Relapse of pemphigus vulgaris after topical application of ingenol mebutate.

Ingenol mebutate is a recently approved topical agent for the treatment of actinic keratosis. Its most common adverse effects are transient local skin reactions. We report a 63-year-old white man who presented with a red-brownish crusted plaque involving the dorsum of his nose and an eroded area on his lower lip, which appeared soon after topical application of ingenol mebutate gel. Clinical, histological and immunopathological features were consistent with a diagnosis of pemphigus vulgaris (PV). To our knowledge, this is the first report of relapse of PV after topical application of ingenol mebutate gel. The temporal relationship between the application of the drug and the outbreak of PV supports the involvement of this agent in triggering the disease. It is plausible that ingenol mebutate may have induced the disease by its action on the production of proinflammatory cytokines.

Environmental quality of the operating theaters in Campania Region: long lasting monitoring results.

BACKGROUND: The health risk level in the operating theaters is directly correlated to the safety level offered by the healthcare facilities. This is the reason why the national Authorities released several regulations in order to monitor better environmental conditions of the operating theaters, to prevent occupational injuries and disease and to optimize working conditions. For the monitoring of environmental quality of the operating theaters following parameters are considered: quantity of supplied gases, anesthetics concentration, operating theatres volume measurement, air change rate, air conditioning system and air filtration. The objective is to minimize the risks in the operating theaters and to provide the optimal environmental working conditions. This paper reports the environmental conditions of operating rooms performed for several years in the public hospitals of the Campania Region. METHODS: Investigation of environmental conditions of 162 operating theaters in Campania Region from January 2012 till July 2014 was conducted. Monitoring and analysis of physical and chemical parameters was done. The analysis of the results has been made considering specific standards suggested by national and international regulations. RESULTS: The study showed that 75% of the operating theaters presented normal values for microclimatic monitoring, while the 25% of the operating theaters had at least one parameter outside the limits. The monitoring of the anesthetics gases showed that in 9% of measurements of nitrous oxides and 4% of measurements of halogenated was not within the normal values.

The kiwi fruit peptide kissper displays anti-inflammatory and anti-oxidant effects in in-vitro and ex-vivo human intestinal models.

Literature reports describe kiwi fruit as a food with significant effects on human health, including anti-oxidant and anti-inflammatory activity. Fresh fruit or raw kiwi fruit extracts have been used so far to investigate these effects, but the molecule(s) responsible for these health-promoting activities have not yet been identified. Kissper is a kiwi fruit peptide displaying pore-forming activity in synthetic lipid bilayers, the composition of which is similar to that found in intestinal cells. The objective of this study was to investigate the kissper influence on intestinal inflammation using cultured cells and ex-vivo tissues from healthy subjects and Crohn's disease (CD) patients. The anti-oxidant and anti-inflammatory properties of kissper were tested on Caco-2 cells and on the colonic mucosa from 23 patients with CD, by challenging with the lipopolysaccharide from Escherichia coli (EC-LPS) and monitoring the appropriate markers by Western blot and immunofluorescence. EC-LPS challenge determined an increase in the intracellular concentration of calcium and reactive oxygen species (ROS). The peptide kissper was highly effective in preventing the increase of LPS-induced ROS levels in both the Caco-2 cells and CD colonic mucosa. Moreover, it controls the calcium increase, p65-nuclear factor (NF)-kB induction and transglutaminase 2 (TG2) activation inflammatory response in Caco-2 cells and CD colonic mucosa. Kissper efficiently counteracts the oxidative stress and inflammatory response in valuable model systems consisting of intestinal cells and CD colonic mucosa. This study reports the first evidence supporting a possible correlation between some beneficial effects of kiwi fruit and a specific protein molecule rather than generic nutrients.

Cutaneous melanoma in solid organ transplant patients.

Solid organ transplant patients are at greatly increased risk of developing a wide variety of skin cancers, particularly epithelial skin cancers. On the other hand, it is well known that an intact immune system limits the development of benign melanocytic lesions. The eruptive nevi phenomenon, which we can observe in solid organ transplant recipients, is indicative of the relationship between melanocyte proliferation and immune system. Regression of melanocytic nevi after restoration of complete immune responsiveness is a further clinical example the role of immunosurveillance on melanocyte proliferation. However, melanoma incidence in organ transplant recipients appears only 2-3 folds higher than in general population. To this regard, organ transplant recipients who develop de novo melanomas thicker than 2mm seem to have a significantly worse outcome with a greatly increased risk of dying of metastatic melanoma, whereas those who develop a ≤2 mm thickness melanoma seem to have a prognosis similar to that of the general population. Furthermore, there is no evidence supporting an increased risk of melanoma recurrences after transplant in patients with a history of low-risk melanoma. Melanoma is also one of the most frequent and lethal donor-derived malignancies suggesting that a history of invasive melanoma should be considered an absolute contraindication to donation. The aim of this review is to investigate the relationship between immunosuppression and melanoma and to discuss its clinical implications for the management of transplant-associated melanoma.

Current practice and recent advances in pediatric pain management.

BACKGROUND: Differently from the adult patients, in pediatric age it is more difficult to assess and treat efficaciously the pain and often this symptom is undertreated or not treated. In children, selection of appropriate pain assessment tools should consider age, cognitive level and the presence of eventual disability, type of pain and the situation in which it is occurring. Improved understanding of developmental neurobiology and paediatric analgesic drugs pharmacokinetics should facilitate a better management of childhood pain. AIM: The objective of this review is to discuss current practice and recent advances in pediatric pain management. METHODS: Using PubMed we conducted an extensive literature review on pediatric pain assessment and commonly used analgesic agents from January 2000 to January 2012. CONCLUSIONS: A multimodal analgesic regimen provides better pain control and functional outcome in children. Cooperation and communication between the anaesthesiologist, surgeon, and paediatrician are essential for successful anaesthesia and pain management.

Notes on the conservation threats to the western lesser spot-nosed monkey (Cercopithecus petaurista buettikoferi) in the Bijagós Archipelago (Guinea-Bissau, West Africa).

The lesser spot-nosed monkey (Cercopithecus petaurista) is a widely distributed West African guenon, which is generally considered less vulnerable to local extinctions than many sympatric primate species. Guinea-Bissau harbours the westernmost populations of the species, which is thought to be very rare or even extinct on the mainland, but to have putative populations on some islands of the Bijagós Archipelago. However, due to a lack of regional studies, baseline information on these insular populations is missing. We collected baseline data on the anthropogenic activities that possibly threaten the long-term conservation of this primate by using non-systematic ethnographic methodologies. The species was reported to be decreasing in number or rare by locals on two of the islands, and we identified two main conservation threats to it: generalised habitat loss/degradation, and hunting. While subsistence hunting has been recorded before in these areas, we report, to the best of our knowledge for the first time for these islands, the presence of a semi-organised commercial wild meat trade. The carcasses of western lesser spot-nosed monkeys were observed being stored and shipped from seaports to be sold at urban hubs (Bissau and Bubaque Island). The effect of commercial trade on the species could be severe, considering the small, naturally occurring, carrying capacities typical of insular ecosystems. The results of this study highlight the importance of understanding the leading social drivers of wild meat hunting of lesser spot-nosed monkeys on the Bijagós Archipelago, and the need to conduct baseline research on these insular populations, for which qualitative and quantitative methods could be combined.

Human parvovirus B 19 and Epstein-Barr virus co-infection in a child with hereditary spherocytosis.

BACKGROUND: In patients with chronic congenital haemolytic disorders, human Parvovirus B19 (HPV B19) is frequently involved in pure red-cell aplastic crises. Furthermore, it may inhibit three-lineage haematopoiesis in the bone marrow, causing severe pancytopenia. In such patients, Epstein Barr virus (EBV) infection also seems to share the same mechanism as HPV B19 in inducing bone marrow aplasia, but at present the clinical effect of an infection sustained by both viruses is unknown. CLINICAL REPORT: We present a 7-year-old boy affected by hereditary spherocytosis (HS) who suffered from transient aplastic crisis, in whom laboratory findings revealed a double HPV B19 and EBV infection. CONCLUSIONS: To our knowledge, this is the first report of a case of HPV B19 and EBV co-infection diagnosis in a paediatric patient. Despite underlying HS, no signs of haemolytic anaemia were detected, but the infection only produced transient pancytopenia. Nevertheless, the reason why there was no additive effect of the two viruses on the aplastic crisis is still unclear.

CD30+ lymphoproliferative disorders of the skin: still an open question.

CD30+ lymphoproliferative disorders of the skin represent a well-defined spectrum of primary cutaneous T-cell lymphomas. They include lymphomatoid papulosis and cutaneous anaplastic large-cell lymphoma which are characterized by the common expression of the CD30 antigen, but different clinical, histological and molecular features. Recent progress in the pathobiology and identification of therapeutic targets has contributed to our current understanding of this peculiar group of cutaneous lymphoproliferative disorders. The characteristic features of this group of cutaneous lymphoproliferative disorders are reviewed with particular emphasis to their diagnosis and treatment strategies.

Markers of Cardiotoxicity in Early Breast Cancer Patients Treated With a Hypofractionated Schedule: A Prospective Study.

PURPOSE: To evaluate, in a series of early breast cancer (BC) patients treated with hypofractionated adjuvant radiotherapy (RT), whether N-terminal-pro hormone B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I assay measurements can predict acute clinical or preclinical cardiotoxicity. PATIENTS AND METHODS: The study comprised 44 consecutive patients, who underwent conservative surgery with or without (neo)adjuvant chemotherapy and hypofractionated adjuvant RT. The RT schedule consisted in a total dose of 42.4 Gy in 16 fractions administered 5 days per week. Twenty-one patients received a subsequent boost to the tumor bed consisting of a total dose of 10 Gy in 4 fractions delivered via a direct electron field. All patients underwent 12-lead electrocardiogram, echocardiogram, and cardiac clinical examinations before RT to assess cardiovascular risk factors; these examinations were repeated yearly for 5 consecutive years. High-sensitivity cardiac troponin I and NT-proBNP were analyzed from serum samples at baseline, after delivery of the fourth and 16th RT fractions, and 12 months after treatment completion. RESULTS: No increase in cardiac troponin I and B-type natriuretic peptide levels related to left breast irradiation was observed. No statistical difference in NT-proBNP and high-sensitivity troponin I levels between left- and right-sided BC was found. An increase was observed of B-type natriuretic peptide levels at baseline, during treatment, and until 12 months after RT related to hypertension, with the P value near to the .05 threshold for age and chemotherapy. CONCLUSION: Conformational hypofractionated RT in left-sided BC may not cause acute myocardial damage. Early cardiac screening may be used to identify patients with cardiologic risk factors, patients who are older than 60 years, and patients who received chemotherapy that could result in clinically relevant cardiac pathologies.

In ataxia-teleangiectasia betamethasone response is inversely correlated to cerebellar atrophy and directly to antioxidative capacity.

BACKGROUND AND PURPOSE: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by alterations of the A-T mutated (ATM) gene. Although A-T is a non-curable disease, we, previously, documented a clear improvement of cerebellar functions during a short-term betamethasone trial. The aim of this study was to define the underlying biochemical mechanism. METHODS: In six A-T patients receiving a short-term steroid therapy, intracellular glutathione (GSH) levels were evaluated with a colorimetric assay. The lipid peroxidation level and reactive oxygen species (ROS) production were evaluated using commercial assays. All the parameters were compared with the improvement of cerebellar functions expressed as delta (Delta) of the Scale for the Assessment and Rating of Ataxia (SARA). RESULTS: We observed an inverse correlation between Delta SARA and the severity of cerebellar atrophy and between the latter and basal GSH values. Four of the five patients with the highest Delta SARA also had the highest GSH values. Moreover, even though basal ROS values were comparable in patients and controls, in the only patient studied at different time-points of therapy, a remarkable reduction in ROS levels was documented. CONCLUSION: We suggest that antioxidative mechanisms play a role in favouring the improvement of cerebellar functions observed in A-T patients receiving a short-term betamethasone trial.

Platelet dysfunction in central obesity.

Central obesity is a relevant risk factor for major cardiovascular events due to the atherosclerotic involvement of coronary, cerebral and lower limb arterial vessels. A major role in the increased cardiovascular risk is played by platelets, which show an increased activation and a reduced sensitivity to the physiological and pharmacological antiaggregating agents. This review focuses on platelet dysfunction in central obesity. The mechanisms involved are related to: i) the reduced sensitivity to insulin and other substances acting via intracellular cyclic nucleotides, such as nitrates and prostacyclin; ii) the altered intracellular ionic milieu with elevated cytosolic Ca(2+); and iii) the increased oxidative stress, which elicits isoprostane production from arachidonic acid. Therapeutic guidelines recommend a multifactorial prevention of cardiovascular disease including antiplatelet drugs in high risk patients, even though, at present, the protective effect of antiplatelet therapy in obese, insulin resistant subjects has not been evaluated by specific trials. Some reports, however, suggest a decreased sensitivity to the antiaggregating effects of both acetylsalicylic acid (aspirin) and thienopyridines in human obesity. Platelet defects may play a pivotal role in the reduced efficacy of antiplatelet therapy in obese subjects in the setting of cardiovascular prevention and acute coronary syndrome treatment. Thus, a specifically tailored antiaggregating therapy is likely necessary in obese, insulin resistant subjects, especially in the presence of type 2 diabetes mellitus.

Efficacy of budesonide therapy in the early phase of treatment of adult coeliac disease patients with malabsorption: an in vivo/in vitro pilot study.

1. Budesonide is a glucocorticosteroid with a local anti-inflammatory effect. Coeliac disease is an immune-mediated disease caused by gluten ingestion in intolerant patients. The aim of the present study was to investigate the efficacy of budesonide in malabsorptive coeliac patients and its effect in an in vitro gliadin challenge. 2. Twenty coeliac patients with malabsorption were enrolled in the present study and were randomly assigned to one of two 4 week treatments: (i) a gluten-free diet alone; or (ii) a gluten-free diet plus 6 mg budesonide daily. At the end of 4 weeks treatment, all patients underwent clinical evaluation, laboratory tests and self-evaluation of well-being using a visual analogue scale. Intestinal biopsies from five coeliac patients (selected randomly) and four non-coeliac disease controls who underwent upper endoscopy for intestinal bleeding were challenged with gliadin (0.5 mg/mL) and budesonide (10-30 microg/mL) for 3 and 24 h. Biopsies were tested by immunohistochemistry and immunofluorescence for known markers of inflammation. 3. Treatment of patients with 6 mg budesonide daily for 4 weeks resulted in increased bodyweight, a decreased number of evacuations and decreased stool weight compared with patients on a gluten-free diet alone for 4 weeks. Well-being scores were higher in patients treated with both a gluten-free diet and budesonide compared with those receiving a gluten-free diet alone. 4. In vitro studies showed that budesonide reduced epithelial tyrosine phosphorylation and expression of histocompatibility leucocyte antigen complex DR (HLA-DR) elicited by gliadin-derived peptides. In addition, the expression of cyclo-oxygenase (COX)-2 and intercellular adhesion molecule (ICAM)-1 in the lamina propria was reduced in patients treated with both gliadin and budesonide compared with patients treated with gliadin alone. Budesonide alone decreased HLA-DR in crypt enterocytes, as well as ICAM-1 and COX-2 expression in the lamina propria of biopsy specimen of coeliac patients. Budesonide had no effect in control samples. 5. In conclusion, the results of the present study indicate that budesonide shows efficacy in the treatment of symptoms in adult coeliac patients with overt malabsorption. The mechanism underlying the effects of budesonide in reducing symptoms was elucidated by in vitro studies involving a gliadin challenge.

Resistance to the nitric oxide/cyclic guanosine 5'-monophosphate/protein kinase G pathway in vascular smooth muscle cells from the obese Zucker rat, a classical animal model of insulin resistance: role of oxidative stress.

Some in vivo and ex vivo studies demonstrated a resistance to the vasodilating effects of nitric oxide (NO) in insulin-resistant states and, in particular, obese Zucker rats (OZR). To evaluate the biochemical basis of this phenomenon, we aimed to identify defects of the NO/cGMP/cGMP-dependent protein kinase (PKG) pathway in cultured vascular smooth muscle cells (VSMCs) from OZR and lean Zucker rats (LZR) by measuring: 1) NO donor ability to increase cGMP in the absence and presence of inhibitors of soluble guanylate cyclase (sGC) and phosphodiesterases (PDEs); 2) NO and cGMP ability to induce, via PKG, vasodilator-stimulated phosphoprotein (VASP) phosphorylation at serine 239 and PDE5 activity; 3) protein expression of sGC, PKG, total VASP, and PDE5; 4) superoxide anion concentrations and ability of antioxidants (superoxide dismutase+catalase and amifostine) to influence the NO/cGMP/PKG pathway activation; and 5) hydrogen peroxide influence on PDE5 activity and VASP phosphorylation. VSMCs from OZR vs. LZR showed: 1) baseline cGMP concentrations higher, at least in part owing to reduced catabolism by PDEs; 2) impairment of NO donor ability to increase cGMP, even in the presence of PDE inhibitors, suggesting a defect in the NO-induced sGC activation; 3) reduction of NO and cGMP ability to activate PKG, indicated by the impaired ability to phosphorylate VASP at serine 239 and to increase PDE5 activity via PKG; 4) similar baseline protein expression of sGC, PKG, total VASP, and PDE5; and 5) higher levels of superoxide anion. Antioxidants partially prevented the defects of the NO/cGMP/PKG pathway observed in VSMCs from OZR, which were reproduced by hydrogen peroxide in VSMCs from LZR, suggesting the pivotal role of oxidative stress.

FOXN1 homozygous mutation associated with anencephaly and severe neural tube defect in human athymic Nude/SCID fetus.

The forkhead, Fox, gene family comprises a diverse group of 'winged-helix' transcription factors that play important roles in development, metabolism, cancer and aging. Recently, several forkhead genes have been demonstrated to play critical roles in lymphocyte development and effector functions. Alterations of the FOXN1 gene in both mice and humans result in a severe combined immunodeficiency caused by an intrinsic defect of the thymus associated with congenital alopecia (Nude/severe combined immunodeficiency phenotype). FOXN1 is a member of the class of proteins involved in the development and differentiation of the central nervous system. We identified a human fetus homozygous for a mutation in FOXN1 gene who lacked the thymus and also had abnormal skin, anencephaly and spina bifida. Moreover, we found that FOXN1 gene is expressed in mouse developing choroid plexus. These observations suggest that FOXN1 may be involved in neurulation in humans.

Steroid-induced improvement of neurological signs in ataxia-telangiectasia patients.

A recent clinical observation reported on a dramatic improvement of neurological symptoms following short-term betamethasone administration in a child affected with ataxia-teleangiectasia (A-T). The aim of this study was to extend this observation to additional A-T patients followed at a single Immunodeficiency Center. Six consecutive patients (three males; mean age 16.3 years, range 5-30 years) were enrolled into this monocentric before-after trial. A cycle of oral betamethasone at the dosage of 0.1 mg/kg/day was administered for 10 days. The neurological evaluation was performed through the Scale for the Assessment and Rating of Ataxia. Overall, five of the six patients exhibited a clear amelioration of the neurological performances. Only in two patients, a slight amelioration persisted 7 days after the therapy withdrawal, whilst in the other patients the score reached approximately the pre-treatment value at the end of the therapy. Twenty-eight of the 46 evaluated neurological items (60%) improved during therapy. The speech disturbance, finger chase and nose-finger test showed the more significant improvement. The clinical amelioration was inversely correlated with the level of cerebellum atrophy, as revealed by the magnetic resonance. Our data indicate that neurological signs in A-T are susceptible of beneficial pharmacological intervention even years after the disease onset.

Immune-surveillance and programmed cell death-related genes are significantly overexpressed in the normal breast epithelium of postmenopausal parous women.

Endocrine and reproductive influences significantly affect the lifetime risk of breast cancer. Nulliparity is one of the most firmly established risk factors for breast cancer, whereas early full-term pregnancy and parity confer a significant protection. The breast attains its maximum development during pregnancy and lactation. After menopause the breast regresses in both nulliparous and parous women containing lobular structures designated lobules type 1 (Lob 1). We have postulated that the degree of differentiation acquired through early pregnancy changes the 'genomic signature' that differentiates the Lob 1 from the early parous women from that of the nulliparous women by shifting the Stem cell 1 to a Stem cell 2, making this the mechanism of protection conferred by early full-term pregnancy. In order to elucidate the molecular pathways through which pregnancy exerts a protective effect, we have analyzed the genomic profile of Lob 1 present in reduction mammoplasty specimens obtained from parous and nulliparous postmenopausal women. The genes differentially expressed are related to immune-surveillance, DNA repair, programmed cell death, transcription, and chromatin structure/activators/co-activator. In the present study we performed real-time RT-PCR using a low-density array or a microfluid card for genes related to the immune system and programmed cell death, using 18S as an internal control [TaqMan(R) Low Density Array Human Immune Panel (Applied Biosystems)]. Breast epithelial cells from parous women significantly overexpressed 17 out of 20 genes (p<0.001) with respect to the nulliparous breast. BCL2-associated X protein, Complement component 3, CD45 antigen, glyceraldehyde-3-phosphate dehydrogenase, granulysin, and chemokine (C-C motif) ligand 19 were expressed more than 30-fold with respect to nulliparous breast cells. Only three out of 20 genes [selectin P (granule membrane protein 140 kDa, antigen CD62), Fas (TNF receptor superfamily, member 6) and chemokine (C-X-C motif) ligand 11], were downregulated in parous breast with respect to nulliparous breast cells. The data lead us to conclude that an early pregnancy, by shifting the Stem cell 1 to Stem cell 2, makes the latter more easily recognized by the immune-surveillance system, which initiates the programmed cell death pathway if exposure to toxic or carcinogenic agents occurs.

A case of clear renal cell cancer associated to meningioma and verrucous carcinoma of frontal region in an old patient.

Here we report the concomitant development in an 82 year-old patient of three different neoplasms with different histology, degree of differentiation and clinical aggressiveness. In fact, the patient presented a verrucous carcinoma with unusual location at her head frontal region and a concomitant calcified meningioma of the frontal region of the brain. At the moment of the examination also a clear renal cell carcinoma, that was the cause of patient decease, was discovered. At our knowledge, this is the first case of concomitant presentation of these three tumours. Even if the present case was not correlated with any hereditary feature the presence of a genetic predisposition common to all the three tumours can not be excluded, but the casual co-existence of different both genetic and environmental factors can be also suggested.

[Environmental quality of the operating theatres in Campania: long lasting monitoring results]. / La qualità ambientale di sale operatorie nella regione Campania: i risultati di un monitoraggio pluriennale.

In this study the microbiological, physical and chemical results of an investigation concerning the environmental conditions of operating theatres in 38 public hospitals of the Campania Government are presented. The analysis of the results has been made by considering specific standards suggested by national and international regulations. The results showed that 84% of the operating theatres presented normal microbiological values, in relation to the total bacterial load, while 16% did not. By considering the microclimatic monitoring 55% of the operating theatres showed normal values while 45% at least a microclimatic index did not. In relation to the concentrations of anaesthetics gases the survey pointed out that the nitrous oxides was within non prescribed environmental limits (50 ppm for N2O); while 15% of the halogenated was not in normal values.

Detection of chromosomal aberrations by comparative genomic hybridization during transformation of human breast epithelial cells in vitro.

Breast cancer is the most frequent malignancy in women. It is well recognized that tumorigenesis is a multistep process resulting from the accumulation of sequential genetic alterations. In breast cancers LOH has been described on one or both arms of multiple chromosomes. Comparative genomic hybridization (CGH) analysis was performed to identify chromosomal imbalances in the breast epithelial cells (HBEC). We have used a human in vitro-in vivo system in which the environmental carcinogen benz(a)pyrene (BP) and the c-Ha-ras oncogene were utilized for inducing in vitro transformation of HBEC. Immortal MCF-10F cells were treated with BP which resulted in the transformed cell line BP-1 that was further enhanced by transfection with the c-Ha-ras to generate the cell line BP-1-Tras. This cell line is tumorigenic when injected in severe combined immunodeficient (SCID) mice, generating the tumor cell line BP-1-Tras T J#4. Our comparative genomic hybridization analysis indicates that the most overrepresented segment after cell transformation and in the BP-1, BP-1-Tras and in the tumor cell line were 1p (80%), 5q21-ter (80%), 8q24.1 (90%) and Xq27-28 (60%). DNA sequence amplification at 10p14-15 was observed in BP-1-Tras T J#4 cells. Allelic losses of chromosome 4, 8p11-21 and 15q11-12, occur after cell transformation and are maintained consistently during tumorigenesis.

Developmental stage of the rat mammary gland as determinant of its susceptibility to 7,12-dimethylbenz[a]anthracene.

Postnatal development of the mammary gland was studied in 80 noninbred Sprague-Dawley virgin rats ranging in age from 2 to 112 days, and the changes induced by 7,12-dimethylbenz[a]anthracene (DMBA) were studied in 60 noninbred Sprague-Dawley virgin rats that, at the age of 55 days, were inoculated intragastrically with 10 mg DMBA/100 g body weight. To correlate the sequential structural changes in the two groups, animals of both groups were killed weekly and their mammary glands removed and processed for wholemount. Terminal endbuds (TEB), terminal ducts (TD), alveolar buds (AB), and lobules per square millimeter were counted in wholemount preparations under a stereomicroscope. During postnatal development, the mammary gland tree grew by sprouting numerous ducts ending in club-shaped TEB. The density of TEB reached a peak when the rats were 21 days old (25 +/- 2 TEB/mm2), decreased sharply until the animals were 63 days old, and then decreased slowly until they were 84 days of age. The number of TEB decreased because of their differentiation mainly into AB or their evolution to TD. AB later differentiated into lobules. AB increased in number steadily to a plateau when the animals were 70--84 days old. After DMBA was administered to the rats at 55 days of age, the number of TEB remained higher than that in the control animals and the TEB became larger and had higher mitotic activities. Such TEB were called intraductal proliferations (IDP); they evolved to adenocarcinomas. DMBA increased the number of TD and decreased the number of AB and lobules in relation to the control animals. These findings led to the conclusion that DMBA administration to 55-day-old rats alters the differentiation of TEB leads to AB leads to lobules, inducing instead the sequence TEB leads to IDP leads to adenocarcinoma.