Perioperative mortality in bariatric surgery: meta-analysis.

BACKGROUND: Bariatric surgery is an established treatment for severe obesity; however, fewer than 1 per cent of eligible patients undergo surgery. The perceived risk of surgery may contribute to the low uptake. The aim of this study was to determine perioperative mortality associated with bariatric surgery, comparing different operation types and data sources. METHODS: A literature search of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies published between 1 January 2014 and 31 July 2020. Inclusion criteria were studies of at least 1000 patients reporting short-term mortality after bariatric surgery. Data were collected on RCTs. Meta-analysis was performed to establish overall mortality rates across different study types. The primary outcome measure was perioperative mortality. Different operation types were compared, along with study type, in subgroup analyses. The study was registered at PROSPERO (2019: CRD 42019131632). RESULTS: Some 4356 articles were identified and 58 met the inclusion criteria. Data were available on over 3.6 million patients. There were 4707 deaths. Pooled analysis showed an overall mortality rate of 0.08 (95 per cent c.i. 0.06 to 0.10; 95 per cent prediction interval 0 to 0.21) per cent. In subgroup analysis, there was no statistically significant difference between overall, 30-day, 90-day or in-hospital mortality (P = 0.29). There was no significant difference in reported mortality for RCTs, large studies, national databases or registries (P = 0.60). The pooled mortality rates by procedure type in ascending order were: 0.03 per cent for gastric band, 0.05 per cent for sleeve gastrectomy, 0.09 per cent for one-anastomosis gastric bypass, 0.09 per cent for Roux-en-Y gastric bypass, and 0.41 per cent for duodenal switch (P < 0.001 between operations). CONCLUSION: Bariatric surgery is safe, with low reported perioperative mortality rates.

Weight loss surgery helps patients with severe obesity. This study looked at the risk of dying after weight loss surgery in over 3.6 million patients. The risk was less than 1 in 1000 (0.08 per cent). The risk was lowest for gastric band and sleeve gastrectomy, then for gastric bypasses and highest for the duodenal switch operation. This shows that weight loss surgery is safe, with a low risk of dying similar to that of other common operations.

Gene expression profiles of inflammatory breast cancer: correlation with response to neoadjuvant chemotherapy and metastasis-free survival.

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive disease. To date, no molecular feature reliably predicts either the response to chemotherapy (CT) or the survival. Using DNA microarrays, we searched for multigene predictors. PATIENTS AND METHODS: The World IBC Consortium generated whole-genome expression profiles of 137 IBC and 252 non-IBC (nIBC) samples. We searched for transcriptional profiles associated with pathological complete response (pCR) to neoadjuvant anthracycline-based CT and distant metastasis-free survival (DMFS) in respective subsets of 87 and 106 informative IBC samples. Correlations were investigated with predictive and prognostic gene expression signatures published in nIBC (nIBC-GES). Supervised analyses tested genes and activation signatures of 19 biological pathways and 234 transcription factors. RESULTS: Three of five tested prognostic nIBC-GES and the two tested predictive nIBC-GES discriminated between IBC with and without pCR, as well as two interferon activation signatures. We identified a 107-gene signature enriched for immunity-related genes that distinguished between responders and nonresponders in IBC. Its robustness was demonstrated by external validation in three independent sets including two IBC sets and one nIBC set, with independent significant predictive value in IBC and nIBC validation sets in multivariate analysis. We found no robust signature associated with DMFS in patients with IBC, and neither of the tested prognostic GES, nor the molecular subtypes were informative, whereas they were in our nIBC series (220 stage I-III informative samples). CONCLUSION: Despite the relatively small sample size, we show that response to neoadjuvant CT in IBC is, as in nIBC, associated with immunity-related processes, suggesting that similar mechanisms responsible for pCR exist. Analysis of a larger IBC series is warranted regarding the correlation of gene expression profiles and DMFS.

Potent inhibition by ropivacaine of metastatic colon cancer SW620 cell invasion and NaV1.5 channel function.

BACKGROUND: Metastatic breast and colon cancer cells express neonatal and adult splice variants of NaV1.5 voltage-activated Na(+) channels (VASCs). Block of VASCs inhibits cell invasion. Local anaesthetics used during surgical tumour excision inhibit VASC activity on nociceptive neurones providing regional anaesthesia. Inhibition of VASCs on circulating metastatic cancer cells may also be beneficial during the perioperative period. However, ropivacaine, frequently used to provide analgesia during tumour resection, has not been tested on colon cancer cell VASC function or invasion. METHODS: We used reverse transcription-polymerase chain reaction and sequencing to identify NaV1.5 variants in the SW620 metastatic colon cancer cell line. Recombinant adult and neonatal NaV1.5 variants were expressed in human embryonic kidney cells. Voltage-clamp recordings and invasion assays were used to examine the effects of ropivacaine on recombinant NaV1.5 channels and the metastatic potential of SW620 cells, respectively. RESULTS: SW620 cells expressed adult and neonatal NaV1.5 variants, which had similar steady-state inactivation profiles, but distinctive activation curves with the neonatal variant having a V1/2 of activation 7.8 mV more depolarized than the adult variant. Ropivacaine caused a concentration-dependent block of both NaV1.5 variants, with IC50 values of 2.5 and 3.9 µM, respectively. However, the reduction in available steady-state current was selective for neonatal NaV1.5 channels. Ropivacaine inhibited SW620 invasion, with a potency similar to that of inhibition of NaV1.5 channels (3.8 µM). CONCLUSIONS: Ropivacaine is a potent inhibitor of both NaV1.5 channel activity and metastatic colon cancer cell invasion, which may be beneficial during surgical colon cancer excision.

A choroid plexus metastasis of a prostatic adenocarcinoma mimicking a choroid plexus carcinoma: A case report.

A multicystic intraventricular tumour of the right ventricular atrium was incidentally diagnosed on follow-up imaging of a 61-year-old man with a history of prostatic adenocarcinoma. Surgical resection of the lesion was performed after a one-year radio-clinical follow-up due to progressive expansion of the lesion size and a rising prostate specific antigen blood-level. Morphological features with papillary pattern on pathological examination were compatible with malignant adenocarcinoma or choroid plexus carcinoma. The immunoprofile was conclusive for an exceptional choroid plexus metastasis (CPM) of a prostatic adenocarcinoma. To our knowledge, this is the first report of a proven prostatic origin of a CPM.

International expert panel on inflammatory breast cancer: consensus statement for standardized diagnosis and treatment.

BACKGROUND: Inflammatory breast cancer (IBC) represents the most aggressive presentation of breast cancer. Women diagnosed with IBC typically have a poorer prognosis compared with those diagnosed with non-IBC tumors. Recommendations and guidelines published to date on the diagnosis, management, and follow-up of women with breast cancer have focused primarily on non-IBC tumors. Establishing a minimum standard for clinical diagnosis and treatment of IBC is needed. METHODS: Recognizing IBC to be a distinct entity, a group of international experts met in December 2008 at the First International Conference on Inflammatory Breast Cancer to develop guidelines for the management of IBC. RESULTS: The panel of leading IBC experts formed a consensus on the minimum requirements to accurately diagnose IBC, supported by pathological confirmation. In addition, the panel emphasized a multimodality approach of systemic chemotherapy, surgery, and radiation therapy. CONCLUSIONS: The goal of these guidelines, based on an expert consensus after careful review of published data, is to help the clinical diagnosis of this rare disease and to standardize management of IBC among treating physicians in both the academic and community settings.

Deep oxygenated ground water: anomaly or common occurrence?

Contrary to the prevailing notion that oxygen-depleting reactions in the soil zone and in the aquifer rapidly reduce the dissolved oxygen content of recharge water to detection limits, 2 to 8 milligrams per liter of dissolved oxygen is present in water from a variety of deep (100 to 1000 meters) aquifers in Nevada, Arizona, and the hot springs of the folded Appalachians and Arkansas. Most of the waters sampled are several thousand to more than 10,000 years old, and some are 80 kilometers from their point of recharge.

Improving Near-Surface Retrievals of Surface Humidity Over the Global Open Oceans From Passive Microwave Observations.

Ocean evaporative fluxes are a critical component of the Earth's energy and water cycle, but their estimation remains uncertain. Near-surface humidity is a required input to bulk flux algorithms that relate mean surface values to the turbulent fluxes. Several satellite-derived turbulent flux products have been developed over the last decade that utilize passive microwave imager observations to estimate the surface humidity. It is known, however, that these estimates tend to diverge from one another and from in situ observations. Analysis of current state-of-the-art satellite estimates provided herein reveals that regional-scale biases in these products remain significant. Investigations reveal a link between the spatial coherency of the observed biases to atmospheric dynamical controls of water vapor vertical stratification, cloud liquid water, and sea surface temperature. This information is used to develop a simple state-dependent bias correction that results in more consistent ocean surface humidity estimates. A principal conclusion is that further improvements to ocean near-surface humidity estimation using microwave radiometers requires incorporation of prior information on water vapor stratification and sea surface temperature.

Determinants of Radiation Dose in Selective Ophthalmic Artery Chemosurgery for Retinoblastoma.

BACKGROUND AND PURPOSE: Retinoblastoma is the most common pediatric ocular neoplasm. Multimodality treatment approaches are commonplace, and selective ophthalmic artery chemosurgery has emerged as a safe and effective treatment in selected patients. Minimizing radiation dose in this highly radiosensitive patient cohort is critical. We explore which procedural factors affect the radiation dose in a single-center cohort of children managed in the UK National Retinoblastoma Service. MATERIALS AND METHODS: A retrospective review was performed of 177 selective ophthalmic artery chemosurgery procedures in 48 patients with retinoblastoma (2013-2017). Medical records, angiographic imaging, and radiation dosimetry data (including total fluoroscopic screening time, skin dose, and dose-area product) were reviewed. RESULTS: The mean fluoroscopic time was 13.5 ± 13 minutes, the mean dose-area product was 11.7 ± 9.7 Gy.cm2, and the mean total skin dose was 260.9 ± 211.6 mGy. One hundred sixty-three of 177 procedures (92.1%) were technically successful. In 14 (7.9%), the initial attempt was unsuccessful (successful in 13/14 re-attempts). Screening time and radiation dose were associated with drug-delivery microcatheter location and patient age; screening time was associated with treatment cycle. CONCLUSIONS: In selective ophthalmic artery chemosurgery, a microcatheter tip position in the proximal or ostial ophthalmic artery and patient age 2 years or younger were associated with reduced fluoroscopic screening time and radiation dose; treatment beyond the first cycle was associated with reduced fluoroscopic screening time.

Loss of mammary epithelial prolactin receptor delays tumor formation by reducing cell proliferation in low-grade preinvasive lesions.

Top quartile serum prolactin levels confer a twofold increase in the relative risk of developing breast cancer. Prolactin exerts this effect at an ill defined point in the carcinogenic process, via mechanisms involving direct action via prolactin receptors within mammary epithelium and/or indirect action through regulation of other hormones such as estrogen and progesterone. We have addressed these questions by examining mammary carcinogenesis in transplants of mouse mammary epithelium expressing the SV40T oncogene, with or without the prolactin receptor, using host animals with a normal endocrine system. In prolactin receptor knockout transplants the area of neoplasia was significantly smaller (7 versus 17%; P < 0.001 at 22 weeks and 7 versus 14%; P = 0.009 at 32 weeks). Low-grade neoplastic lesions displayed reduced BrdU incorporation rate (11.3 versus 17% P = 0.003) but no change in apoptosis rate. Tumor latency increased (289 days versus 236 days, P < 0.001). Tumor frequency, growth rate, morphology, cell proliferation and apoptosis were not altered. Thus, prolactin acts directly on the mammary epithelial cells to increase cell proliferation in preinvasive lesions, resulting in more neoplasia and acceleration of the transition to invasive carcinoma. Targeting of mammary prolactin signaling thus provides a strategy to prevent the early progression of neoplasia to invasive carcinoma.

Improving access to ART in low-income settings through knowledge transfer: a case study from Zimbabwe.

It may be assumed that infertility is not a problem in resource-poor areas where fertility rates are high. However, evidence overwhelmingly shows that childlessness is highly stigmatized in these settings and that women who are unable to bear children suffer significant social and psychological consequences. The World Health Organization has recommended that infertility be considered a global health problem and stated the need for ART to be adapted to low-resource settings. This paper describes a model for improving access to ART in low-resource settings. Experienced ART health professionals from Australia and Italy representing medical science, embryology, nursing and counselling used knowledge transfer to support a clinician, a laboratory scientist and a nurse to establish an ART service in Harare, Zimbabwe. Support and mentorship provided between October 2016 and December 2017 included: hosting the clinician and the embryologist for the new service in established ART clinics for short periods and providing them with dedicated mentorship and training during their stay; funding an experienced embryologist to travel to Zimbabwe (three times) to oversee the setting up of the lab and provide hands-on embryology training; funding a scientist and a nurse to travel to Zimbabwe to troubleshoot and establish protocols for record keeping and psychosocial care; and contributing approximately AUD $15,000 to the purchase of some equipment. By 31 March 2018, the team at IVF Zimbabwe had performed 166 ART procedures, which at time of writing had resulted in 16 births and 4 ongoing pregnancies. This case study demonstrates that with mentorship and modest financial support from ART experts from high-income settings, health professionals in low-income settings can deliver affordable ART with successful outcomes.

Sources of phosphorus lost from a grazed pasture receiving simulated rainfall.

Nutrients exported from grazing systems contribute to eutrophication of surface waters. In this study the contributions of soil, pasture-plants, and dung to P exports in overland flow were compared using simulated rainfall. The treatments were (i) grazed pasture-plants (isolated from soil by application of petrolatum to the soil surface), (ii) grazed pasture-plants and supporting soil, (iii) grazed pasture-plants and soil and treading, and (iv) grazed pasture-plants and soil and treading and dung. In general, dissolved reactive P (DRP) accounted for the majority of the P exported and P losses decreased in the order: treading and dung treatment>treading>pasture-plants and soil>pasture-plants. Very little dissolved organic P was lost in overland flow and the effects of treading diminished with time. Over a normal grazing cycle (30 d), the portion of P lost from pasture-plants was approximately half that lost from pasture-plants and soil, one-third that lost from treaded pasture-plants and soil, and one-quarter that lost from treaded pasture-plants, soil, and dung. The DRP in the pasture-plants treatment was approximately half that in the pasture-plants and soil treatment and suggests that a significant portion of the P exported from these systems is derived directly from pasture-plants. Due to higher proportions of particulate P (PP) in the treaded and dung treatments, DRP accounted for less of total P than in the pasture-plants and pasture-plants and soil treatments. Lower infiltration capacities probably caused by mechanical disaggregation at the soil surface are consistent with the higher proportions of PP in the treading treatments. These results were used to estimate P exports from a field trial site in Southland, New Zealand. The results suggested that P export attributable to fertilizer, dung, pasture-plants, and soil components were approximately 10, 30, 20, and 40%, respectively. These results suggest that since 90% of the P exports are derived from the soil-plant system and dung returns, managements to lessen P exports should continue to focus on maintaining soil P within the optimal range for pasture-plant production and maintaining soil surface properties that maximize infiltration and minimize overland flow.

Higher bone resorption excretion in South Asian women vs. White Caucasians and increased bone loss with higher seasonal cycling of vitamin D: Results from the D-FINES cohort study.

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n=373 women (four groups; South Asian postmenopausal n=44, South Asian premenopausal n=50, Caucasian postmenopausal n=144, Caucasian premenopausal n=135) (mean (±SD) age 48 (14) years; age range 18-79years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006-2007). A mixed between-within subjects ANOVA (n=192) showed a between subjects effect of the four groups (P<0.001) on uNTX concentration, but no significant main effect of season (P=0.163). Bonferroni adjusted Post hoc tests (P≤0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P=0.04) and spring (P=0.007), premenopausal Asian women had a 16 to 20nmolBCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD)=0.213 (0.015) and 95% CI (0.182, 0.245; P<0.001) in a non-linear mixed model (n=154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD)=-0.035 (0.004), and 95% CI (-0.043, -0.028; P<0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health.

Identification of epidermal cell subpopulations with increased ornithine decarboxylase activity following treatment of murine epidermis with 12-O-tetradecanoylphorbol-13-acetate.

Ornithine decarboxylase (ODC), the initial enzyme in the polyamine biosynthetic pathway, has been used as a marker for the hyperplasia that occurs following exposure of mouse epidermis to the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Using flow cytometry in combination with polyclonal antibodies to ODC, we examined the levels of ODC-associated immunoreactive protein present within mouse epidermal cells at 4 and 24 h after a single topical application of TPA, as well as following chronic exposure to TPA and in papillomas. Basal levels of ODC-specific antibody binding were detectable in acetone-treated CD-1 mouse epidermis and were increased 3-fold at 4 h after TPA treatment. The amount of ODC antibody binding detected after exposure to 17 nmol TPA twice weekly for 3 weeks was similar to that detected within cells isolated from papillomas and was 2.5-fold higher than in cells isolated at 4 h after a single topical treatment of mice with TPA. These observations support the hypothesis that specific subpopulations of keratinocytes constitutively express high levels of ODC following chronic exposure to TPA. The novel method for ODC detection described in these studies provides a means to identify, isolate, and further characterize epidermal cells that may give rise to papillomas and carcinomas.

Production of hydrogen peroxide by murine epidermal keratinocytes following treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

The ability of murine epidermal cells to produce intracellular hydrogen peroxide was analyzed by flow cytometry and the measurement of 2',7'- dichlorofluorescin (DCFH) oxidation. Epidermal cells isolated from acetone-treated CD-1 mice for 24 h were relatively homogeneous in cell size and density and oxidized low levels of DCFH. However, following 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of mice (10 micrograms; 24 h), two cytokeratin-positive populations of cells were identified that were heterogeneous with respect to size and density. These two TPA-derived cell populations oxidized levels of DCFH that were time and dose dependent and were between 2- and 10-fold higher than levels of DCFH oxidized by cells isolated from acetone-treated mice. The ability of catalase, the enzyme that detoxifies hydrogen peroxide, to suppress DCFH oxidation to control levels suggested that intracellular hydrogen peroxide was responsible for the enhanced rate of DCFH oxidation in epidermal cells isolated from TPA-treated mice. The ability of mouse epidermal keratinocytes to oxidize DCFH in response to TPA treatment was confirmed using a cloned keratinocyte cell line. These results suggest that specific subpopulations of keratinocytes produce elevated levels of intracellular peroxides following treatment with TPA either in vivo or in culture.

Temporal sequence of pulmonary cytokine gene expression in response to endotoxin in C3H/HeN endotoxin-sensitive and C3H/HeJ endotoxin-resistant mice.

Although previous studies suggested that tumor necrosis factor alpha (TNF-alpha) was a critical cytokine responsible for the inflammation observed after exposure to endotoxin, other mediators may also play an important role in the regulation of systemic inflammatory responses independent of TNF-alpha. The present study compared the temporal sequence of endotoxin-induced TNF-alpha, interleukin-1 alpha (IL-1 alpha), and interleukin-10 (IL-10) gene expression and cellular localization of cytokine proteins in pulmonary tissue of two strains of mice that have a genetically based differential sensitivity to endotoxin. Lung tissue and plasma were harvested from endotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after intraperitoneal (i.p.) injection of 5 mg/kg endotoxin (Escherichia coli-derived lipopolysaccharide, serotype 0111:B4). There were significant elevations in both TNF-alpha gene and IL-1 alpha expression immediately (15 min) after endotoxin injection in C3H/HeN mice. Although levels of TNF-alpha mRNA in the two mouse strains were similar at 1-2 h, the IL-1 alpha gene expression in pulmonary tissue isolated from endotoxin-resistant mice was not comparable to the levels detected in C3H/HeN endotoxin-sensitive mice at the same times. The most dramatic difference in endotoxin-induced cytokine gene expression between the two strains of mice was in IL-10 mRNA levels in pulmonary tissue isolated from endotoxin-sensitive mice, compared to the lack of detectable increase in IL-10 gene expression in C3H/HeJ endotoxin-resistant mice above baseline at any time point examined. Quantitation of neutrophil infiltration into pulmonary tissue using immunochemical detection of GR-1, a myeloid differentiation-specific antibody, demonstrated that there was a significantly decreased inflammatory infiltrate in pulmonary tissue isolated from C3H/HeJ mice following endotoxin administration, which correlated with decreased levels of proinflammatory cytokine immunoreactive protein within pulmonary cells. Pulmonary cytokine synthesis and immunoreactive protein production did not directly correlate with either the magnitude or the temporal sequence of increases in plasma cytokine levels, suggesting that systemic levels of cytokines may not accurately reflect the cytokine response within the local tissue milieu. The present observations demonstrate that the differential synthesis and production of immunosuppressive cytokines as well as proinflammatory cytokines may be important variables in the determination of the extent of infiltration of inflammatory cells into the local pulmonary site in response to endotoxin and may significantly contribute to the determination of sensitivity or resistance to endotoxin in this murine model.

Distinct patterns of chemotactic peptide-induced calcium mobilization in differentiated myeloid leukemia cells and peripheral blood neutrophils.

Flow cytometry was used to compare intracellular calcium mobilization in mature neutrophilic granulocytes (PMN) with HL-60 promyelocytic leukemia cells induced to differentiate with dibutyryl cyclic adenosine 3',5'-monophosphate (dbcAMP). Using the calcium-specific probe indo-1 acetoxymethyl ester, we found that the ability of differentiating HL-60 cells to mobilize calcium in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP) developed concomitantly with expression of receptors on the cells for this peptide. Mobilization of calcium in HL-60 cells, as well as in PMN, in response to fMLP was dose dependent and was related to the presence of calcium in the culture medium. In calcium-free medium, tenfold higher concentrations of fMLP were required to induce calcium mobilization than in calcium-containing medium. In HL-60 cells, calcium mobilization occurred more rapidly than in PMN and was independent of extracellular calcium. Furthermore, the response of HL-60 cells to fMLP was more prolonged than the response of PMN and was also of greater magnitude. Calcium mobilization in both HL-60 cells and PMN was partially inhibited by the calcium channel blocker, verapamil, but completely blocked by trimethylbenzoic acid 8-(diethylamino) octyl ester, an intracellular calcium antagonist. These results indicate that although both cell types mobilize calcium in response to fMLP, the characteristics of the responses are distinct. These differences may underlie distinct functional responses of PMN and differentiated HL-60 cells to fMLP.

Failure of F-Met-Leu-Phe to induce chemotaxis in differentiated promyelocytic (HL-60) leukemia cells.

Treatment of HL-60 promyelocytic leukemia cells with dibutyryl cyclic adenosine 3',5'-monophosphate (dbcAMP) induced these cells to differentiate toward mature neutrophilic granulocytes (PMN). DbcAMP was found to produce a rapid time- and dose-dependent inhibition of HL-60 cell proliferation, reaching a maximum after 48 hr treatment of the cells with 250-500 microM. This was associated with morphologic alterations consistent with maturing PMN. Using immunofluorescence and flow cytometry, we found that dbcAMP-treated HL-60 cells expressed some, but not all, surface markers characteristic of mature phagocytes. Thus receptors for the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP); the monocyte/granulocyte markers My-8, Mo-1, and Leu-15; as well as the monocyte markers Mo-2 and My-4 were identified on the cells. In contrast, dbcAMP-treated cells did not express the PMN-specific antigen DL1.2. We also found that dbcAMP-treated HL-60 cells produced hydrogen peroxide in response to the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). However, the magnitude of this response was significantly less than that observed in mature PMN. In contrast, fMLP-stimulated levels of hydrogen peroxide production were comparable in both cell types. In addition, despite the fact that dbcAMP-treated cells expressed fMLP receptors, they did not exhibit directed migration toward this chemotactic peptide. Taken together, these data suggest that dbcAMP-induced differentiation of HL-60 cells is incomplete.

A diaphragmatic retroperitoneal cyst.

Diaphragmatic lesions are usually congenital bronchogenic cysts. A patient with a known diaphragmatic cyst presented with new onset right upper quadrant pain. Repeat imaging showed enlargement of the cyst, the CA19-9 cancer marker was raised at 312 iu/ml (normal: <27 iu/ml) and positron emission tomography combined with computed tomography showed focally increased uptake in the cystic wall. In view of symptoms and risk of neoplasia, the lesion was excised. Histology showed a benign epidermoid cyst. Features falsely suggesting neoplasia have been reported previously with benign splenic cysts but not with a benign diaphragmatic epidermoid cyst.

Prolactin signaling influences the timing mechanism of the hair follicle: analysis of hair growth cycles in prolactin receptor knockout mice.

Pituitary PRL regulates seasonal hair follicle growth cycles in many mammals. Here we present the first evidence implicating PRL in the nonseasonal, wave-like pelage replacement of laboratory mice. In this study we show that messenger RNA transcripts encoding the one long and two short forms of PRL receptor are present in the skin of adult and neonate mice. The receptor protein was immunolocalized to the hair follicle as well as the epidermis and sebaceous glands. Furthermore, PRL messenger RNA was detected within skin extracts, suggesting a possible autocrine/paracrine role. Analysis of the hair growth phenotype of PRL gene-disrupted mice (PRLR(-/-)) revealed a change in the timing of hair cycling events. Although no hair follicle development differences were noted in PRLR(-/-) neonates, observations of the second generation of hair growth revealed PRLR(-/-) mice molted earlier than wild types (PRLR(+/+)). The advance was greater in females (29 days) than in males (4 days), resulting in the elimination of the sexual dimorphism associated with murine hair replacement. Heterozygotes were intermediate between PRLR(-/-) and PRLR(+/+) mice in molt onset. Once initiated, the pattern and progression of the molt across the body were similar in all genotypes. Although all fiber types were present and appeared structurally normal, PRLR(-/-) mice had slightly longer and coarser hair than wild types. These findings demonstrate that PRL has an inhibitory effect on murine hair cycle events. The pituitary PRL regulation of hair follicle cycles observed in seasonally responsive mammals may be a result of pituitary PRL interacting with a local regulatory mechanism.