged rabbits].

Objective: To investigate the effects and mechanism of digoxin on atrium electrical remodeling and susceptibility of atrial fibrillation (AF) in aged rabbits. Methods: Twenty aged male New Zealand rabbits were divided into aged group and aged plus digoxin group (n=10 each). Electrical parameters including heart rate (HR), RR and QT interval, ST segment and P wave dispersion from normal Ⅱ electrocardiogram, and the maximum upstroke velocity (Max(dv/dt)), plateau potential (plateau P), action potential duration of 10%, 20% and 90% (APD(10), APD(20), APD(90)) from recording of monophasic action potential (MAP), as well as atrial effective refractory period (AERP(200)) and dispersion (dERP(200)) with 200 ms of basic cycle length (BCL), and frequency self adaptation of AERP with 300 ms and 150 ms of BCLs (fERP) were recorded and compared between the 2 groups. BCLs and inducibility of AF post programmed electrical stimulation and Burst-pacing in left atrium tissue of rabbits in vivo were also analyzed. The L-type calcium current (I(Ca-L)) in 2 groups were recorded via whole-cell patch clamp technique, and the fluorescence intensity of intracellular free Ca(2+) was detected with Flup-3/AM loading by the laser scanning confocal microscope in enzymatically dissociated single rabbit atrial myocytes. Results: Compared with aged group, the heart rate was faster, RR and QT interval were obvious shorter, ST segment was raised and P wave dispersion was significantly increased in aged plus digoxin group (all P<0.05). Moreover, compared with aged group, the Max(dv/dt) and plateau P were obviously increased, APD(10) and APD(20) were significantly prolongated, and APD(9)0 was significantly shorter in aged plus digoxin group (all P<0.01). Otherwise, the fERP was markedly increased (0.81±0.15 vs. 0.67±0.05), and the induced rate of AF was obviously higher in aged plus digoxin group than in aged group (6/8 vs. 4/9) (all P<0.01). With voltage clamp model, digoxin significantly increased I(Ca-L) of atrial myocytes of aged rabbits, When command potential was 10 mV, the current densities of I(Ca-L) were significantly higher in digoxin group than that in aged group ((15.45±2.38) pA/pF vs. (7.03±1.69) pA/pF, P<0.01). Otherwise, the I-V curve of I(Ca-L) was downward shifted of all I-V curves in digoxin perfused aged atrial cells of rabbits. Moreover, the fluorescence intensities of intracellular free Ca(2+) was significantly higher in aged plus digoxin group than in aged group ((1 748±173) µmol/L vs. (478.13±87.63) µmol/L, P<0.01). Conclusion: Digoxin could aggravate the atrial electrical remodeling in atrium of aged rabbits, facilitate susceptibility of atrial fibrillation in aged rabbit, increased current density of I(Ca-L) and concentration of intracellular free Ca(2+), followed Ca(2+) overload and oscillations might be part of the underlying mechanisms.

Structure-activity relationship (SAR) studies of synthetic glycogen synthase kinase-3ß inhibitors: A critical review.

Glycogen Synthase Kinase-3 (GSK-3) is a constitutively dynamic, omnipresent serine/threonine protein kinase regularly called as a "multitasking kinase" due to its pliable function in diverse signaling pathways. It exists in two isoforms i.e., GSK-3α and GSK-3ß. Inhibition of GSK-3 may be useful in curing various diseases such as Alzheimer's disease, type II diabetes, mood disorders, cancers, chronic inflammatory agents, stroke, bipolar disorders and so on, but the approach poses significant challenges. Lithium was the first GSK-3ß inhibitor to be used for therapeutic outcome and has been effectively used for many years. In recent years, a large number of structurally diverse potent GSK-3ß inhibitors are reported. The present review focuses on the recent developments in the area of medicinal chemistry to explore the diverse chemical structures of potent GSK-3ß inhibitors and also describes its structure-activity relationships (SAR) and molecular binding interactions of favorable applicability in various diseases.

Unexpectedly high prevalence of Treponema pallidum infection in the oral cavity of human immunodeficiency virus-infected patients with early syphilis who had engaged in unprotected sex practices.

Between 2010 and 2014, we obtained swab specimens to detect Treponema pallidum, with PCR assays, from the oral cavities of 240 patients with 267 episodes of syphilis who reported engaging in unprotected sex practices. The detected treponemal DNA was subjected to genotyping. All of the syphilis cases occurred in men who have sex with men (MSM), and 242 (90.6%) occurred in human immunodeficiency virus-infected patients. The stages of syphilis included 38 cases (14.2%) of primary syphilis of the genital region, 76 (28.5%) of secondary syphilis, 21 (7.9%) of primary and secondary syphilis, 125 (46.8%) of early latent syphilis, and seven (2.6%) others. Concurrent oral ulcers were identified in 22 cases (8.2%). Treponemal DNA was identified from the swabs of 113 patients (42.2%), including 15 (68.2%) with oral ulcers. The most common genotype of T. pallidum was 14f/f. The presence of oral ulcers was associated with identification of T. pallidum in the swab specimens (15/22 (68.2%) vs. 98/245 (40.0%)) (p = 0.01). In multivariate analysis, secondary syphilis (adjusted OR 6.79; 95% CI 1.97-23.28) and rapid plasma reagin (RPR) titres of ≥1: 32 (adjusted OR 2.23; 95% CI 1.02-4.89) were independently associated with the presence of treponemal DNA in patients without oral ulcers. We conclude that detection of treponemal DNA in the oral cavity with PCR assays is not uncommon in MSM, most of whom reported having unprotected oral sex. Although the presence of oral ulcers is significantly associated with detection of treponemal DNA, treponemal DNA is more likely to be identified in patients without oral ulcers who present with secondary syphilis and RPR titres of ≥1: 32.

PHRF1 promotes genome integrity by modulating non-homologous end-joining.

Methylated histone readers are critical for chromatin dynamics, transcription, and DNA repair. Human PHRF1 contains a plant homeodomain (PHD) that recognizes methylated histones and a RING domain, which ubiquitinates substrates. A recent study reveals that PHRF1 is a tumor suppressor that promotes TGF-ß cytostatic signaling through TGIF ubiquitination. Also, PHRF1 is a putative phosphorylation substrate of ataxia telangiectasia-mutated/ataxia telangiectasia and Rad3-related kinases; however, the role of PHRF1 in DNA damage response is unclear. Here we report a novel function of PHRF1 in modulating non-homologous end-joining (NHEJ). PHRF1 quickly localizes to DNA damage lesions upon genotoxic insults. Ablation of PHRF1 decreases the efficiency of plasmid-based end-joining, whereas PHRF1 overexpression leads to an elevated NHEJ in H1299 reporter cells. Immunoprecipitation and peptide pull-down assays verify that PHRF1 constitutively binds to di- and trimethylated histone H3 lysine 36 (H3K36) (H3K36me2 and H3K36me3) via its PHD domain. Substitution of S915DT917E to ADAE in PHRF1 decreases its affinity for NBS1. Both PHD domain and SDTE motif are required for its NHEJ-promoting activity. Furthermore, PHRF1 mediates PARP1 polyubiquitination for proteasomal degradation. These results suggest that PHRF1 may combine with H3K36 methylation and NBS1 to promote NHEJ and stabilize genomic integrity upon DNA damage insults.

Multicentre surveillance of prevalence of the 23S rRNA A2058G and A2059G point mutations and molecular subtypes of Treponema pallidum in Taiwan, 2009-2013.

Resistance mutations A2058G and A2059G, within the 23S rRNA gene of Treponema pallidum, have been reported to cause treatment failures in patients receiving azithromycin for syphilis. Genotyping of T. pallidum strains sequentially isolated from patients with recurrent syphilis is rarely performed. From September 2009 to August 2013, we collected 658 clinical specimens from 375 patients who presented with syphilis for genotyping to examine the number of 60-bp repeats in the acidic repeat protein (arp) gene, T. pallidum repeat (tpr) polymorphism, and tp0548 gene, and to detect A2058G and A2059G point mutations by restriction fragment length polymorphism. Treponemal DNA was identified in 45.2% (n = 298) of the specimens that were collected from 216 (57.6%) patients; 268 (40.7%) specimens tested positive for the 23S rRNA gene, and were examined for macrolide resistance. Two isolates (0.7%) harboured the A2058G mutation, and no A2059G mutation was identified. A total of 14 strains of T. pallidum were identified, with 14f/f (57.5%) and 14b/c (10.0%) being the two predominant strains. Forty patients who presented with recurrent episodes of syphilis had T. pallidum DNA identified from the initial and subsequent episodes, with five cases showing strain discrepancies. One patient had two strains identified from different clinical specimens collected in the same episode. Our findings show that 14f/f is the most common T. pallidum strain in Taiwan, where the prevalence of T. pallidum strains that show A2058G or A2059G mutation remains low. Different genotypes of T. pallidum can be identified in patients with recurrent episodes of syphilis.

Spirochetemia due to Treponema pallidum using polymerase-chain-reaction assays in patients with early syphilis: prevalence, associated factors and treatment response.

Between 2009 and 2013, polymerase-chain-reaction assay was used to detect Treponema pallidum in the blood samples collected from 296 patients with early syphilis (241 being HIV infected) and 102 patients (34.5%) had spirochetemia. The presence of spirochetemia was associated with lower CD4 counts (per 10-cell/mm(3) decrease, adjusted odds ratio (AOR), 1.020; 95% CI, 1.006-1.036) and secondary syphilis (AOR, 4.967; 95% CI, 2.016-12.238). Patients with early latent syphilis were less likely to achieve serological response compared with those with primary or secondary syphilis (AOR, 0.317; 95% CI, 0.142-0.708). However, serological response was not affected by presence of spirochetemia or antibiotic regimens.

Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus.

Chronic hepatitis B virus (HBV) infection is closely related to the development of severe liver complications, including hepatocellular carcinoma. In previous studies, we reported that in vivo long-term HBV suppression in transgenic mice can be achieved without apparent toxicity by short hairpin RNA sequentially delivered using adeno-associated viral (AAV) vectors of different serotypes. Our goal herein was to address the clinical utility of this delivery system and, in particular, to determine whether RNA interference (RNAi) and its ability to induce long-term HBV suppression will modulate the development of HBV-associated liver pathology. As a model system, we used a unique HBV transgenic mouse model, containing a 1.3 times over length of the HBV genome, on the ICR mouse background. These transgenic mice produce high serum HBV titers comparable with human chronic HBV patients, and, importantly, manifest characteristic HBV-associated pathology, including progressive hepatocellular injury and the development of hepatocellular adenoma. Using this system, we injected animals with AAV vectors expressing either HBV-specific or a control luciferase-specific short hairpin RNA and followed animals for a total of 18 months. We report herein that AAV-mediated RNAi therapy profoundly inhibits HBV replication and gene expression, with a significant reduction in hepatic regeneration, liver enzymes and, importantly, the appearance of liver adenomas. Indeed, the therapeutic effect of RNAi correlated with the reduction in HBV titers. Our data demonstrate that appropriately designed RNAi therapy has the potential to prevent formation of HBV-associated hepatocellular adenoma.

Risk factors for incident diabetes mellitus among HIV-infected patients receiving combination antiretroviral therapy in Taiwan: a case-control study.

OBJECTIVES: Recent studies suggest that patients with HIV infection are at increased risk for incident diabetes mellitus (DM). We investigated the incidence and risk factors of DM among HIV-infected patients receiving combination antiretroviral therapy (CART) in Taiwan. METHODS: Incident cases of DM were identified among HIV-infected patients at the National Taiwan University Hospital between 1993 and 2006. A retrospective case-control study was conducted after matching cases with controls for sex, age at HIV diagnosis, year of HIV diagnosis, mode of HIV transmission and baseline CD4 lymphocyte count. A multivariate analysis was performed to identify risk factors for incident DM among HIV-infected patients. RESULTS: In 824 HIV-infected patients eligible for analysis, 50 cases of incident DM were diagnosed, resulting in an incidence of 13.1 cases per 1000 person-years of follow-up. In total, 100 matched controls were identified. Risk factors for incident DM were a family history of DM [odds ratio (OR) 2.656; 95% confidence interval (CI) 1.209-5.834], exposure to zidovudine (OR 3.168; 95% CI 1.159-8.661) and current use of protease inhibitors (OR 2.528; 95% CI 1.186-5.389). CONCLUSIONS: Incident DM was associated with a family history of DM, exposure to zidovudine and current use of protease inhibitors in HIV-infected patients receiving CART in Taiwan.

Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA.

RNA interference (RNAi) was reported to block hepatitis B virus (HBV) gene expression and replication in vitro and in vivo. However, it remains a technical challenge for RNAi-based therapy to achieve long-term and complete inhibition effects in chronic HBV infection, which presumably requires more extensive and uniform transduction of the whole infected hepatocytes. To increase the in vivo transfection efficiency in liver, we used a double-stranded adeno-associated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. HBV transgenic mice were used as an animal model to evaluate the inhibition effects of the RNAi-based gene therapy. A single administration of dsAAV2/8 vector, carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HBV transgenic mice, leading to up to 2-3 log(10) decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. These results underscore the potential for developing RNAi-based therapy by dsAAV2/8 vector to treat HBV chronic infection, and possibly other persistent liver infections as well.

Growth of preterm infants fed nutrient-enriched or term formula after hospital discharge.

OBJECTIVE: At hospital discharge, preterm infants may have low body stores of nutrients, deficient bone mineralization, and an accumulated energy deficit. This double-blind, randomized study evaluated the growth of premature infants with birth weights <1800 g who were fed a 22 kcal/fl oz nutrient-enriched postdischarge formula (PDF) or a 20 kcal/fl oz term-infant formula (TF) from hospital discharge to 12 months' corrected age (CA). METHODS: Infants were randomized to PDF or TF a few days before hospital discharge with stratification by gender and birth weight (<1250 g or >/=1250 g). The formulas were fed to 12 months' CA. Growth was evaluated using analysis of variance controlling for site, feeding, gender, and birth weight group. Interaction effects were also assessed. Secondary analyses included a repeated measures analysis and growth modeling. RESULTS: One hundred twenty-five infants were randomized; 74 completed to 6 months' CA and 53 to 12 months' CA. PDF-fed infants weighed more than TF-fed infants at 1 and 2 months' CA, gained more weight from study day 1 to 1 and 2 months' CA, and were longer at 3 months' CA. There were significant interactions between feeding and birth weight group-among infants with birth weights <1250 g, those fed PDF weighed more at 6 months' CA, were longer at 6 months' CA, had larger head circumferences at term 1, 3, 6, and 12 months' CA, and gained more in head circumference from study day 1 to term and to 1 month CA. The repeated measures and growth modeling analyses confirmed the analysis of variance results. The PDF formula seemed to be of particular benefit for the growth of male infants. Infants fed the PDF consumed less formula and had higher protein intakes at several time points. Energy intakes, however, were not different. CONCLUSIONS: Growth was improved in preterm infants fed a nutrient-enriched postdischarge formula after hospital discharge to 12 months' CA. Beneficial effects were most evident among infants with birth weights <1250 g, particularly for head circumference measurements.

Enhanced antitumor immunity by fusion of CTLA-4 to a self tumor antigen.

The idiotypic determinant (Id) of the immunoglobulin expressed by a B-cell malignancy can serve as an effective tumor-specific antigen but is only weakly immunogenic. This study demonstrates that the immunogenicity of the tumor Id protein can be dramatically increased by directing it to antigen-presenting cells (APCs). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) present on activated T cells has a strong binding affinity to both B7-1 and B7-2 molecules, which are primarily expressed on APCs. After construction of a fusion protein consisting of Id and CTLA-4 (Id-CTLA4), mice immunized with the fusion protein induced high titers of Id-specific antibody and T-cell proliferative responses without adjuvants and were protected from lethal tumor challenge. The Id-CTLA4 fusion protein was so potent that even low doses (down to 0.1 microg) of the immunogen were able to elicit strong antibody responses. By using an Id-CTLA4 mutant protein, the ability to bind B7 molecules on APCs was shown to be required for the enhanced immunogenicity of Id-CTLA4. These findings demonstrate that fusing CTLA-4 to a potential tumor antigen represents an effective approach to prime antitumor immunities in vivo and may be applicable to the design of vaccines for a variety of other diseases. (Blood. 2000;96:3663-3670)

Accelerated clearance of polyethylene glycol-modified proteins by anti-polyethylene glycol IgM.

Tumor therapy by the preferential activation of a prodrug at tumor cells targeted with an antibody-enzyme conjugate may allow improved treatment efficacy with reduced side effects. We examined antibody-mediated clearance of poly(ethylene glycol)-modified beta-glucuronidase (betaG-sPEG) as a method to reduce serum concentrations of enzyme and minimize systemic prodrug activation. Enzyme-linked immunosorbent assay and immunoblot analysis of two monoclonal antibodies generated by immunization of BALB/c mice with an antibody-betaG-sPEG conjugate showed that mAb 1E8 (IgG1) bound betaG and betaG-sPEG whereas mAb AGP3 (IgM) bound poly(ethylene glycol). Neither antibody affected the betaG activity. mAb 1E8 and AGP3 were modified with 36 and 208 galactose residues (1E8-36G and AGP3-208G) with retention of 72 and 48% antigen-binding activity, respectively, to target immune complexes to the asialoglycoprotein receptor on liver cells. mAb 1E8 and AGP3 cleared betaG-PEG from the circulation of mice as effectively as 1E8-36G and AGP3-208G, respectively. mAb AGP3, however, cleared betaG-sPEG more completely and rapidly than 1E8, reducing the serum concentration of betaG-sPEG by 38-fold in 8 h. AGP3 also reduced the concentration of an antibody-betaG-sPEG conjugate in blood by 280-fold in 2 h and 940-fold in 24 h. AGP3-mediated clearance did not produce obvious damage to liver, spleen, or kidney tissues. In addition, AGP3 clearance of betaG-sPEG before administration of BHAMG, a glucuronide prodrug of p-hydroxyaniline mustard, prevented toxicity associated with systemic activation of the prodrug based on mouse weight and blood cell numbers. AGP3 should be generally useful for accelerating the clearance of PEG-modified proteins as well as for improving the tumor/blood ratios of antibody-betaG-PEG conjugates for glucuronide prodrug therapy of cancer.

Glutamine supplementation for low-birth-weight and very low-birth-weight infants.

Glutamine is a conditionally essential amino acid for low-birth-weight (LBW) and very low-birth-weight (VLBW) infants by virtue of its ability to serve as a primary respiratory fuel for proliferating cells, a carrier of nitrogen between tissues, maintain acid-base balance, promote the growth and integrity of the gastrointestinal tract and promote immunologic responses. While adults can synthesize glutamine in the muscles and brain to meet essential requirements under normal state of health, the LBW and VLBW infants may not be able to do so since the enzymes (glutamine synthetase and glutaminase) activities are low. In addition, these infants are under stress due to conditions like the respiratory distress syndrome, acid-base imbalances, infections, and inadequate immunologic responses. Current amino acid mixtures and formula preparations are inadequate to meet the needs of these infants for this amino acid. Thus supplementation of parenteral and enteral nutrition with glutamine would be beneficial.

The management of patients with advanced motor neuron disease.

BACKGROUND: There is no specific treatment for motor neuron disease (MND) except hospice or palliative care to improve patients' quality of life and decrease complications. This topic is seldom discussed in Taiwan. METHODS: A retrospective study was conducted of patients with terminal MND who were treated and died at the Veterans General Hospital-Taipei from March 1986 through April 1996. Patients' characteristics, management, length of survival and cause of death were analyzed. RESULTS: Twenty-three patients (M/F, 17/6) were included. The median age of onset was 59 years (range, 24-69). The median interval from onset of symptoms to diagnosis was nine months (range, 2-36). Seventeen patients received mechanical ventilation for an average median of six months. Nineteen patients had dysphagia, 17 received long-term nasogastric tube feeding, one had gastrostomy and one was treated with cricopharyngeal myotomy. Pain over the neck, trunk or limbs was reported by 18 patients; none received narcotics. Only two patients received respiratory exercise training and two had a cervical collar for stabilization. Electronic communication aids were not available. The median survival from onset of symptoms was 36 months (range, 7-99). The causes of death included sepsis (n = 13), respiratory failure (n = 7), heart disease (n = 2) and MND-related cachexia (n = 1). Cardiopulmonary resuscitation was performed for 12 patients. CONCLUSIONS: In Taiwan, management of patients with advanced MND is mainly hospital-based and most of the effort is focused on life-sustaining. More attention needs to be paid to improvement of the quality of life and dignity of the patient.

Poly(ethylene glycol) modification of beta-glucuronidase-antibody conjugates for solid-tumor therapy by targeted activation of glucuronide prodrugs.

Methoxypoly(ethylene glycol) (PEG) modification of Escherichia coli beta-glucuronidase (betaG) was examined as a method to improve the stability and pharmacokinetics of antibody-betaG conjugates for the targeted activation of glucuronide prodrugs at tumor cells. Introduction of 3 PEG molecules did not affect betaG activity whereas higher degrees of PEG modification produced progressively greater loss of enzymatic activity. The enzyme was found to be stable in serum regardless of PEG modification. PEG-modified betaG was coupled via a thioether bond to mAb RH1, an IgG2a antibody that binds to the surface of AS-30D hepatoma cells, to produce conjugates with 3 (RH1-betaG-3PEG), 5.2 (RH1-betaG-5PEG) or 9.8 (RH1-betaG-10PEG) PEG molecules per betaG with retention of 75%, 45% and 40% of the combined antigen-binding and enzymatic activity of the unmodified conjugate RH1-betaG. In contrast to the rapid serum clearance of RH1-betaG observed in mice, the PEG-modified conjugates displayed extended serum half-lives. RH1-betaG-3PEG and RH1-betaG-5PEG also exhibited reduced spleen uptake and greater tumor accumulation than RH1-betaG. BHAMG, the glucuronide prodrug of p-hydroxyaniline mustard (pHAM), was relatively nontoxic in vivo. Injection of 6 mg/kg or 12 mg/kg pHAM i.v. depressed white blood cell numbers by 46% and 71% whereas 80 mg/kg BHAMG reduced these levels by 22%. Although the tumor/blood ratio of RH1-betaG-5PEG was adversely affected by slow clearance from serum, combined therapy of small solid hepatoma tumors with this conjugate, followed 4 and 5 days later with i.v. injections of BHAMG, cured all of seven mice with severe combined immunodeficiency. Combined treatment with a control antibody-betaG conjugate and BHAMG delayed tumor growth and cured two of six mice while treatment with pHAM or BHAMG alone was ineffective.

Infant of diabetic mother: a continuing challenge for perinatal-neonatal medicine.

Current increase in the incidence of diabetes mellitus complicating pregnancy is of concern since it is associated with an increase in mortality and morbidity of the fetus and neonate. Pregnancy itself is diabetogenic caused by increased insulin resistance due to the production of hormones like estrogen, progesterone, cortisol, human chorionic somatomammotropin (hCS) and human placental lactogen (hPL). The latter increases lypolysis which provides free fatty acids and ketones as fuels for energy for the pregnant mother. This spares maternal blood glucose, amino acids and ketones which cross the placenta to the fetus. The influx of nutrients increases fetal insulin production which together with hPL induce somatogenesis. Maternal hyperglycemia and fetal hypoxemia are shown to be responsible for structural congenital anomalies of the rapidly developing organs of the fetus during the early weeks of gestation while continuing hyperglycemia and hypoxemia in the second and third trimester are factors related to the production of macrosomia, including cardiomyopathy, delay in lung maturation, and polycythemia. Metabolic problems such as hypoglycemia, hypocalcemia, hypomagnesemia and hyperbilirubinemia are common neonatal morbidities. Follow-up of the infants of diabetic mothers indicates that these infants have a 20 fold increase in acquiring diabetes. Early identification of maternal diabetes with strict metabolic control prior to conception as well as throughout pregnancy together with careful fetal monitoring can reduce the incidence of congenital anomalies and morbidities in the fetus and neonate.

Effects of the callipyge phenotype on serum creatinine, total cholesterol, low-density lipoproteins, very-low-density lipoproteins, high-density lipoproteins, and triacylglycerol in growing lambs.

The goals of this study were to investigate the effects of the callipyge (CLPG) phenotype on serum creatinine and lipid profiles of growing lambs. Preliminary studies in our laboratories indicated that creatinine may have utility in distinguishing the CLPG phenotype and that expression of the CLPG gene altered concentrations of serum total cholesterol (TC). As a result, in this study, we examined the influence of the CLPG gene on concentrations of creatinine, TC, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and triacylglycerol (TG) at varying stages of maturity in lambs. Ten homozygous (c/c) Polypay ewes were crossed with Dorset rams heterozygous for the CLPG gene (C/c). From this cross, 20 lambs (13 females and 7 males) were born, of which 11 were homozygotic (c/c) and 9 were heterozygotic (C/c; CLPG) based on muscle weights and longissimus dorsi (LD) area at slaughter. Blood samples were taken at monthly intervals and serum lipid constituents were assayed. At 1 mo of age, no differences (P > .05) in plasma lipids were detectable between phenotypes. However, at 2 mo age, CLPG lambs had higher (P < .01) concentration of TG, TC, HDL, and VLDL compared to homozygotic (c/c) lambs. Triglycerides and VLDL were elevated (P < .05) in CLPG lambs at 3 mo of age. By slaughter, no differences (P > .05) in serum lipid constituents were detectable between genotypes. Hence, the increase in serum TC is due to elevated levels of HDL and VLDL. These observations indicate that creatinine may be used to distinguish CLPG lambs and that the CLPG gene alters serum lipid profiles during the postnatal period.

[Ultrasonography of hips in neonates].

For evaluation of the development of the hip joints in young infants, between Jun., 1988 and Oct., 1991, 522 hips of the infants under 4 months of age were studied by ultrasonography based on the method well described by Graf. The results revealed only 48% of the hips of neonatal group was type I (stable type). But this percentage increased with age: 90% in the group under 2 months of age; 97% in the group under 4 months of age. Compared with the findings of other studies in Europe, the development and the stability of the hips of our neonatal group seemed poorer. But this condition improved much within 2 months after birth. So we concluded that, except the high risk group, the ultrasonographic screening approach should be performed after 2 months of age, but not in neonatal period under considering the cost-benefit.