Connexin 43 maintains tissue polarity and regulates mitotic spindle orientation in the breast epithelium.

Cell-cell communication is essential for tissue homeostasis, but its contribution to disease prevention remains to be understood. We demonstrate the involvement of connexin 43 (Cx43, also known as GJA1) and related gap junction in epithelial homeostasis, illustrated by polarity-mediated cell cycle entry and mitotic spindle orientation (MSO). Cx43 localization is restricted to the apicolateral membrane of phenotypically normal breast luminal epithelial cells in 3D culture and in vivo Chemically induced blockade of gap junction intercellular communication (GJIC), as well as the absence of Cx43, disrupt the apicolateral distribution of polarity determinant tight junction marker ZO-1 (also known as TJP1) and lead to random MSO and cell multilayering. Induced expression of Cx43 in cells that normally lack this protein reestablishes polarity and proper MSO in 3D culture. Cx43-directed MSO implicates PI3K-aPKC signaling, and Cx43 co-precipitates with signaling node proteins ß-catenin (CTNNB1) and ZO-2 (also known as TJP2) in the polarized epithelium. The distribution of Cx43 is altered by pro-inflammatory breast cancer risk factors such as leptin and high-fat diet, as shown in cell culture and on tissue biopsy sections. The control of polarity-mediated quiescence and MSO may contribute to the tumor-suppressive role of Cx43.

Male patients affected by mosaic PCDH19 mutations: five new cases.

Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy. Custom-targeted next generation sequencing gene panels for epilepsy genes were used. Clinical data were collected from medical records. All patients were mosaic in blood for likely pathogenic variants in the PCDH19 gene. In most, clinical features were very similar to the female phenotype, with normal development before seizure onset, which occurred between 5 and 10 months of age, clustering of seizures and sensitivity to fever. Four out of five patients had mild to severe ID and behavioural problems. We reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (ages 10-14 years).

A novel landscape genetic approach demonstrates the effects of human disturbance on the Udzungwa red colobus monkey (Procolobus gordonorum).

A comprehensive understanding of how human disturbance affects tropical forest ecosystems is critical for the mitigation of future losses in global biodiversity. Although many genetic studies of tropical forest fragmentation have been conducted to provide insight into this issue, relatively few have incorporated landscape data to explicitly test the effects of human disturbance on genetic differentiation among populations. In this study, we use a newly developed landscape genetic approach that relies on a genetic algorithm to simultaneously optimize resistance surfaces to investigate the effects of human disturbance in the Udzungwa Mountains of Tanzania, which is an important part of a universally recognized biodiversity hotspot. Our study species is the endangered Udzungwa red colobus monkey (Procolobus gordonorum), which is endemic to the Udzungwa Mountains and a known indicator species that thrives in large and well-protected blocks of old growth forest. Population genetic analyses identified significant population structure among Udzungwa red colobus inhabiting different forest blocks, and Bayesian cluster analyses identified hierarchical structure. Our new method for creating composite landscape resistance models found that the combination of fire density on the landscape and distance to the nearest village best explains the genetic structure observed. These results demonstrate the effects that human activities are having in an area of high global conservation priority and suggest that this ecosystem is in a precarious state. Our study also illustrates the ability of our novel landscape genetic method to detect the impacts of relatively recent landscape features on a long-lived species.

Dynamic processes at the ends of collisional mountain chains.

Understanding of the relationships between tectonic deformation and exhumation in the Himalaya remains incomplete, especially at the ends of the chain.

Climate controls on erosion in tectonically active landscapes.

The ongoing debate about the nature of coupling between climate and tectonics in mountain ranges derives, in part, from an imperfect understanding of how topography, climate, erosion, and rock uplift are interrelated. Here, we demonstrate that erosion rate is nonlinearly related to fluvial relief with a proportionality set by mean annual rainfall. These relationships can be quantified for tectonically active landscapes, and calculations based on them enable estimation of erosion where observations are lacking. Tests of the predictive power of this relationship in the Himalaya, where erosion is well constrained, affirm the value of our approach. Our model allows estimation of erosion rates in fluvial landscapes using readily available datasets, and the underlying relationship between erosion and rainfall offers the promise of a deeper understanding of how climate and tectonic evolution affect erosion and topography in space and time and of the potential influence of climate on tectonics.

Laser 40Ar/39Ar Evaluation of Slow Cooling and Episodic Loss of 40Ar from a Sample of Polymetamorphic Muscovite.

Volume diffusion models predict that crystals with large diffusion dimensions can record a wide range of thermal conditions in the Earth's crust. Direct measurements of the zoning of radiogenic argon-40 in single muscovite porphyroblasts, from a complex terrain in the Vermont Appalachians, record multiple crustal events that span 150 million years. The crystal radius was the effective dimension for argon diffusion (approximately 1000 micrometers). Late deformation features inside the crystals locally decreased the diffusion dimension and promoted loss of argon-40. Zoning patterns of radiogenic isotopes, as observed in this study, are an increasingly important diagnostic tool for studying the thermal record of tectonic processes.

The kangmar dome: a metamorphic core complex in southern xizang (tibet).

The Kangmar metamorphic-igneous complex is one of the most accessible examples of an enigmatic group of gneiss domes (the North Himalayan belt) that lies midway between the Greater Himalaya and the Indus-Tsangpo suture in southern Tibet. Structural analysis suggests that the domal structure formed as a consequence of extensional deformation, much like the Tertiary metamorphic core complexes in the North American Cordillera. Unlike its North American counterparts, the Kangmar dome developed in an entirely convergent tectonic setting. The documentation of metamorphic core complexes in the Himalayan orogen supports the emerging concept that extensional processes may play an important role in the evolution of compressional mountain belts.

Simultaneous miocene extension and shortening in the himalayan orogen.

The South Tibetan detachment system separates the high-grade metamorphic core of the Himalayan orogen from its weakly metamorphosed suprastructure. It is thought to have developed in response to differences in gravitational potential energy produced by crustal thickening across the mountain front. Geochronologic data from the Rongbuk Valley, north of Qomolangma (Mount Everest) in southern Tibet, demonstrate that at least one segment of the detachment system was active between 19 and 22 million years ago, an interval characterized by large-scale crustal thickening at lower structural levels. These data suggest that decoupling between an extending upper crust and a converging lower crust was an important aspect of Himalayan tectonics in Miocene time.

Relation of plasma oxytocin and prolactin concentrations to milk production in mothers of preterm infants: influence of stress.

Responses of oxytocin and PRL to mechanical breast pumping and the influence of physiological indicators of stress were measured at 2, 4, and 6 weeks postpartum to determine potential causes of inadequate milk production in 18 women with prematurely delivered, nonnursing (<1500 g) infants. Median milk production was similar to that reported in breastfeeding mothers, but a third of mothers were producing less than half as much by week 6. Plasma oxytocin was similar to that previously reported for breastfeeding mothers. The oxytocin area under the curve (AUC) for breast-pumping sessions (70 min) was correlated at each occasion (r = 0.37, 0.58, and 0.55, respectively) with milk yield. Unlike reports of PRL levels in breast-feeding women, PRL AUC declined between weeks 2 and 6 weeks postpartum (P = 0.03); significant increases in plasma PRL occurred in response to pumping at 2 and 4 weeks, but not at 6 weeks. Salivary amylase, a measure of alpha-adrenergic activity, was highly negatively correlated on each occasion with PRL AUC (r = -0.58, -0.68, and -0.86, respectively), but not with oxytocin. Salivary cortisol was negatively correlated to a lesser degree. We hypothesize that deficiencies in preterm lactation are mediated in part upon stress-induced suppression of PRL secretion through an adrenergic mechanism.

Current perspectives on childhood depression: an overview.

The rapidly increasing research interest in childhood depression indicates that it has become a recognized disorder. The authors review the literature on depression in children, focusing on epidemiology, various diagnostic criteria, classification schemes, assessment instruments, and intervention studies that have been applied to childhood depression. Given that there are many etiological factors, it will be important to study the disorder from various conceptual frameworks, including biochemical, genetic learned helplessness, life stresses, cognitive distortion, behavioral reinforcement, and sociological models.

Transformation of the small cell variant Ki-1+ lymphoma to anaplastic large cell lymphoma: pathologic and clinical features.

The disease spectrum of anaplastic large cell lymphoma (ALCL) includes a biologically aggressive small cell variant (SCV). The SCV may progress to ALCL, but little is known about the transformation process and its significance. The goals of this study were (1) to identify the clinical and pathologic features that characterize ALCL arising in SCV and (2) to determine whether some cases with ALCL histologic appearance at the outset arose from an SCV. Seventeen SCV were reviewed, and four cases (24%) transformed to ALCL as shown by subsequent biopsy. The ALCLs were predominantly monomorphic (3 cases) rather than pleomorphic (1 case). Residual SCV was detected at transformation in 3 of 4 cases. Twenty-one de novo T-cell ALCLs were reviewed for an SCV component; such a component was identified in two ALCLs with monomorphic features, suggesting a preceding SCV phase. There was no change in the immunophenotype between the SCV and ALCL, all marking as EMA+ T cells. Expression of p80 was detected in 3 of 4 (75%) SCV with transformation and 10 of 12 (77%) SCV without transformation. Chromosomal abnormalities involving the sex chromosomes and 6, 7, 9, and 15, in addition to the characteristic t(2;5)(p23;q35), were present in 2 cases at transformation. Times to transformation ranged from 1 to 146 months (mean: 63 months) after diagnosis. Transformation to ALCL signaled a rapid clinical course, with 75% of patients dying in less than a year; one patient remains alive at 15 months. In summary, some ALCLs, particularly those with monomorphic features, arise from an SCV. Transformation to ALCL signals a rapid course, with death occurring in less than a year in most cases. Necrosis in the SCV may be predictive of transformation. Chromosomal abnormalities in addition to the t(2;5)(p23;q35) are present at transformation, suggesting that multiple genetic alterations are involved in disease progression.

Impairment in cochlear function produced by chloramphenicol and noise.

Ototoxic interaction between chloramphenicol and noise was studied in two separate investigations. In the first study, permanent ototoxicity was demonstrated in a group of rats which were subjected to short-duration, high-intensity noise and were then given chloramphenicol orally. The anatomical damage in this group was consistent with observed changes in cochlear round window recordings of cochlear microphonics at 4 kHz and of the N1 component of the eighth nerve action potential. In the second study, a temporary depression in the function of the cochlea was observed in rats subjected to the noise-chloramphenicol regimen used in the first study. Depressions in recordings of the round window similar to those in the first study were seen only during the first five days of recordings. After the fifth day, the recordings of the round window were normal, indicating recovery from a temporary shift in threshold produced by chloramphenicol and noise. Incidence of purulent otitis media was found in 57 and 0% of the animals in the first and second studies, respectively. The combination of chloramphenicol and noise appears to be responsible for the production of temporary cochlear deficits. The addition of the third variable, otitis media, appears to result in permanent impairment of the cochlea.

Rarity of genomic instability in pathogenesis of systemic anaplastic large cell lymphoma (ALCL) in immunocompetent patients.

Microsatellite instability (MSI) is a recently described type of genetic alteration resulting from defects in the DNA mismatch repair genes that appears to play an integral role in neoplastic transformation. MSI has been described in a wide variety of malignancies; however, data regarding the role of MSI in the pathogenesis of non-Hodgkin's lymphoma (NHL) are limited. MSI appears to be important in some T-cell lymphomas, including ALCL arising in immunocompromised patients. In addition, MSI has recently been identified in CD30+ cutaneous lymphoproliferative processes and lymphoblastic lymphoma. In this study, we have analyzed five well-characterized cases of systemic T-cell ALCL arising in immunocompetent patients for the presence of MSI. Genomic DNA isolated from paired normal and tumor tissue was analyzed at seven microsatellite loci by polymerase chain reaction. We were unable to identify MSI or loss of heterozygosity (LOH) in our cases, suggesting that abnormalities in the DNA mismatch repair system do not play a major role in the pathogenesis of most systemic ALCL. Our data provide additional molecular evidence that the various subgroups of lymphoma with ALCL morphology are biologically distinct processes.

Computer-assisted work station timing analysis of instrument labor efficiency.

Labor use ratings assigned to instruments by the Workload Recording Method (WRM) do not change with batch size or walk-away time use. The authors evaluated the effect of both on the labor use of the analyzers Paramax B6100 (Baxter Paramax, Irvine, CA) and Ektachem 700 (Eastman Kodak, Rochester, NY) by timing all worked and walk-away intervals on both instruments. Extrapolation of the data to a workload of slightly more than 1.1 million tests showed that reapportionment of tests to various batch sizes caused Paramax-Ektachem labor cost differences to fluctuate between $37,254 and $34,995. When the minimum usable walk-away interval length was varied from 1 to 20 minutes, Ektachem savings over Paramax increased from $8,700 to $61,400. The WRM predicted a constant $29,050 labor cost advantage for Ektachem over Paramax. If other instruments show similar labor use characteristics with respect to batch size and walk-away utility, laboratory managers who do not consider these factors may fail to select the most cost-effective instruments for their laboratories.

Internal consistency of DSM-III diagnoses using the symptom scales of the Child Assessment Schedule.

Internal consistency of the major diagnostic categories for children was assessed, using the symptom scale scores of the Child Assessment Schedule. Alpha coefficients were calculated for three samples: 116 nonpsychotic psychiatrically disturbed children, 63 children with cystic fibrosis, and 177 children from a community based sample. For the psychiatric sample, a high level of internal consistency was demonstrated for all the symptom scales (i.e., attention deficit, conduct, anxiety, and depression). For the nonpsychiatric samples, the attention deficit and depression scales were reliable, with lower levels of endorsement and more variability observed for the other scales. These results are supportive of the clustering of diagnostic criteria present in DSM-III.

Salivary estradiol and progesterone levels in conception and nonconception cycles in women: evaluation of a new assay for salivary estradiol.

OBJECTIVE: To determine the usefulness of salivary E2 and progesterone for noninvasive assessment of ovarian function. DESIGN: Prospective study of salivary hormone levels in women planning a pregnancy. SETTING: Department of Obstetrics and Gynecology at Northwestern University Medical School in Chicago, Illinois. PATIENT(S): Fourteen women aged 23-39 years with regular menstrual cycles who were planning a pregnancy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Salivary estradiol and progesterone concentrations. RESULT(S): The sensitivity of the E2 assay is 2.0 pmol/L; the interassay coefficient of variation was 5.2% (mean value 17 pmol/L). Recovery of E2 added to saliva was 106%. The correlation with simultaneous serum samples was 0.71. Menstrual cycle patterns contained a preovulatory depression and a midcycle surge. By comparison with nonconception cycles, the luteal phases of conception cycles had significantly elevated salivary E2 within the first 5 days after ovulation. Salivary progesterone was significantly elevated but not until 10 days after ovulation. CONCLUSION(S): Salivary measurements of E2 and progesterone can be used as noninvasive methods for assessment of ovarian function. Salivary specimens can be collected at home and brought to the laboratory for analysis, obviating the need for frequent phlebotomy. The sensitivity and precision of the salivary E2 assay make it comparable with assays of serum E2 for assessing changes in hormone levels.

Intellectual ability and achievement in psychiatrically hospitalized children with conduct, anxiety, and affective disorders.

The IQ and academic achievement of psychiatrically hospitalized children were studied. The sample consisted of 76 children, with a mean age of 10 years, who received diagnoses of conduct, oppositional, anxiety, and affective disorders on the basis of a structured diagnostic interview. A relative deficit in verbal abilities was observed for conduct-disordered children, extending to pre-adolescents the findings previously obtained for adolescent delinquents. Depressed children were characterized by underachievement, which is consistent with the learned helplessness literature. Contrary to expectations, children with an anxiety disorder had a lower IQ than children without the disorder. No cognitive deficits were observed for children diagnosed as oppositional.

Transcranial Doppler pulsatility in vasodilation and stenosis.

Although blood velocity in the major intracranial vessels is readily measured with transcranial Doppler ultrasound (TCD), the interpretation of velocity changes is by no means straightforward. For example, a velocity increase can arise from either a local stenosis or a decrease in downstream resistance, and these mechanisms have contradictory implications for blood flow. To determine whether TCD pulsatility might distinguish these two mechanisms, Doppler ultrasonic readings were taken from an artificial vascular model under conditions of either stenosis or distal dilation. In addition, TCD studies of nine patients with unihemispheric arteriovenous malformations (AVM's) and 16 TCD studies of seven patients with unihemispheric aneurysmal vasospasm were reviewed, and pulsatilities of the AVM's (representing decreased resistance) were compared with those of the vasospastic vessels (representing stenosis). The average percentage drop in pulsatility in the vasodilated configuration of the model/percentage increase in velocity was 0.38 +/- 0.08 (+/- standard error of the mean), while that for stenosis was 0.20 +/- 0.01. Similar comparisons of the patient population yielded 0.67 +/- 0.16 for the AVM group and 0.26 +/- 0.04 for the vasospasm group. These differences were significant (p less than 0.05). The fall in pulsatility associated with a given increase in velocity is significantly greater when the velocity increase arises from diminished downstream resistance than from stenosis.

Intracarotid hydroxyethyl methacrylate solution causing stroke in dogs.

Hydroxyethyl methacrylate (HEMA) has been advocated as a polymerizing solution with which to prevent deflation of detachable balloons in interventional neuroradiology. It is pertinent to know if unpolymerized HEMA would have untoward effects if accidentally released into the carotid artery by balloon rupture or deflation. Seven mongrel dogs underwent transfemoral catheterization of the common carotid artery and subsequent injection of HEMA solution in volumes of 1 cc in five dogs, 2 cc in one, and 4 cc in one. Angiography performed at the time of injection revealed evidence of intravascular thrombosis as well as possible spasm. Three surviving animals were sacrificed at 48 hours; the brains were fixed and examined histopathologically. One brain was normal and one was autolyzed and could not be examined. Five of the seven animals had histopathologically documented cerebral infarctions of varying size. No foreign substance was seen within the blood vessels to suggest intravascular polymerization. The animals injected with 2 or 4 cc HEMA solution did not survive 48 hours. Literature review reveals little documentation of the toxicology of intravascular HEMA. With its increasing popularity as a compound for polymerization in detachable balloons introduced into the brain, further investigations are warranted to understand the physical properties of the compound and potential risks of its use.