Influence of antibody diversification on the mechanism of haplotype exclusion of immunoglobulin gene expression

Allelic, or haplotype, exclusion of immunoglobulin gene expression ensures that the products of a single allele or light chain isotype are expressed on the B cell surface. Evidence has accumulated in rodent and primate models to indicate that the products of successful rearrangement regulate this process. In contrast, haplotype exclusion of chicken immunoglobulin gene expression is regulated at the level of variable region gene rearrangement. We discuss here alternative models for ensuring haplotype exclusion that may operate in the chicken and extend the discussion to address the issue as to how two apparently distinct mechanisms may have evolved to yield the same outcome.     

Correlation of dietary intake and colorectal cancer incidence among Mexican-American migrants: the multiethnic cohort study

Studies of migrants, along with geographic and temporal variations in incidence, indicate that colorectal cancer is especially sensitive to changes in environmental factors, including, most importantly, diet. The goal of this research was to examine the changes in dietary practices that may be consistent with the changing incidence of colorectal cancer in the Los Angeles Mexican-American population. Cancer incidence and dietary intake data were available for over 35,000 Latinos of Mexican national origin currently participating in the prospective Multiethnic Cohort Study, representing the largest sample of Mexican-origin Latinos of any such study in the United States. The dataset is unique in that changes in cancer rates and in dietary behaviors across three generations could be examined. Most of the change in colorectal cancer rates occurred between the first and second generations, and, correspondingly, nearly all the dietary change also occurred between the first and second generations. Although some food traditions were retained by Mexican Americans, the dietary changes due to acculturation were significant and support an association between colorectal cancer risk and certain dietary components, notably, alcohol as a risk factor and nonstarch polysaccharides and vegetables as protective factors.     

Quantitative T2 in the occipital lobe: the role of the CPMG refocusing rate

PURPOSE: To investigate the dependence of occipital gray and white matter T(2) on the Carr-Purcell-Meiboom-Gill (CPMG) refocusing interval, thereby testing the basis of a novel functional magnetic resonance imaging (fMRI) method for blood volume quantification, and addressing recent questions surrounding T(2) contrast in the occipital lobe. MATERIALS AND METHODS: A CPMG sequence with 1 x 1 x 5 mm(3) resolution was used to quantify T(2) in a single axial slice at the midlevel of the occipital lobe in 23 healthy adult volunteers. Refocusing intervals of 8, 11, and 22 msec were compared. A Bayesian classifier was used to classify a 1 x 1 x 1 mm(3) T(1)-weighted three-dimensional data set into gray matter, white matter, and cerebrospinal fluid, with an average 95% a posteriori probability used as the threshold for inclusion into a tissue-specific region of interest (ROI). RESULTS: The usual T(2) contrast between the gray and white matter (i.e., T(2GM) > T(2WM)) was observed, with a highly significant effect of tissue type on the estimated T(2) (P < 10(-5)). The observed T(2) gradually decreased with increasing refocusing interval, for a decrease of 3.3 +/- 1.5 msec in gray matter and 3.0 +/- 1.5 msec in white matter between the 8 and 22 msec refocusing interval acquisitions. CONCLUSION: The observed T(2) shortening is consistent with the effect of the dramatic decrease in T(2) of partly deoxygenated blood on this range of refocusing rates.     

Surveillance of Scrub Typhus in the fringe areas around Pune : Potential for Transmission does exist

A field based epidemiological study was undertaken to assess the potential of transmission of scrub typhus in the sylvatic and transitional (fringe) areas at ten different locations around Pune. Parameters studied included rodent trapping and identification, entomological parameters, immunological studies on rodent sera, and rodent organ impression smears. The study revealed that Rattus r rufescence, Rattus meltada, Suncus murinus and Rattus blanfordi were the predominant sylvatic rodent species. All the species showed mild to moderate infestation with trombiculid mite larvae, with Rr rufescence and S murinus showing even higher levels of infestation. Pooled rodent sera showed mild rise of OX2 in 13.9%, OX19 in 5.6% and OXK in 9.8% of the pooled sera. The rise in titres was appreciable among rodents from Lonavala, Khadakvasla, Panchet, Singhgadh and Kondhwa areas. Based on the findings of the study, certain recommendations on prevention, surveillance and epidemic investigations of scrub typhus in the Armed Forces have been submitted.Key Words: Mite, Rodent, Scrub typhus, Weil-Felix     

Estrogen and exercise interact to regulate brain-derived neurotrophic factor mRNA and protein expression in the hippocampus

We investigated the possibility that estrogen and exercise interact in the hippocampus and regulate brain-derived neurotrophic factor (BDNF), a molecule increasingly recognized for its role in plasticity and neuron function. An important aspect of this study is to examine the effect of different time intervals between estrogen loss and estrogen replacement intervention. We demonstrate that in the intact female rat, physical activity increases hippocampal BDNF mRNA and protein levels. However, the exercise effect on BDNF up-regulation is reduced in the absence of estrogen, in a time-dependent manner. In addition, voluntary activity itself is stimulated by the presence of estrogen. In exercising animals, estrogen deprivation reduced voluntary activity levels, while estrogen replacement restored activity to normal levels. In sedentary animals, estrogen deprivation (ovariectomy) decreased baseline BDNF mRNA and protein, which were restored by estrogen replacement. Despite reduced activity levels in the ovariectomized condition, exercise increased BDNF mRNA levels in the hippocampus after short-term (3 weeks) estrogen deprivation. However, long-term estrogen-deprivation blunted the exercise effect. After 7 weeks of estrogen deprivation, exercise alone no longer affected either BDNF mRNA or protein levels. However, exercise in combination with long-term estrogen replacement increased BDNF protein above the effects of estrogen replacement alone. Interestingly, protein levels across all conditions correlated most closely with mRNA levels in the dentate gyrus, suggesting that expression of mRNA in this hippocampal region may be the major contributor to the hippocampal BDNF protein pool. The interaction of estrogen, physical activity and hippocampal BDNF is likely to be an important issue for maintenance of brain health, plasticity and general well-being, particularly in women.     

The influence of chemotherapy on the prognosis of rhabdomyosarcoma

A study of 77 consecutive cases of childhood rhabdomyosarcoma treated initially at the Children's Hospital of Los Angeles from 1950 to 1972 demonstrated an impressive improvement in survival of patients when intensive chemotherapy was combined with surgery and radiation therapy. The major improvement in survival occurred in Stage II and Stage III disease. Eight out of 9 patients with a primary lesion of the lower extremities developed intra-abdominal disease. A general approach for treatment of Stage II, III, and IV rhabdomyosarcoma is proposed which involves intensive chemotherapy, following biopsy, as the principle treatment, with radiation and surgery used as adjuvants.     

PET imaging of brain 5-HT1A receptors in rat in vivo with 18F-FCWAY and improvement by successful inhibition of radioligand defluorination with miconazole.

18F-FCWAY (18F-trans-4-fluoro-N-(2-[4-(2-methoxyphenyl) piperazin-1-yl)ethyl]-N-(2-pyridyl)cyclohexanecarboxamide) is useful in clinical research with PET for measuring serotonin 1A (5-HT1A) receptor densities in brain regions of human subjects but has significant bone uptake of radioactivity due to defluorination. The uptake of radioactivity in skull compromises the accuracy of measurements of 5-HT1A receptor densities in adjacent areas of brain because of spillover of radioactivity through the partial-volume effect. Our aim was to demonstrate with a rat model that defluorination of 18F-FCWAY may be inhibited in vivo to improve its applicability to measuring brain regional 5-HT1A receptor densities. METHODS: PET of rat head after administration of 18F-FCWAY was used to confirm that the distribution of radioactivity measured in brain is dominated by binding to 5-HT1A receptors and to reveal the extent of defluorination of 18F-FCWAY in vivo as represented by radioactivity (18F-fluoride ion) uptake in skull. Cimetidine, diclofenac, and miconazole, known inhibitors of CYP450 2EI, were tested for the ability to inhibit defluorination of 18F-FCWAY in rat liver microsomes in vitro. The effects of miconazole treatment of rats on skull radioactivity uptake and, in turn, its spillover on brain 5-HT1A receptor imaging were assessed by PET with venous blood analysis. RESULTS: PET confirmed the potential of 18F-FCWAY to act as a radioligand for 5-HT1A receptors in rat brain and also revealed extensive defluorination. In rat liver microsomes in vitro, defluorination of 18F-FCWAY was almost completely inhibited by miconazole and, to a less extent, by diclofenac. In PET experiments, treatment of rats with miconazole nitrate (60 mg/kg intravenously) over the 45-min period before administration of 18F-FCWAY almost obliterated defluorination and bone uptake of radioactivity. Also, brain radioactivity almost doubled while the ratio of radioactivity in receptor-rich ventral hippocampus to that in receptor-poor cerebellum almost tripled to 14. The plasma half-life of radioligand was also extended by miconazole treatment. CONCLUSION: Miconazole treatment, by eliminating defluorination of 18F-FCWAY, results in effective imaging of brain 5-HT1A receptors in rat. 18F-FCWAY PET in miconazole-treated rats can serve as an effective platform for investigating 5-HT1A receptors in rodent models of neuropsychiatric conditions or drug action.     

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT₄) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT₄ receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT₄ receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT₄ receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [¹²³I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT₄ receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT₄ receptor antagonist, SB 204070, at 20 min before [¹²³I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [¹²³I]SB 207710 is an effective radioligand for imaging brain 5-HT₄ receptors in vivo.For preliminary accounts of this work, see Pike VW et al., J Nucl Med 1998; 39 (Suppl):185; Eur J Nucl Med 1999; 26:991.