Skeletal variation in Tennessee Walking Horses maps to the LCORL/NCAPG gene region.

Conformation has long been a driving force in horse selection and breed creation as a predictor for performance. The Tennessee Walking Horse (TWH) ranges in size from 1.5 to 1.7 m and is often used as a trail, show, and pleasure horse. To investigate the contribution of genetics to body conformation in the TWH, we collected DNA samples, body measurements, and gait/training information from 282 individuals. We analyzed the 32 body measures with a principal component analysis. Principal component (PC)1 captured 28.5% of the trait variance, while PC2 comprised just 9.5% and PC3 6.4% of trait variance. All 32 measures correlated positively with PC1, indicating that PC1 describes overall body size. We genotyped 109 horses using the EquineSNP70 bead chip and marker association assessed the data using PC1 scores as a phenotype. Mixed-model linear analysis (EMMAX) revealed a well-documented candidate locus on ECA3 (raw P = 3.86 × 10(-9)) near the LCORL gene. A custom genotyping panel enabled fine-mapping of the PC1 body-size trait to the 3'-end of the LCORL gene (P = 7.09 × 10(-10)). This position differs from other reports suggesting single nucleotide polymorphisms (SNPs) upstream of the LCORL coding sequence regulate expression of the gene and, therefore, body size in horses. Fluorescent in situ hybridization analysis defined the position of a highly homologous 5 kb retrogene copy of LCORL (assigned to unplaced contigs of the EquCab 2.0 assembly) at ECA9 q12-q13. This is the first study to identify putative causative SNPs within the LCORL transcript itself, which are associated with skeletal size variation in horses.

Combination of oxaliplatin plus irinotecan in patients with gastrointestinal tumors: results of two independent phase I studies with pharmacokinetics.

PURPOSE: Two phase I studies of the oxaliplatin and irinotecan combination were performed in advanced gastrointestinal cancer patients to characterize the safety and pharmacokinetics of the regimen. PATIENTS AND METHODS: Patients with a performance status (PS) of < or = 2 and normal hematologic, hepatic, and renal functions received oxaliplatin (2-hour intravenous infusion) followed 1 hour later by irinotecan administered over a 30-minute period, every 3 weeks. Dose levels that were explored ranged from 85 to 110 mg/m(2) for oxaliplatin and 150 to 250 mg/m(2) for irinotecan. Plasma pharmacokinetics of total and ultrafiltrable platinum, irinotecan, SN-38, and its glucuronide, SN-38G, were determined. RESULTS: Thirty-nine patients with gastrointestinal carcinomas (24 with colorectal cancer [CRC], four with pancreas cancer, four with gastric cancer, three with hepatocarcinoma, and four with other) received 216 treatment cycles. Median age was 54 years (range, 21 to 72 years); 95% had PS of 0 to 1; all but six had failed fluorouracil (5-FU) chemotherapy. The maximum-tolerated dose was oxaliplatin 110 mg/m(2) plus irinotecan 200 mg/m(2) in one study and oxaliplatin 110 mg/m(2) plus irinotecan 250 mg/m(2) in the other study. Grade 3 to 4 diarrhea and febrile neutropenia were dose-limiting toxicities; other toxicities included emesis and dose-cumulative neuropathy. Recommended dose for phase II studies is oxaliplatin 85 mg/m(2) and irinotecan 200 mg/m(2). At this dose (12 patients, 65 cycles), grade 3 and 4 toxicities per patient included the following: emesis in 42% of patients, neutropenia in 33% (febrile episodes in 17%), peripheral neuropathy in 25%, delayed diarrhea in 17%, and thrombocytopenia in 8%. Two patients with Gilbert's syndrome experienced severe irinotecan toxicity. No plasmatic pharmacokinetic interactions were detected. Seven partial responses were observed in 24 CRC patients. CONCLUSION: This combination is feasible, with activity in 5-FU-resistant CRC patients. Phase I studies that explore the every-2-weeks schedule, in addition to phase II studies of this schedule (as well as in combination with 5-FU) as second-line therapy of metastatic CRC, are ongoing.

Docetaxel in combination with doxorubicin or vinorelbine.

The rationale for the development of a new drug combination is to combine optimal doses of drugs with single-agent activity that are not cross-resistant or have similar toxicities. Docetaxel, with its unique mechanism of action and its high response rates in metastatic breast cancer, provides both opportunities and challenges for the development of combination chemotherapy. Anthracyclines are widely accepted as the agents of choice for first-line treatment of metastatic breast cancer and they have been studied in combination with taxoids. Preliminary results with a combination of docetaxel and doxorubicin indicate an overall response rate of 74%, with the dose-limiting toxicities being neutropenia and infection. Vinorelbine also has single-agent activity against metastatic breast cancer and preclinical studies have demonstrated synergism when vinorelbine and docetaxel are combined. The dose-limiting toxicities of the vinorelbine-docetaxel combination are febrile neutropenia and mucositis. The overall response rate to treatment with this combination is 67%. We therefore conclude that docetaxel can be combined with doxorubicin or vinorelbine to provide high response rates and acceptable toxicity.

Relation between perfusion defects on stress technetium-99m sestamibi SPECT scintigraphy and the location of a subsequent acute myocardial infarction.

Although the presence of perfusion defects on stress myocardial perfusion imaging has been shown to correlate with future cardiac events, including acute myocardial infarction (AMI), it is unknown whether the location of the AMI can be predicted. Therefore, for 25 patients who had an AMI following a stress technetium-99m sestamibi single-photon emission computed tomographic (SPECT) imaging study and whose infarct location could be determined, the territory of infarction was correlated with the location of previous myocardial perfusion defects. A SPECT perfusion defect had been present in 24 patients (96%). The AMI occurred in territories that showed a reversible defect in 14 patients (56%), whereas 3 infarctions (12%) were in territories that revealed a fixed defect, and 8 infarctions (32%) were in territories that had not shown a defect on prior SPECT imaging. Whereas the incidence of infarction in territories with a reversible defect was highest at 14 of 26 (54%), the incidence of infarction in territories with a fixed defect was 3 of 7 (43%), and in territories with no defect was 8 of 42 (19%) (p = 0.011). Neither the time interval between SPECT imaging and infarction, nor the perfusion defect severity, was related to the correlation between perfusion defect and infarct location. Thus, although AMI occurs most often at the site of previous perfusion defects, reversible or fixed, a substantial percentage occur in territories without a perfusion defect. These findings suggest that abnormalities on SPECT perfusion imaging, although they serve as markers of significant coronary disease and increase the likelihood of infarction, do not always predict the exact location of infarction.

del(18p) syndrome with complex tetralogy of Fallot in an infant with 45,X,t(Y;18)(q12;q11.2).

We report on an infant with multiple congenital anomalies, tetralogy of Fallot, and Karyotype 45,X,t(Y;18)(q12;11.2). The infant's anomalies are consistent with a del(18p) syndrome, except for the exceptional severity of the heart defect.

A comparative study of the awareness and attitude of HIV/AIDS among students living in India and migrants to the United States.

The goal of the current study was to collect preliminary data regarding HIV/AIDS awareness among Indian students who are residing in India and those who have migrated to the United States. A questionnaire was distributed to thirty-four college students in the United States and thirty-eight college students who are residing in India, between ages 18-26 years. 74% of the Indian group and 53% of the USA group felt that their knowledge of this disease is not adequate. 3% felt that this disease is completely curable. Only 13% of the Indian group and 23% of the USA group thought that tuberculosis is linked to HIV infection. Both groups felt that the newspapers and magazines are good sources of information. The majority of the Indian (71%) and USA (50%) groups felt that HIV/AIDS education should begin in high school. 90% of the Indian group and 79% of the USA group felt that people in India do not have adequate knowledge about AIDS. The majority felt that the high-risk population should be screened and there should be more governmental support.

In vitro deletions in the partition locus of plasmid pSC101.

Deletion mutants in the 375-base-pair EcoRI-AvaI fragment carrying the partition locus of plasmid pSC101 were formed by the combined action of exonuclease III and nuclease S1. Six deletion mutants were isolated, and the endpoints of the deletions were sequenced. One of the deletions extended 69 base pairs from the EcoRI site without impairing plasmid stability. The other five deletions caused the plasmid to be unstable and extended 199 to 251 base pairs from the EcoRI site.

Mebendazole poisoning in infancy.

Accidental mebendazole poisoning in an 8-week-old infant and respiratory arrest with tachyarrhythmia associated with continuous seizures is reported. Exchange transfusion was undertaken as a life-saving measure. Mebendazole, like piperazine citrate, has considerable neurotoxicity, especially in infancy, and we propose the use of exchange transfusion as a means of mebendazole elimination in infants.

Neonatal congenital Factor X deficiency.

Four neonates with congenital Factor X deficiency presented soon after birth with bleeding episodes. Two of the newborns had intracranial hemorrhages; one of them also had antenatal ventricular dilatation and postnatal hydrocephalus and died of massive intracerebral hemorrhage at four months. One patient was lost for follow up. The two surviving infants were followed up for four years and two years respectively, while on replacement therapy with three injections of 40 units/kg prothrombin complex a month. In spite of markedly elevated prothrombin time and partial thromboplastin time, these two infants remain free of major bleeding manifestations except for troublesome petechiae and ecchymoses. A schedule for substitution therapy with Factor X is proposed for infants and children to prevent bleeding in severe Factor X deficiency.

Cord blood IgE levels in the United Arab Emirates.

Cord blood IgE was assayed in 164 newborn babies from the United Arab Emirates. The serum IgE levels ranged between < or = 0.1-13.5 kU/l with a geometric mean of 0.28 kU/l. The cord blood IgE in the 89 babies without immediate family history of allergy was < or = 0.1-3.2 kU/l with a geometric mean of 0.25 kU/l and 1.13 kU/l as the 90th percentile. An influence of prenatal sensitization to helminth antigens on cord blood IgE level was not likely. The data are similar to cord blood IgE values reported in other populations. This indicates that ethnic differences do not influence cord blood IgE levels and that previously published studies on the predictive value of cord blood IgE determination in Caucasians are relevant also for other populations.

Molecular characterization of beta-thalassemia in the United Arab Emirates.

This study is to identify the various beta-thalassemic alleles in the United Arab Emirates (UAE), and compare them with the UAE residents from neighboring countries suffering from the same problem. Gene amplification, dot-blot hybridization with synthetic probes, restriction enzyme analyses, and sequencing were the tools used. Thirteen different mutations were observed in the UAE patients and seventeen mutations in the non-locals. The IVS-I-5 (G-->C) Asian Indian mutation was the most frequent mutation in both groups. Homozygous mutations in both groups were relatively higher than double heterozygous mutations.

A significant beta-thalassemia heterogeneity in the United Arab Emirates.

The Dubai Thalassemia Center has identified 35 different beta-thalassemia mutations in 570 chromosomes from the United Arab Emirates population using gene amplification, hybridization with specific labeled oligonucleotide probes, sequencing of amplified DNA, restriction enzymes, and amplification refractory mutation system techniques. This large number of mutations which represent 21% of the total beta-mutations discovered worldwide reflects the heterogenous nature of the population living in the United Arab Emirates (1). We found that 50% of our beta-thalassemia patients have a concomitant alpha-thalassemia; namely the -alpha 3.7 kb deletion. Co-inheritance of alpha-thalassemia especially in the form of two alpha-globin gene deletions have an ameliorating effect on the phenotype presentation of our beta-thalassemia. Nine patients (one homozygote and eight compound heterozygotes) were identified with Hb Monroe (IVS-I,-1 (G-->C)), a thalassemic hemoglobin characterized by an Arg-->Thr substitution in codon 30 of the beta-globin gene. In addition, one of the patients was a compound heterozygote for Hb Tacoma [IVS-I, +1 (G-->C)]; a point mutation affecting the third nucleotide of codon 30 (G-->C) causing an Arg-->Ser replacement.

A novel frameshift mutation causing beta-thalassemia in a Sikh.

During our survey of beta-thalassemia mutations among residents of the United Arab Emirates, we came across a Sikh family who had two new beta-thalassemia mutations. The father had a frameshift mutation at codons 47/48 (+ATCT), and the mother another frameshift mutation at codons 57/58 (+C). The offspring of this family were two daughters with beta-thalassemia trait and a boy with a compound heterozygosity. The boy, who was transfusion-dependent from the age of 7 months, had a successful bone marrow transplant from his eldest sister at the age of 13 months.

alpha-thalassemia in the United Arab Emirates.

A neonatal screening survey of alpha-thalassemia (alpha-thal) among the United Arab Emirates (UAE) nationals was conducted on 418 consecutive cord blood samples. Our findings demonstrate that 49% of the cases studied were found with an alpha-globin gene defect. The gene frequency of the -alpha3.7 was 0.2847 and that of the -alpha4.2 was 0.0072. Four nondeletional alpha-thal mutations were found; alphaPA-1, alphaPA-2, Hb CS and alpha-5nt del with gene frequencies of 0.0036, 0.0012, 0.0024, and 0.0072, respectively. We also report here the genotype-phenotype correlation in 22 patients with Hb H disease or Hb H-like syndrome. Of these, 6 were homozygous for the alphaPA-1 mutation, 2 were homozygous for Hb CS, and 14 were compound heterozygous for either alphaPA-1, Hb CS, alpha-5nt del or --MED-I, with the -alpha3.7. The data reported here demonstrate that a considerable heterogeneity of alpha-thal mutations occurs in the UAE and that the incidence of alpha-thal in the indigenous population is one of the highest in the world. Our clinical data suggest that Hb H disease in the UAE has, in general, a mild to moderate phenotypic presentation.

Genotype-phenotype correlation of sickle cell disease in the United Arab Emirates.

We have identified the beta s-globin gene haplotypes of 85 patients with sickle cell disease attending the Dubai Thalassemia Center and assessed the influence of haplotype, alpha-thalassemia, and fetal hemoglobin on the clinical presentation. Identification of the beta s haplotypes was based on mutation analyses in the promoter sequences of the G gamma- and A gamma-globin genes. The Arabian-Indian haplotype was found in 52% of the beta s chromosomes, whereas the remaining were the Bantu and Benin haplotypes. Those with the Arabian-Indian haplotype in this group had a significantly higher fetal hemoglobin (Hb F) level (mean 27%) and a milder clinical course. In contrast, those with the African haplotypes, Bantu and Benin, expressed relatively lower Hb F levels (mean 11.3%), with a severe clinical presentation. Coinheritance of alpha-thalassemia trait in the African haplotypes had an ameliorating effect on hemolytic episodes, but vaso-occlusive crises were more frequent.

A comparative study of the awareness and attitude of HIV / AIDS among students living in India and migrants to the United States.

PIP: The authors compared the nature and level of HIV/AIDS awareness among Indian students living in India and those who have migrated to the US. A questionnaire was distributed to 38 college students living in India and 34 college students who had migrated to the US, all aged 18-26 years. 30% of sampled students in India were male compared to 65% in the US. 3% of the students in India and 12% of the students in the US knew someone infected with HIV. 74% of the Indian group and 53% of the US group felt that their knowledge of AIDS was inadequate. 3% of both groups believed that AIDS is completely curable. 13% of the students in India and 23% of the students in the US believe that tuberculosis is linked to HIV infection, both groups consider newspapers and magazines to be good sources of information, 71% of students in India and 50% of students in the US believe that HIV/AIDS education should begin in high school, and 90% of students in India and 79% of students in the US feel that people in India do not know enough about AIDS. The majority felt that high-risk populations should be screened and that there should be more governmental support for HIV/AIDS prevention and control.^ieng

Acclimation Processes in the Light-Harvesting System of the Cyanobacterium Anacystis nidulans following a Light Shift from White to Red Light.

Cyanobacteria acclimate to changes in light by adjusting the amounts of different cellular compounds, for example the light-harvesting macromolecular complex. Described are the acclimatization responses in the light-harvesting system of the cyanobacterium Anacystis nidulans following a shift from high intensity, white light to low intensity, red light.The phycocyanin and chlorophyll content and the relative amount of the two linker peptides (33 and 30 kilodaltons) in the phycobilisome were studied. Both the phycocyanin and chlorophyll content per cell increased after the shift, although the phycocyanin increased relatively more. The increase in phycocyanin was biphasic in nature, a fast initial phase and a slower second phase, while the chlorophyll increase was completed in one phase. The phycocyanin and chlorophyll responses to red light were immediate and were completed within 30 and 80 hours for chlorophyll and phycocyanin, respectively. An immediate response was also seen for the two phycobilisome linker peptides. The amount of both of them increased after the shift, although the 33 kilodalton linker peptide increased faster than the 30 kilodalton linker peptide. The increase of the content of the two linker peptides stopped when the phycocyanin increase shifted from the first to the second phase. We believe that the first phase of phycocyanin increase was due mainly to an increase in the phycobilisome size while the second phase was caused only by an increase in the amount of phycobilisomes. The termination of chlorophyll accumulation, which indicates that no further reaction center chlorophyll antennae were formed, occurred parallel to the onset of the second phase of phycocyanin accumulation.