Ovarian oestrogen-dependent maturation of the LH/FSH surge mechanism during prepubertal development in the gilt

An involvement of ovarian secretions and in particular oestradiol-17 beta in the maturation of the positive feedback mechanism controlling gonadotrophin surge secretion was studied in prepubertal gilts. The LH/FSH responses to an intramuscular injection of age- and body weight-related doses of oestradiol benzoate (OB) were compared in intact gilts at 60 days of age with or without oestradiol-17 beta pretreatment from 30 to 52 days of age. Four further groups of gilts were challenged with OB at 160 days and were intact, ovariectomized at 60 days, ovariectomized at 60 days and given oestrogen therapy from days 60 to 130 or ovariectomized at 130 days. A significant increase in the magnitude of LH surge responses to OB and a decrease in the time to the first consistent period of surge secretion in intact gilts at 160 compared to 60 days of age confirmed earlier studies and is considered to represent a real maturational change in positive feedback activity. A longer response interval was also present in the majority of ovariectomized gilts. Furthermore a significant reduction in the magnitude of OB-induced LH responses at day 160 occurred in gilts ovariectomized at day 60 compared to those ovariectomized at day 130 and with intact control animals. Oestrogen therapy after ovariectomy at day 60 effectively restored the magnitude of the LH response however. It is concluded that maturation of the positive feedback mechanism is ovarian, and probably oestrogen, dependent.     

Use of anorectal manometry during rectal infusion of saline to investigate sphincter function in incontinent patients

Anal and rectal pressures and external sphincter electromyogram were recorded continuously during rectal infusion of 1.5 L saline in 18 normal subjects and 37 patients who complained of diarrhea and fecal incontinence. All subjects exhibited a pattern of regular fluctuations in anorectal pressure and electromyogram. All except 1 of the normal subjects were able to retain 1500 ml saline without leakage, and their pressure record comprised simultaneous rectal contractions, internal sphincter relaxations, and external sphincter contractions. None of the incontinent patients were able to retain 1500 ml saline without leakages, and leakages always coincided with the peaks of rectal pressure. Two manometric patterns were observed. Fifty-nine percent of incontinent patients exhibited a pattern of contractions of similar profile occurring throughout the anorectum. This finding was associated with low basal sphincter pressures, an easily inhibited anal sphincter tone, an obtuse anorectal angle, and a funnel-shaped configuration to the anal canal. These results suggested that, in this group, the internal sphincter was weak and easily inhibited so that the whole anorectum behaved as one fluid-filled compartment recording contractions of the external sphincter. The remaining 41% of incontinent patients exhibited a normal pattern of anorectal pressure fluctuations and had normal maximum basal pressures, although maximum squeeze pressures, rectoanal inhibitory reflex, and anorectal angles were abnormal. Peak rectal pressures were abnormally high in this group during saline infusion, suggesting that abnormally strong rectal contractions may play a role in the incontinence in this group.     

Conversion of a stem cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2''-deoxycoformycin.

Selective failure of lymphoid development occurs in genetic deficiency of adenosine deaminase (ADA). We examined the in vivo effects of a potent inhibitor of ADA, 2'-deoxycoformycin, which was used to treat a patient with refractory acute leukemia. Unexpectedly, within 7 days of starting treatment, the leukemic phenotype underwent complete conversion from T lymphoblastic to promyelocytic, with kinetics that suggested a precursor-product relationship between the two cell populations. Pretreatment T lymphoblasts and posttreatment promyelocytes had the same abnormal karyotype. Upon culture in vitro, the former transformed spontaneously over several weeks into mature myeloid cells. We conclude that the leukemia arose from a multipotent stem cell capable of both lymphoid and myeloid differentiation. Effects of ADA inhibition on leukemia cells during treatment included expansion of the deoxyadenosine nucleotide pool and accumulation of S-adenosylhomocysteine, a potent inhibitor of S-adenosylmethionine-dependent methylation. The influence of these changes on the leukemic phenotype is discussed in terms of (i) selective cytotoxicity to T lymphoblasts, which accumulated deoxyadenosine nucleotides more efficiently than did the patient's promyelocytes during in vitro incubation with deoxycoformycin plus deoxyadenosine, and (ii) induction of an altered program of differentiation.     

A New Model for Catalyzing Translational Science: The Early Stage Investigator Mentored Research Scholar Program in HIV Vaccines

Engagement of early stage investigators (ESIs) in the search for a safe and effective vaccine is critical to the success of this highly challenging endeavor. In the wake of disappointing results from a large‐scale efficacy trial, the HIV Vaccine Trials Network (HVTN) and Center for HIV/AIDS Vaccine Immunology (CHAVI) developed a novel mentored research program focused on the translation of findings from nonhuman primate studies to human trials of experimental vaccines. From 2008 to 2011, 14 ESI Scholars were selected from 42 complete applications. Post program surveys and tracked outcomes suggest that the combination of flexible funding, transdisciplinary mentorship, and structured training and networking promoted the scientific contributions and career development of promising ESIs. Embedding a multicomponent research program within collaborative clinical trial networks and research consortia is a promising strategy to attract and retain early career investigators and catalyze important translational science.