Chronic treatment of female rhesus monkeys with low doses of the antiprogestin ZK 137 316: establishment of a regimen that permits normal menstrual cyclicity

Large doses of antiprogestin typically disrupt menstrual cyclicity. A chronic low-dose regimen of the potent new antiprogestin ZK 137 316, which permits continued menstrual cyclicity but alters gonadal- reproductive tract activity, was established. Rhesus monkeys received vehicle (n = 6) or 0.01 (n = 8), 0.03 (n = 8) or 0.1 (n = 5) mg ZK 137 316/kg body weight daily for five menstrual cycles (C-1 to C-5). Oestradiol, progesterone and gonadotrophin profiles were normal during cycles involving vehicle and 0.01 and 0.03 mg ZK 137 316/kg body weight. In the 0.1 mg/kg group, mid-cycle oestradiol and gonadotrophin surges, and subsequent progesterone production, were absent in C-3 and C-5. Ovarian cyclicity was accompanied by timely menstruation in the vehicle and 0.01 mg/kg groups. By C-3, half the animals in the 0.03 mg/kg group and all animals in the 0.1 mg/kg group were amenorrhoeic. A corpus luteum was noted during the mid-luteal phase of C-5 in the vehicle, 0.01 mg/kg and 0.03 mg/kg groups. Large antral and cystic follicles were evident in the 0.1 mg/kg group. Thus, a daily treatment with 0.01 mg/kg ZK 136317 permitted normal menstrual cyclicity in macaques. While the daily administration of 0.03 mg/kg ZK 136 317 allowed ovarian cyclicity, menstruation was disrupted in some animals. Increasing the dose to 0.1 mg/kg antagonized pituitary function and resulted in anovulation and amenorrhoea. A chronic low-dose regimen of the antiprogestin ZK 137 316, which permits normal ovarian/menstrual cyclicity, has potential as a contraceptive in women.      

Heterogeneity of immune responsiveness in healthy elderly subjects

We studied a group of healthy elderly subjects (satisfying the SENIEUR Protocol admission criteria), chosen as a model of age-associated immune deficiency on the basis of their reduced skin reactivity to recall antigens. Results show that aged subjects, taken as a whole, display impaired T-cell functions: reduced blastogenetic responses to mitogens, IL-2 production, responsiveness to exogenous IL-2, and percentage of Tac positive blasts. However, the age-associated immune defect shows a wide range of impairment, even in a relatively homogeneous group of anergic/hypoergic subjects. In fact, a considerable proportion of our elderly subjects displays responses comparable with those of adult controls. These observations suggest that (a) immune deficiency is not a characteristic of aging per se; (b) cutaneous delayed hypersensitivity is not a criterion sensitive enough to identify people with age-associated immune deficit; and (c) more than one test is required to evaluate T-cell impairment in aging.     

Granzyme A expression by normal rat natural killer (NK) cells in vivo and by interleukin 2-activated NK cells in vitro

Granzyme A (TSP-1) is a serine esterase expressed in cytotoxic T and natural killer (NK) cell lines. Its presence in in vivo primed T cells is disputed at present. Here we show that normal rat NK cells contain granzyme A in vivo and that its expression is augmented by their short-term in vitro treatment with IL 2. Granzyme A expression in a NK cell population with LAK activity has also been examined.     

Localization of neurons projecting into the extrinsic penile smooth musculature of the pig: an experimental study on the retractor penis muscle

The aim of this study was to locate in male pigs the sensory and autonomic ganglia innervating the retractor penis muscle (RPM), which was taken as an experimental model of the genital smooth musculature. The retrograde neuronal tracers horseradish peroxidase (HRP), Fast Blue (FB), and diamidino yellow (DY) were injected into the bulbopenile portion of the left RPM. The tracers highlighted a different affinity for the neuronal structures, although labelled cells supplying the RPM were generally found in bilateral dorsal root ganglia (DRGs, S1-S3), in bilateral paravertebral ganglia (PaGs, L2-S3), and in the left and right caudal mesenteric ganglia (CMGs). The mean number of labelled FB cells was 795 (range, 645-952) in DRGs, 16046.25 (range, 10226-18742) in PaGs, and 635.25 (range, 333-786) in CMGs. The mean diameter of pseudounipolar DRG cells was 60-75 microm, while the multipolar neurons of PaGs and CMGs had dimensions varying between 20-50 microm and 20-30 microm, respectively.     

Lectin histochemistry on the dorsal epidermis of the Breton dog

Expression of sugar residues and the nature of oligosaccharide linkage during keratinocyte maturation in the epidermis of the Breton dog were studied with the use of lectin histochemistry. Thirteen lectins were used. Labelling was not observed with GSA I-B4, GSA II, UEA-I, and LTA. The cytoplasm of keratinocytes reacted with PNA, HPA, Con A, and WGA from the basal layer to the granular layer. PNA and Con A showed highest reactivity in the granular cell layer. The cell surface showed increased reactivity with PNA, HPA, and WGA with maturation of keratinocytes. KOH-neuraminidase treatment (KOH-Neu) increased PNA and RCA120 staining during keratinocyte differentiation thus indicating an increase in oligosaccharides terminating with sialic acid-Galbeta(1,3)GalNAc and sialic acid-Galbeta(1,4)GlcNAc, respectively. Labelling of the glycocalyx of basal and spinous keratinocytes with SNA and MAA revealed terminal Neu5acalpha(2,6)Gal/GalNAc and Neu5acalpha(2,3)Galbeta(1,4)GlcNAc. KOH-Neu-DBA showed oligosaccharides terminating with sialic acid-GalNAcalpha(1,3)GalNAc in the spinous and granular layers. A selective glycocalyx labelling of granular keratinocytes was observed with DBA and SBA. Reactions with MAA, PNA, DBA, RCA120, SBA, HPA, and WGA disappeared after the beta-elimination reaction. Our findings indicate that Breton dog epidermis contains more O-linked than N-linked oligosaccharides and confirm that different subpopulations of keratinocytes can be distinguished by lectin histochemistry.     

Efficient T cell activation requires an optimal dwell-time of interaction between the TCR and the pMHC complex

Cytotoxic T cell (CTL) activation by antigen requires the specific detection of peptide-major histocompatibility class I (pMHC) molecules on the target-cell surface by the T cell receptor (TCR). We examined the effect of mutations in the antigen-binding site of a Kb-restricted TCR on T cell activation, antigen binding and dissociation from antigen.These parameters were also examined for variants derived from a Kd-restricted peptide that was recognized by a CTL clone. Using these two independent systems, we show that T cell activation can be impaired by mutations that either decrease or increase the binding half-life of the TCR-pMHC interaction. Our data indicate that efficient T cell activation occurs within an optimal dwell-time range of TCR-pMHC interaction. This restricted dwell-time range is consistent with the exclusion of either extremely low or high affinity T cells from the expanded population during immune responses.     

A novel mutation of varicella-zoster virus associated to fatal hepatitis.

BACKGROUND: Lethal varicella in immunocompetent hosts is rare and its pathogenesis is largely unknown. The discovery of glycoprotein E (gE) mutants showing attributes consistent with increased virulence in vitro and in animal models, provided a possible molecular mechanism underlying a more aggressive virus infection. However, these mutants have never been associated with unusually severe clinical cases. OBJECTIVES: To varicella-zoster virus (VZV) mutations that correlate with increased virulence. RESULTS: We report a case of fatal hepatitis caused by a VZV bearing a novel mutation on the 3B3 monoclonal antibody epitope of gE in an immunocompetent host. CONCLUSIONS: This report describes a mutant VZV responsible for an aggressive clinical course in an immunocompetent host. Linking these severe clinical presentations of VZV infection to virus mutations might provide insights into the underlying pathogenic mechanisms.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Physicians at the roadside: Pre-hospital emergency care in the United Kingdom

In some parts of the United Kingdom (UK), family doctors (or "general practitioners" as they are called in the UK) are routinely called upon by the emergency medical services (EMS) system to attend road accidents. The doctors are volunteers and travel to the scene of the accident in their own cars. Members of one such general practitioner accident service operating in Mid-Anglia complete an accident report form after attending each incident. In 1983, the Mid-Anglia General Practitioner Accident Service (MAGPAS) received 1,715 calls for medical assistance, and in 95% of these a doctor was sent immediately. Of these calls, 57% were passed to the doctor within one minute of the receipt of the call in the MAGPAS control room, and 78% were relayed within two minutes. This rapid call-out, combined with the close proximity of the local doctor to the accident site, resulted in the doctors arriving ahead of the ambulance in 42% of the calls. A total of 54 patients with airway obstruction were treated by the doctors prior to the arrival of the ambulance. Ninety-nine patients required immediate intravenous fluid replacement in the pre-hospital phase of their medical care. This report suggests that general practitioners in rural areas can play a vital role in the early management of trauma patients, especially in the absence of ambulance personnel trained in advanced life support skills.     

Breast cancer in young women: Imaging and clinical course

The purpose of this study was to characterize presenting imaging findings in women younger than 40 diagnosed with invasive breast cancer in the context of pathology and clinical course. Retrospective chart and imaging reviews were performed in patients under 40 diagnosed with breast cancer between July 1, 2004, and December 31, 2013. Patient demographic, imaging, pathology, and clinical data were collected. Overall and recurrence-free survival were estimated using the Kaplan-Meier method. Univariate Cox proportional hazards models were performed to identify factors associated with recurrence-free survival. Our study cohort consisted of 110 patients with invasive mammary carcinoma. One hundred one (91.8%) presented with a palpable mass. The mean size of all lesions on imaging was 3.5 cm ± 2.9 cm. Malignant calcifications were present in 54 (49.1%) cases. Imaging demonstrated multifocal or multicentric disease in 45 (40.9%) cases. Seventy four (67.3%) cancers were high grade. Luminal genomic subtypes were the most common (n = 61, 55.5%). At presentation, 4 (3.6%) patients had bilateral malignancy and 8 (7.3%) patients had distant metastatic disease. Ninety seven (88.2%) underwent neoadjuvant chemotherapy and 67 (60.9%) underwent radiation therapy. Seventy five (68.2%) of the patients underwent mastectomy. The restricted mean time to recurrence was 9.01 years (standard error 3.162 months). ER positivity was associated with compromised recurrence-free survival. The overall survival rate was 0.962 at 10 years. Young patients diagnosed with breast cancer typically present with advanced breast imaging findings and undergo aggressive treatment. Recurrence often occurs >5 years from diagnosis, and ER positive subtypes are at increased risk for recurrence.