Computer-Generated R.E.N.A.L. Nephrometry Scores Yield Comparable Predictive Results to Those of Human-Expert Scores in Predicting Oncologic and Perioperative Outcomes.

PURPOSE: We sought to automate R.E.N.A.L. (for radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry scoring of preoperative computerized tomography scans and create an artificial intelligence-generated score (AI-score). Subsequently, we aimed to evaluate its ability to predict meaningful oncologic and perioperative outcomes as compared to expert human-generated nephrometry scores (H-scores). MATERIALS AND METHODS: A total of 300 patients with preoperative computerized tomography were identified from a cohort of 544 consecutive patients undergoing surgical extirpation for suspected renal cancer at a single institution. A deep neural network approach was used to automatically segment kidneys and tumors, and geometric algorithms were developed to estimate components of R.E.N.A.L. nephrometry score. Tumors were independently scored by medical personnel blinded to AI-scores. AI- and H-score agreement was assessed using Lin's concordance correlation and their predictive abilities for both oncologic and perioperative outcomes were assessed using areas under the curve. RESULTS: Median age was 60 years (IQE 51-68), and 40% were female. Median tumor size was 4.2 cm and 91.3% had malignant tumors, including 27%, 37% and 24% with high stage, grade and necrosis, respectively. There was significant agreement between H-scores and AI-scores (Lin's ⍴=0.59). Both AI- and H-scores similarly predicted meaningful oncologic outcomes (p <0.001) including presence of malignancy, necrosis, and high-grade and -stage disease (p <0.003). They also predicted surgical approach (p <0.004) and specific perioperative outcomes (p <0.05). CONCLUSIONS: Fully automated AI-generated R.E.N.A.L. scores are comparable to human-generated R.E.N.A.L. scores and predict a wide variety of meaningful patient-centered outcomes. This unambiguous artificial intelligence-based scoring is intended to facilitate wider adoption of the R.E.N.A.L. score.

Infant media use: A harm reduction approach.

There are a myriad of potentially harmful developmental outcomes associated with infant digital media use. Studies revealing risk associated with early media use have informed the current American Academy of Pediatrics (AAP) recommendations that discourage most digital media use among children under 18 months of age. Recent research advances, however, suggest potential benefits of technology engagement in this age group. Additionally, surveys of parents reveal that most infants engage with digital media for at least 30 min a day, exceeding the AAP recommendations. In response to these discoveries and cultural trends, some scholars have made compelling cases to adapt the AAP guidelines for infants. A helpful model for developing infant digital media use guidelines for families may be the harm reduction approach. The intent of this review is to suggest adaptations to the AAP guidelines for infant media engagement using a harm reduction framework. This review describes the challenge of restrictive guidelines, briefly summarizes the harm reduction approach, provides a review of risks and benefits associated with infant media use in each developmental domain (physical, cognitive, and socioemotional), summarizes correlates of infant screen media use, and examines intervention strategies for reducing screen time. The paper concludes with examples of possible adaptations to current AAP infant media use recommendations using harm reduction and bioecological frameworks.

Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming.

Despite intense investigation, acute respiratory distress syndrome (ARDS) remains an enormous clinical problem for which no specific therapies currently exist. In this study, we used intratracheal lipopolysaccharide or Pseudomonas bacteria administration to model experimental acute lung injury (ALI) and to further understand mediators of the resolution phase of ARDS. Recent work demonstrates macrophages transition from a predominant proinflammatory M1 phenotype during acute inflammation to an anti-inflammatory M2 phenotype with ALI resolution. We tested the hypothesis that IL-4, a potent inducer of M2-specific protein expression, would accelerate ALI resolution and lung repair through reprogramming of endogenous inflammatory macrophages. In fact, IL-4 treatment was found to offer dramatic benefits following delayed administration to mice subjected to experimental ALI, including increased survival, accelerated resolution of lung injury, and improved lung function. Expression of the M2 proteins Arg1, FIZZ1, and Ym1 was increased in lung tissues following IL-4 treatment, and among macrophages, FIZZ1 was most prominently upregulated in the interstitial subpopulation. A similar trend was observed for the expression of macrophage mannose receptor (MMR) and Dectin-1 on the surface of alveolar macrophages following IL-4 administration. Macrophage depletion or STAT6 deficiency abrogated the therapeutic effect of IL-4. Collectively, these data demonstrate that IL-4-mediated therapeutic macrophage reprogramming can accelerate resolution and lung repair despite delayed use following experimental ALI. IL-4 or other therapies that target late-phase, proresolution pathways may hold promise for the treatment of human ARDS.

Extrapolation from ten sections can make CT-based quantification of lung aeration more practicable.

PURPOSE: Clinical applications of quantitative computed tomography (qCT) in patients with pulmonary opacifications are hindered by the radiation exposure and by the arduous manual image processing. We hypothesized that extrapolation from only ten thoracic CT sections will provide reliable information on the aeration of the entire lung. METHODS: CTs of 72 patients with normal and 85 patients with opacified lungs were studied retrospectively. Volumes and masses of the lung and its differently aerated compartments were obtained from all CT sections. Then only the most cranial and caudal sections and a further eight evenly spaced sections between them were selected. The results from these ten sections were extrapolated to the entire lung. The agreement between both methods was assessed with Bland-Altman plots. RESULTS: Median (range) total lung volume and mass were 3,738 (1,311-6,768) ml and 957 (545-3,019) g, the corresponding bias (limits of agreement) were 26 (-42 to 95) ml and 8 (-21 to 38) g, respectively. The median volumes (range) of differently aerated compartments (percentage of total lung volume) were 1 (0-54)% for the nonaerated, 5 (1-44)% for the poorly aerated, 85 (28-98)% for the normally aerated, and 4 (0-48)% for the hyperaerated subvolume. The agreement between the extrapolated results and those from all CT sections was excellent. All bias values were below 1% of the total lung volume or mass, the limits of agreement never exceeded ± 2%. CONCLUSION: The extrapolation method can reduce radiation exposure and shorten the time required for qCT analysis of lung aeration.

The role of post-transcriptional regulation in chemokine gene expression in inflammation and allergy.

The aim of this review is to discuss recent advances in the understanding of the regulation of chemokine expression occurring during chronic inflammatory conditions, such as allergic diseases. The focus will be on current data, which suggest that post-transcriptional regulation plays a larger role in chemokine gene regulation than previously recognised. In particular, a growing body of data indicates that mechanisms controlling mRNA stability may be relevant in determining, or maintaining, the increased levels of chemokine gene expression in this context. Such regulatory pathways may be important targets of novel anti-inflammatory strategies.

Assessment of signal transducer and activator of transcription 6 as a target of glucocorticoid action in human airway epithelial cells.

BACKGROUND: Activation of signal transducer and activator of transcription (STAT)6 by IL-4 and IL-13 is essential in many key epithelial responses in the asthmatic airway including expression of numerous chemokines, goblet cell differentiation and mucus production and expression of other allergic inflammatory genes. While these responses are all inhibited by glucocorticoids (GC) administered systemically or by inhalation, the inhibitory mechanisms are unknown. OBJECTIVE: To test the hypothesis that GC suppress allergic responses by blocking IL-4-induced STAT6 signalling in airway epithelial cells. METHODS: Western blotting and reporter gene assays were used to determine whether GC could inhibit STAT6 production, phosphorylation or nuclear translocation, or whether GC could affect STAT6 transcriptional activity in the BEAS-2B airway epithelial cell line. RESULTS: Our results showed that GC had no inhibitory effect on the total cellular or nuclear levels of STAT6 or phospho-STAT6. GC did not inhibit transcription from three different STAT6-driven reporter constructs, indicating that GC also did not inhibit STAT6 function. CONCLUSION: We conclude that airway epithelial STAT6 is not the central target of GC in allergic inflammation and that the inhibitory effect of GC on STAT6-mediated IL-4- and IL-13-induced responses is exerted by targeting pathways distinct from STAT6.

Xenopus Pax-2/5/8 orthologues: novel insights into Pax gene evolution and identification of Pax-8 as the earliest marker for otic and pronephric cell lineages.

Pax genes are a family of transcription factors playing fundamental roles during organogenesis. We have recently demonstrated the expression of Pax-2 during Xenopus embryogenesis [Heller N, Brändli AW (1997): Mech Dev 69: 83-104]. Here we report the cloning and characterization of Xenopus Pax-5 and Pax-8, two orthologues of the Pax-2/5/8 gene family. Molecular phylogenetic analysis indicates that the amphibian Pax-2/5/8 genes are close relatives of their mammalian counterparts and that all vertebrate Pax-2/5/8 genes are derived from a single ancestral gene. Xenopus Pax-2/5/8 genes are expressed in spatially and temporally overlapping patterns during development of at least seven distinct tissues. Most strikingly, Xenopus Pax-8 was identified as the earliest marker of the prospective otic placode and of the intermediate mesoderm, indicating that Pax-8 may play a central role in auditory and excretory system development. Comparison of the expression patterns of fish, amphibian, and mammalian Pax-2/5/8 genes revealed that the tissue specificity of Pax-2/5/8 gene family expression is overall evolutionarily conserved. The expression domains of individual orthologues can however vary in a species-specific manner. For example, the thyroid glands of mammals express Pax-8, while in Xenopus Pax-2 is expressed instead. Our findings indicate that differential silencing of Pax-2/5/8 gene expression may have occurred after the different classes of vertebrates began to evolve separately.

Xenopus Pax-2 displays multiple splice forms during embryogenesis and pronephric kidney development.

Kidney organogenesis is initiated with the formation of the pronephric kidney and requires Pax-2 gene function. We report here the cloning and characterization of Pax-2 cDNAs from the frog Xenopus laevis, a model system suitable for the study of early kidney organogenesis. We show that expression of Xenopus Pax-2 (XPax-2) genes was confined to the nervous system, sensory organs, the visceral arches, and the developing excretory system. DNA sequencing of XPax-2 cDNAs isolated from head and pronephric kidney libraries revealed seven novel alternatively spliced Pax-2 isoforms. They all retain DNA-binding domains, but can differ significantly in their C termini with some isoforms containing a novel Pax-2 exon. We investigated the spectrum of XPax-2 splice events in pronephric kidneys, animal cap cultures and in whole embryos. Splicing of XPax-2 transcripts was found to be extensive and temporally regulated during Xenopus embryogenesis. Since all investigated tissues expressed essentially the full spectrum of XPax-2 splice variants, we conclude that splicing of XPax-2 transcripts does not occur in a tissue-specific manner.

Subcutaneous pedicle flaps in facial repair.

This study shows the importance of rotating subcutaneous pedicle flaps for a wide range of possibilities in face and nose reconstruction. The method described was studied and developed over 10 years in 305 patients with basocellular carcinoma of the face. This method uses areas with natural depressions and provides good aesthetic results, which are sometimes difficult to obtain using conventional reconstruction methods. Because of their circulatory nature, subcutaneous pedicle flaps can be performed on most parts of the face. The flap can be prepared from skin where there is cellular subcutaneous soft tissue (randomized vascularization), in which the facial circulation is tangential and vertical to the skin surface (i.e., like perforating arteries). These characteristics can be found in nasogenian wrinkles, the malar region, the upper and lower lips, and the chin. The flaps can not be prepared, however, from a region corresponding to the front of the face, the cervical, or the nose, where the necessary circulatory details and soft tissue are not available.

Prevalence of ocular microorganisms in hospitalized and stabled horses.

Microorganisms from normal eyes of hospitalized and stabled horses were identified, and the frequency of isolation was compared between the 2 groups. Using standard techniques, swab specimens from both eyes of 22 hospitalized horses and both eyes of 18 stabled horses were cultured for aerobic bacteria and fungi. Ninety-six aerobic bacteria and 57 fungi were isolated. The predominant bacterial isolates were gram-positive organisms, most of which belonged to the genera Corynebacterium, Bacillus, Staphylococcus, and Streptomyces. Gram-negative organisms comprised less than one-fourth of the bacterial isolates, with the genera Neisseria, Moraxella, and Acinetobacter being the most commonly isolated. Environmental fungi Cladosporium and Alternaria accounted for half of all fungal isolates. In only 5 horses were fungi isolated without accompanying isolation of bacteria. The frequency of isolation of fungi was higher (P less than 0.01) in stabled horses. For bacteria, the frequency of isolation was higher (P less than 0.08) in male horses. Results of susceptibility testing were recorded as the percentage of all isolates susceptible to a given antimicrobic drug. Bacterial isolates were highly susceptible (greater than or equal to 90%) to neomycin, polymixin B, gentamicin, and chloramphenicol. Overall, filamentous fungi had highest susceptibility to natamycin (97%). Miconazole was highly efficacious (100% susceptibility) against Fusarium and Aspergillus.

[Immunologic aspects of transitory neonatal hyperthyroidism]. / Immunologische Aspekte der transitorischen Neugeborenen-Hyperthyreose.

The pathogenesis of neonatal transient hyperthyroidism has not been fully established, but the placental transfer of thyroid stimulating immunoglobulins such as thyroid stimulating antibodies is considered the main cause. Clinical signs usually subside with the disappearance of thyroid-stimulating IgG in the serum of the neonate. We report the clinical course of a neonatal transient hyperthyroidism.

Granulocyte lysosomal factors and plasma elastase in uremia: a potential factor of catabolism.

In uremic intoxication proteolytic activity in plasma and striated muscle is enhanced. To get further insights into the underlying mechanisms the lysosomal factors of polymorphonuclear (PMN) leukocytes and the plasma elastase-alpha 1-proteinase inhibitor complex were investigated in patients with acute and chronic renal failure. Lysosomal activity was evaluated in peripheral blood smears by the lysis of erythrocytes and plasma (halo formation) around each neutrophil induced by 0.25 M NaC1 borate buffer. In about half of the patients with chronic renal insufficiency on dietary treatment lysosomal activity of PMN leukocytes was reduced. The plasma concentration of elastase-alpha 1-proteinase inhibitor complex was normal in most subjects, but increased in three patients with the highest serum creatinine levels (greater than 13 mg/d1). In the patients with acute renal failure (ARF) of various origin (postoperatively, septicemia, pancreatitis, or dye-induced) halo formation was either reduced or absent. The plasma elastase-alpha 1-proteinase inhibitor complex was increased in 5/6 of the patients by a factor of two to four. Also in the patients on regular hemodialysis treatment halo formation of PMN leukocytes was substantially reduced, whereas the plasma levels of elastase-alpha 1-proteinase inhibitor complex was slightly increased. The finding of reduced lysosomal activity of PMN neutrophils in uremia may be partly due to an enhanced release of neutral proteinases into the circulation as indicated by the elevated plasma levels of elastase-alpha 1-proteinase inhibitor complex in some patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Release of granulocyte neutral proteinases in patients with acute and chronic renal failure.

In uremic intoxication proteolytic activity in plasma and striated muscle is enhanced. To get further insight into the underlying mechanisms the neutral proteinases of polymorphonuclear (PMN) leukocytes were investigated in patients with acute and chronic renal failure. The following studies were performed: 1. Neutral proteolytic activity of PMN neutrophils in blood smears (according to Klessen, 1978). 2. Serum levels of elastase alpha 1 proteinase inhibitor complex (Neumann et al., 1981). In about half of the patients with chronic renal insufficiency on dietary treatment the proteolytic activity of PMN leukocytes (halo formation are due to digestion of erythrocytes and plasma) was reduced. The serum concentration of elastase alpha 1 proteinase inhibitor complex was normal in most subjects, but increased in 3 patients with the highest serum creatinine levels (greater than 13 mg/dl). In the patients with acute renal failure (ARF) of various origin (postoperatively, septicemia, pancreatitis or dye induced) halo formation was either reduced or absent. Serum elastase alpha 1 proteinase inhibitor was increased in 5/6 patients by a factor of two to four. Also in the 15 patients on regular hemodialysis treatment halo formation was substantially reduced, while the serum levels of elastase alpha 1 proteinase inhibitor complex was slightly increased. The finding of reduced proteolytic activity of PMN neutrophils in uremia is probably due to an enhanced release of proteinases into the circulation as indicated by the elevated serum levels of elastase alpha 1 proteinase inhibitor complex in some patients. The release of proteinases might be in part due to the effect of "uremic toxins". In the RDT patients the contact of the blood with the dialyzer (cuprophane) membrane might be an additional factor. In the patients with ARF the underlying disease (infection, shock, trauma) contributes to the release of proteinases. These disturbances may be harmful for the patient, if the blood concentration or function of the most important proteinase inhibitors (alpha 1 proteinase inhibitor, alpha 2 macroglobulin) is reduced.

Proteolytic enzymes and catabolism: enhanced release of granulocyte proteinases in uremic intoxication and during hemodialysis.

Proteinases are classified into four groups according to their catalytic mechanisms: the serine, cysteine (thiol), aspartic (carboxyl), and metallo-proteinases. Neutrophil granulocytes contain a variety of neutral proteinases and two acid proteinases. Lysosomal proteinases are released from cells during phagocytosis, cell death, or exposure to antigen-antibody complexes, complement factors, and toxins. Under pathological conditions, massive proteinase release may cause tissue injury and degradation of plasma proteins. Plasma proteolytic activity is controlled by inhibitors of blood systems (antithrombin III, C1 inhibitor, and plasmin inhibitor) and by inhibitors against proteinases of various body cells (alpha 1-proteinase inhibitor, alpha 1-antichymotrypsin, beta 1-collagenase inhibitor, and inter-alpha-trypsin inhibitor). Intracellular proteinases are controlled by different cytosolic inhibitors. In hypercatabolic states (septicemia, trauma, burns), the concentrations of many plasma proteins, including proteinase inhibitors, are decreased. Kallikrein-kinin, complement, and fibrinolytic systems may be activated, probably due to enhanced proteinase activity. In acute renal failure, there is a release of granulocyte neutral proteinases. The plasma concentration of the elastase-alpha 1-proteinase inhibitor complex is simultaneously increased. Granulocytes of chronically uremic patients treated with diet or regular dialysis have a slightly to markedly reduced proteinase content as compared with normal controls. There is a dramatic rise of the plasma elastase alpha 1-proteinase inhibitor complex during hemodialysis treatment.

Effect of positive end-expiratory pressure and body position in unilateral lung injury.

Positive end-expiratory pressure (PEEP), by increasing lung volume in acute lung injury, may recruit terminal air spaces in the involved regions, but may also distend noninvolved regions increasing extravascular lung water and worsening gas exchange. We investigated the effect of increasing levels of PEEP on arterial oxygenation in 26 anesthesized dogs with unilateral acid pneumonitis and studied the influences of gravity and distribution of the injury on this effect. Arterial PO2 was consistently higher when the noninjured lung was dependent than in the supine or injured lung-dependent positions. Low levels of PEEP (5, 10 cmH2O) improved arterial oxygenation and reduced intrapulmonary physiological shunt. However, 15 cmH2O PEEP resulted in worsening of gas exchange, increased dead space ventilation, and diminished static compliance. The adverse effects of high levels of PEEP on arterial oxygenation were similar whether the injured lung was dependent or not and were evident a lower levels of PEEP in one group of dogs in which the unilateral injury was more diffuse and in which the upper and middle lobes were also involved. Thus, the compressive effects of high levels of PEEP on alveolar capillaries in the noninjured lung are influenced by the extent and distribution of injury in the injured lung, but not by local forces governing regional blood flow distribution.

Reverse, hormone-dependent sex difference in molar tooth mass in pubertal mice.

The weighed mass of molar teeth of male pubertal (35-day-old) mice was significantly smaller than that of females. X0 females, and chromosomal males (XY) rendered phenotypically female by the testicular feminization gene (Tfm), had high (female-type) molar mass. Chromosomal females (XX or X0) rendered hormonally phenotypically male by the sex reversal gene Sxr, had low (male-type) molar mass. It is concluded that the sex difference was due to hormonal rather than chromosomal factors. Reported sex differences in mammalian tooth size have mainly been in the opposite direction, a discrepancy which may be due to co-existence of opposite dimorphisms of mass and diameter, or to age-specific changes in ontogeny. However, the most likely explanation is that developmental species differences exist.