The actin cytoskeleton in ageing and apoptosis.
Regulated cell death, or apoptosis, has evolved to fulfil a myriad of functions amongst multicellular organisms. It is now apparent that programmed cell death occurs in unicellular organisms such as yeast. In yeast, as in higher eukaryotes, the actin cytoskeleton is an essential component of a number of cellular activities, and many of the regulatory proteins involved are highly conserved. Recent evidence from diverse eukaryotic systems suggests that the actin cytoskeleton has a role in regulating apoptosis via interactions with the mitochondria. This interaction also appears to have a significant impact on the management of oxidative stress and so cellular ageing. In this mini-review we summarise some of the work, which suggests that actin is a key regulator of apoptosis and ageing in eukaryotic cells.


Inhibition of Erb-B2 Receptor Tyrosine Kinase 3 and Associated Regulatory Pathways Potently Impairs Malignant Peripheral Nerve Sheath Tumor Proliferation and Survival.
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, currently untreatable Schwann cell-derived neoplasms with hyperactive mitogen-activated protein kinase and mammalian target of rapamycin signaling pathways. To identify potential therapeutic targets, previous studies used genome-scale shRNA screens that implicated the neuregulin-1 receptor erb-B2 receptor tyrosine kinase 3 (erbB3) in MPNST proliferation and/or survival. The current study shows that erbB3 is commonly expressed in MPNSTs and MPNST cell lines and that erbB3 knockdown inhibits MPNST proliferation and survival. Kinomic and microarray analyses of Schwann and MPNST cells implicate Src- and erbB3-mediated calmodulin-regulated signaling as key pathways. Consistent with this, inhibition of upstream (canertinib, sapitinib, saracatinib, and calmodulin) and parallel (AZD1208) signaling pathways involving mitogen-activated protein kinase and mammalian target of rapamycin reduced MPNST proliferation and survival. ErbB inhibitors (canertinib and sapitinib) or erbB3 knockdown in combination with Src (saracatinib), calmodulin [trifluoperazine (TFP)], or proviral integration site of Moloney murine leukemia kinase (AZD1208) inhibition even more effectively reduces proliferation and survival. Drug inhibition enhances an unstudied calmodulin-dependent protein kinase IIα phosphorylation site in an Src-dependent manner. The Src family kinase inhibitor saracatinib reduces both basal and TFP-induced erbB3 and calmodulin-dependent protein kinase IIα phosphorylation. Src inhibition (saracatinib), like erbB3 knockdown, prevents these phosphorylation events; and when combined with TFP, it even more effectively reduces proliferation and survival compared with monotherapy. These findings implicate erbB3, calmodulin, proviral integration site of Moloney murine leukemia kinases, and Src family members as important therapeutic targets in MPNSTs and demonstrate that combinatorial therapies targeting critical MPNST signaling pathways are more effective.


Application of vocal organ correction combined with language training in the rehabilitation of children with cerebral palsy and language disorder.
To explore the effect of vocal organ correction combined with language training on the rehabilitation of children with cerebral palsy (CP) and language disorder. A total of 98 children with CP and language disorder were divided into two groups (49 cases in each group) using a random number table: the control group and the test group. The control group was given language training alone, while the test group received vocal organ correction combined with language training. The changes in language function classification, efficacy, and family satisfaction before and after the treatments were compared. A significant difference was identified in language function classification between the two groups before and after treatment (P<0.05). The language function classification of the two groups was also significantly different after treatment (P<0.05), as was the distribution of clinical efficacy between the two groups (P<0.05). The total effective rate for the test group was 91.84%, which was higher than the 73.47% for the control group (P<0.05). Family satisfaction between the two groups differed significantly (P<0.05), and the total satisfaction rate of families in the test group was 87.76%, which was higher than the 69.39% in the control group (P<0.05). Vocal organ correction combined with language training can improve the language function of children with CP and language disorder, has ideal efficacy, and can also enhance family satisfaction during rehabilitation.


Negative attitudes of healthy older adults toward unhealthy older adults: Focus on the subjective health.
Negative attitudes toward older adults, especially those with declining physical function and/or advanced dementia (i.e., unhealthy older adults), are serious. It is important to identify psychological factors associated with such negative attitudes toward unhealthy older adults. In this study, we focused on subjective health (subjective perception of one's own health status). We tested the hypothesis that healthy older adults with lower subjective health have more negative attitudes toward unhealthy older adults. We also examined whether this association is still pronounced after controlling for the participants' physical health status and demographics. In this study, an online survey was conducted among Japanese older adults who were not certified as needing long-term care (N = 1,082, aged 65-88). To control for the participants' physical health status, we focus on frailty. We conducted a factor analysis and multiple regression analysis on negative attitudes toward unhealthy older adults. As a result, healthy older participants with lower subjective health perceived unhealthy older adults negatively, and this association was still pronounced even after controlling for the participants' frailty score and demographics. Based on our findings, it is suggested that increasing the subjective health of older adults may help them view each other more positively. Therefore, it is important to devise gerontological and psychological interventions to improve older adults' subjective health. This study has limitations, such as the fact that we conducted only an online survey. Previous studies on how older adults perceive the social group of older adults are scarce, and further studies are expected.


Dominant role of the niche in melanocyte stem-cell fate determination.
Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.


Cholera toxin B decreases bicuculline seizures in prenatally morphine- and saline-exposed male rats.
Prenatal morphine exposure on gestation days 11-18 alters bicuculline-induced seizures in rats during development and in adulthood. Adult, morphine-exposed male progeny exhibit an increased latency to bicuculline seizures, which can be reversed by administration of the opioid receptor antagonist naloxone. In chronically morphine-treated adult mice, cholera toxin B (CTX-B) can reverse the effects of chronic morphine administration. Therefore, the present study investigated whether prenatally morphine-exposed rats show a similar response to CTX-B as chronically morphine-treated adult rodents. Prenatally morphine-, saline- and unexposed male progeny were tested for seizure susceptibility with a 7.5-mg/kg intraperitoneal injection of bicuculline in adulthood. CTX-B or saline was injected subcutaneously at 24, 12, and 0.5 h before bicuculline injection. CTX-B decreased the occurrence of bicuculline-induced seizures in both prenatally saline- and morphine-exposed but not unexposed rats. Furthermore, three, but not one, saline injections administered at 12-h intervals prior to bicuculline administration reversed the increase in seizure latency in prenatally morphine-exposed adult males, suggesting an altered responsiveness of the stress system. The present study demonstrates that CTX-B can decrease the occurrence of bicuculline seizures in prenatally stressed rats and that increased seizure latencies in prenatally morphine-exposed male rats may be related to stress responses.


Treatment of locoregional recurrence of carcinoma of the cervix by radiotherapy after primary surgery.
Eighteen patients with locoregional recurrence after primary surgery for carcinoma of the cervix and treated by radiotherapy were analyzed. An overall complete response of 88%, 16 of 18, was achieved. Five of sixteen patients (31%) developed a second locoregional recurrence. Response to radiotherapy seemed to correlate strongly with tumor volume. The overall 5-year survival for all 18 patients was 44%, and the disease-free survival, 39%. Only 22%, 4 of 18, had distant metastases in the subsequent course of the disease.


Osteochondroma as a cause of scapular winging in an adolescent: a case report and review of the literature.
Winged scapula is defined as the prominence of the medial border of the scapula. The classic etiopathology of scapular winging are injuries to the spinal accessory or long thoracic nerves resulting respectively in trapezius and serratus anterior palsy. To the best of our knowledge, there are only few reports of scapular lesions being mistaken for winging of the scapula. We report a rare case of a large scapular osteochondroma arising from the medial border and causing a pseudowinging of the scapula. A 17-year-old Caucasian boy came to us complaining about a winged left scapula. The patient had a complete painless range of motion, but a large hard bony swelling was palpable along the medial border of his left scapula. A grating sensation was felt when his arm was passively abducted and/or elevated causing discomfort. A lesion revealed on X-rays was diagnosed as an osteochondroma of the medial border of his scapula. After preoperative examinations, he underwent open surgery in order to remove the lesion. A histological examination confirmed the clinical diagnosis of osteochondroma. A clinical examination 3 months later showed a full and painless range of motion, the absence of the grating sensation during passive abduction and elevation and the complete disappearance of his left shoulder deformity. After 2 years of follow-up, there were no clinical or radiological signs of recurrence. Despite its rarity osteochondroma should be considered in the differential diagnosis for any adolescent presenting with a winging of the scapula.


[Clinical and pathological staging of 85 patients with Hodgkin's disease: a clinical contribution (author's transl)].
This is a retrospective study of 85 patients with Hodgkin's disease undergoing studies of clinical staging. Of these, 28 were investigated by laparotomic splenectomy, which revealed evidence of disease progress not otherwise detectable in 10 cases (36%). The authors also note that cases with an unfavorable histotype are associated with a higher incidence of spleen involvement and a more advanced stage of disease.


Ancient Schwannoma: A Rare Intramural Intra-lingual Lesion.
Ancient schwannoma is an uncommon schwannoma variant which is a benign tumour of Schwann cell origin. It is relatively a rare tumour (25%) in the head and neck region. It is encapsulated and well demarcated from the surrounding tissues. A 35 years old patient in this case presented with painless swelling of the tongue. Trans-oral excision of the intramural lesion was performed. Histopathological and immuno-histochemistry confirmed the diagnosis of schwannoma. This case is of interest on account of the complexity of its diagnosis and the atypical site, that is, intra-mural, of appearance of a schwannoma.


[The assessment of the elderly patients' need in medical and social care during remission period].
The article considers the results of medical sociological survey of elderly patients with chronic therapeutic pathology. The issues of assessing the degree of provision of their medical and social needs during remission period are discussed. The sampling included 212 patients aged 65 years and older receiving medical and social care in health institutions of City of Kursk and Lipetskaya oblast. The social demographic profile of patient is defined. The shortcomings in rendering continuous pharmaceutical treatment, diet maintenance, organization of nursing and social care at home, rehabilitation activities.


Consensus on Neonatal Through Preadolescent Acne.
Acne vulgaris is the most common dermatological disorder. Pediatric acne may be a manifestation of the underlying pathology and can occur in the first weeks, months, or years of life. Acne in childhood can be categorized by age and pubertal status. An expert panel of pediatric dermatologists and dermatologists developed a consensus paper on neonatal through preadolescent acne, providing information on differential diagnosis, prevention, treatment, and maintenance of the condition. A systematic literature review explored present clinical guidelines, treatment options, and therapeutic approaches addressing neonatal through preadolescent acne. The information from the literature searches was used together with the panel's expert opinion and experience to adopt consensus statements following established standards. The panel members reached unanimous consensus on seven statements addressing the various age categories of pediatric acne: neonatal acne: birth to ≤ 8 weeks; infantile acne: 8 weeks to ≤1 year; mid-childhood acne: 1 year to <7 years; preadolescent acne: ≥7 to 12 years; adolescent acne: ≥12 to 19 years or after menarche for girls. Health care providers treating children need to pay more attention to pediatric acne and should monitor the risk of endocrine-associated abnormalities, especially in mild-childhood acne. When prescribing acne treatment, newer medications approved for use in children older than nine years of age may offer a suitable option. The differential diagnosis of pediatric acne, as well as its treatment and maintenance, requires much more attention and consideration from health care providers treating children. J Drugs Dermatol. 2020;19(6):592-600. doi:10.36849/JDD.2020.5065.


Effectiveness of the lactational amenorrhea method in Pakistan.
To determine the efficacy of the lactational amenorrhea method of family planning (amenorrhea during full or nearly full breastfeeding for 6 months postpartum). Prospective noncomparative study. Normal breastfeeding women in Karachi and Multan, Pakistan, most delivered at home by a midwife. Three hundred ninety-nine newly delivered mothers who successfully had breastfed a previous child and chose the lactational amenorrhea method to prevent a subsequent pregnancy, 391 of whom were followed for a full year. Mothers were taught, before or shortly after delivery, to use the method and were interviewed in their homes each month by a Lady Health Visitor. Life-table pregnancy rates. Periods of postpartum or lactational abstinence were excluded in the calculation of the pregnancy rates. During full or nearly full breastfeeding, while the women were amenorrheic and not otherwise contracepting, the rate of pregnancy was 0.6%. The pregnancy rate during lactational amenorrhea alone was 1.1% at 1 year postpartum. The lactational amenorrhea method was found to be highly effective for 6 months. A high degree of contraceptive protection endures for a full year during lactational amenorrhea, but not after the return of menses during breastfeeding.


A new combined sensory-instrumental tool for pomegranate seed hardness determination.
Scanning electron microscopy was assayed and linked with previous data with respect to obtaining a new combined sensory-instrumental tool for pomegranate seed hardness determination. The present study aimed to develop an effective tool for the prediction of sensory properties via instrumental determinations. Simple regression analysis determined a high correlation within descriptive seed hardness and thickness of the wall, as well as descriptive wood perception and thickness of the wall, with values of 0.71 in both cases. Multiple regression analysis improved correlations when (i) descriptive seed hardness correlated with instrumental seed hardness and wood index (0.94); (ii) descriptive wood perception correlated with instrumental seed hardness and wood index (0.79); (iii) descriptive seed hardness correlated with instrumental seed hardness and thickness of the seed wall (0.96); and (iv) descriptive wood perception correlated with instrumental seed hardness and thickness of the seed wall (0.82). The same trend was found when (i) seed hardness satisfaction degree correlated with instrumental seed hardness and wood index (0.92); (ii) wood perception satisfaction degree correlated with instrumental seed hardness and wood index (0.82); (iii) seed hardness satisfaction degree correlated with instrumental seed hardness and thickness of the wall (0.99); and (iv) wood perception satisfaction degree correlated with instrumental seed hardness and thickness of the wall (0.99). Regarding mechanical properties, the results of the present study confirm that texture analysis and scanning electron microscopy are an effective tool for obtaining reliable information. This research led to establish an objective tool allowing prediction of the consumer acceptance of pomegranate cultivars worldwide. © 2020 Society of Chemical Industry.


Growth pattern of tumours in mice induced by murine Moloney sarcoma-virus and sarcoma-virus-transformed cells.
Transplantation of a Moloney sarcoma-virus (MSV-M)-transformed producer cell line (Sac(+)) induced progressively or regressively growing tumours in mice. Progressive growth always occurred after transplantation of an MSV-M non-producer transformant (Sac(-)), whereas the MSV-M released from the producer cells (Sac virus) always induced tumours which regressed. In contrast to the non-producer, the producer transformant Sac(+) as well as Sac virus induced a strong immune response, detected in vitro by cell- and antibody-mediated cytotoxicity assays, and in vivo by transplantation immunity. Implantation of Sac(-) cells led to solid, under-vascularized tumours, consisting histologically of uniform densely packed tumour cells. Sac-virus-induced tumours, however, were very well vascularized and arose by proliferation of different connective-tissue cells. After transplantation of Sac(+) cells, tumours were found to consist of typical tumour cells morphologically similar to Sac(-) cells intermingled with proliferated connective-tissue cells. Cultivation of tumour fragments from Sac(+) and Sac(-) tumours was followed by outgrowth of transformed tumour cells with the properties of the originally implanted cells. Tumour explant cultures from Sac-virus-induced tumours did not lead to growth of stably transformed cells. Co-culture of mouse embryo fibroblasts (MEF) with Sac(+) cells resulted in overgrowth of the transformed cells. Infection of MEF with Sac virus led to transiently transformed cells. It is concluded that Sac(+) cell tumours will resist the strong immune defence mechanisms they induce and grow progressively, if the inoculated cells are able to build up a solid, poorly vascularized nodule in the tissue. This always happens after implantation of 10(6) cells, but only occasionally when fewer cells are inoculated. Sac-virus-induced tumours will always regress owing to the strong immune response. The regression is furthered by the fact that MSV-M infection rarely if ever leads to a stable transformation.


Evaluation of change in the vascular density of choriocapillaris on optical coherence tomography angiography in eyes with serpiginous choroiditis.
Serpiginous choroiditis (SC) is primarily an inflammation of choriocapillaris leading to nonperfusion. A quantitative assessment of choriocapillaris perfusion can be done by measuring the flow-density by OCT-Angiography (OCTA). This study measures a change in the flow-density of choriocapillaris with the resolution of inflammation. The OCTA images of a choriocapillaris slab of 30 eyes with active SC were subjected to binarization and vessel density was measured at baseline and final visits and compared. Upon comparing the vessel density of the affected areas by OCTA of choriocapillaris-slab at baseline and final visits, there was statistically significant (P < 0.0001) improvement after the resolution of inflammation. The vessel density of a demarcated normal area was significantly higher when compared to that of lesions at baseline (P < 0.0001) and final visit (P < 0.0001). OCTA is a useful tool to assess reduction in the inflammatory activity on treatment in SC. This study shows that with treatment the perfusion of choriocapillaris improves; however, it remains lower than normal.


Escherichia coli-associated follicular cystitis in dogs: Clinical and pathologic characterization.
Follicular cystitis is an uncommon inflammatory change in the urinary bladder wall characterized by the formation of tertiary lymphoid structures (TLSs) in the submucosa. To characterize clinical and pathologic features of follicular cystitis in dogs and to explore in situ distribution and possible role of Escherichia coli as an associated cause. Eight dogs diagnosed with follicular cystitis and 2 control dogs. Retrospective descriptive study. Dogs diagnosed with follicular cystitis (macroscopic follicular lesions in the urinary bladder mucosa and histopathologic detection of TLSs in bladder wall biopsies) were identified from medical records. Paraffin embedded bladder wall biopsies were subject to in situ hybridization for E. coli 16SrRNA identification. Follicular cystitis was diagnosed in large breed (median weight 24.9 kg, interquartile range [IQR] 18.8-35.4 kg) female dogs with a history of chronic recurrent urinary tract infections (UTIs; median duration of clinical signs 7 months, IQR 3-17 months; median number of previous UTIs 5, IQR 4-6). Positive E. coli 16SrRNA signal was detected within developing, immature and mature TLSs in 7/8 dogs, through submucosal stroma in 8/8 dogs and within the urothelium in 3/8 dogs. Chronic inflammation associated with an intramural E. coli infection in the urinary bladder wall represents a possible triggering factor for the development of follicular cystitis.


Effect of thrombolysis on heart rate variability and life-threatening ventricular arrhythmias in survivors of acute myocardial infarction.
The aim of the present study was to determine the influence of early thrombolysis on ventricular tachyarrhythmias (clinical and inducible) and heart rate variability in survivors of myocardial infarction at high risk for life-threatening ventricular arrhythmias. A greater electrical heart stability may be important in improving survival in patients treated with thrombolysis. Few data are available about the influence of fibrinolysis on postinfarction arrhythmic events and other prognostic variables, such as inducible ventricular tachycardia and heart rate variability. The study group comprised 51 consecutive patients who underwent electrophysiologic study within 30 days of infarction, owing to the presence of two or more of the following criteria: left ventricular ejection fraction < 40%, late potentials and repetitive ventricular ectopic beats. Thirty patients underwent thrombolysis within 6 h of the onset of symptoms (Group A), and 21 received conventional treatment (Group B). Inducibility of sustained monomorphic ventricular tachycardia was tested in both groups, and the standard deviation of all normal RR intervals during 24-h Holter monitoring was calculated. All patients were prospectively evaluated for occurrence of arrhythmic events. The two groups were similar with regard to left ventricular ejection fraction (mean +/- 1 SD 38 +/- 6% [Group A] vs. 36 +/- 8% [Group B]). Ventricular tachycardia was induced in 6 (20%) of 30 Group A patients versus 14 (67%) of 21 Group B patients (p = 0.002). The standard deviation of normal RR intervals was higher in Group A than in Group B (113 +/- 36 vs. 90 +/- 39 ms, p = 0.05). In patients with anterior infarction, the standard deviation of normal RR intervals was higher in 19 patients with thrombolysis than in 16 patients with conventional treatment (118 +/- 41 vs. 74 +/- 24 ms, p = 0.0002). During a mean follow-up period of 23 +/- 11 months, 4 (13%) of 30 Group A patients had an arrhythmic event versus 9 (43%) of 21 Group B patients (p = 0.04). After myocardial infarction, in high risk patients, thrombolysis significantly reduced the occurrence of arrhythmic events independently of left ventricular function. This effect may be related to both an improvement in electrical heart stability, as elucidated by electrophysiologic study, and a favorable action on the cardiac sympathovagal balance.


Intermittent intravenous pantoprazole and continuous cimetidine infusion: effect on gastric pH control in critically ill patients at risk of developing stress-related mucosal disease.
This study aimed to assess intermittent intravenous (IV) pantoprazole for control of gastric acid and the possible prevention of upper gastrointestinal (UGI) bleeding in intensive care units (ICU) patients. This was a multicenter, randomized, open-label, dose-ranging pilot study of IV pantoprazole (40 mg q24 hour; 40 mg q12 hour; 80 mg q24 hour; 80 mg q12 hour; 80 mg q8 hour) or continuously infused cimetidine (300 mg bolus; 50 mg/h) in patients at risk for UGI bleeding. The primary endpoint was percent time gastric pH >/=4.0. UGI bleeding and pneumonia were measured as secondary endpoints. Two hundred two ICU patients were randomized. Gastric pH was well controlled by all treatments. Gastric pH control improved from day 1 to day 2 in all pantoprazole groups, whereas there was decreased pH control in the cimetidine group. There were no cases of protocol defined UGI bleeding in any treatment group. Adverse event frequency and pneumonia incidence were similar between pantoprazole and cimetidine treated patients. This pilot study indicates that intermittent IV pantoprazole effectively controls gastric pH and may protect against UGI bleeding in high risk ICU patients without the development of tolerance.


ENGRAILED-1 transcription factor has a paracrine neurotrophic activity on adult spinal α-motoneurons.
Several homeoprotein transcription factors transfer between cells and regulate gene expression, protein translation, and chromatin organization in recipient cells. ENGRAILED-1 is one such homeoprotein expressed in spinal V1 interneurons that synapse on α-motoneurons. Neutralizing extracellular ENGRAILED-1 by expressing a secreted single-chain antibody blocks its capture by spinal motoneurons resulting in α-motoneuron loss and limb weakness. A similar but stronger phenotype is observed in the Engrailed-1 heterozygote mouse, confirming that ENGRAILED-1 exerts a paracrine neurotrophic activity on spinal cord α-motoneurons. Intrathecal injection of ENGRAILED-1 leads to its specific internalization by spinal motoneurons and has long-lasting protective effects against neurodegeneration and weakness. Midbrain dopaminergic neurons express Engrailed-1 and, similarly to spinal cord α-motoneurons, degenerate in the heterozygote. We identify genes expressed in spinal cord motoneurons whose expression changes in mouse Engrailed-1 heterozygote midbrain neurons. Among these, p62/SQSTM1 shows increased expression during aging in spinal cord motoneurons in the Engrailed-1 heterozygote and upon extracellular ENGRAILED-1 neutralization. We conclude that ENGRAILED-1 might regulate motoneuron aging and has non-cell-autonomous neurotrophic activity.


[Intracytoplasmic sperm injection (ICSI): the Białystok experience].
To present a complete results of Intracytoplasmic Sperm Injection Program (ICSI) performed at IVF Unit in Bialystok, Poland. Retrospective data analysis. A total of 2593 cycles of ICSI treatment were analyzed. The results of controlled ovarian hyperstimulation (COH), parameters of fertilization, early embryo development and clinical pregnancy rates were compared depending on the type of COH used. Overall, for 16708 MII oocytes microinjected, the 2 pronuclear fertilization rate was 54%. Embryo transfer was performed in 94% of started cycles and 629 clinical pregnancies were recorded, giving a clinical pregnancy rate of 24% per cycle and 26% per transfer. No influence of COH on embryological and clinical results was noted. Intracytoplasmic sperm injection can be used successfully to treat couples with male factor infertility and those who have failed standard IVF. Precisely adapted protocol of ovarian hyperstimulation for every patient could diminish the costs of treatment without negative influence on ICSI results.


26th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 3-6 December 2003: update on clinical research.
The San Antonio Breast Cancer Symposium is an international meeting dedicated to the translation of advances in cellular and molecular biology of breast disease into clinical improvements in prevention, diagnosis and treatment. This report summarizes the clinical highlights of the 26th annual meeting held in San Antonio, Texas on 3-6 December 2003. Breast care for women will be improved by reports concerning optimal adjuvant hormonal therapy, advances in chemotherapy and a shift in the clinical philosophy of breast cancer care from maximum tolerable treatment to minimum effective therapy.


Impact of the first-line antiretroviral therapy on soluble markers of inflammation in cohort of human immunodeficiency virus type 1 in Moroccan patients: a prospective study.
Chronic inflammation and immune activation are a hallmark of HIV-1 infection. In this study, we assessed inflammation biomarkers in a cohort of people living with HIV-1 (PLWH) before and after long-term suppressive combined antiretroviral therapy (cART). A single-center prospective cohort study was conducted to assess inflammatory biomarkers in 86 cART-naive PLWH and after receiving suppressive cART and 50 uninfected controls. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and soluble CD14 (sCD14) were measured using enzyme-linked immunosorbent assay (ELISA). No significant difference was found in IL-6 levels between cART-naïve PLWH and controls (p = 0.753). In contrast, TNF-α level showed a significant difference between cART naïve-PLWH and controls (p = 0.019). Interestingly, IL-6 and TNF-α levels were significantly decreased in PLWH after cART (p < 0.0001). The sCD14 showed no significant difference between cART-naïve patients and controls (p = 0.839) and similar levels were observed in pre- and post-treatment (p = 0.719). Our results highlight the critical importance of early treatment to reduce inflammation and its consequences during HIV infection.


Biomarkers for EGFR-antagonist response: in the genes and on the genes!
Patients with non-small cell lung carcinoma containing epidermal growth factor receptor (EGFR)-activating mutations benefit from EGFR-antagonist therapy. EGFR-antagonist sensitivity is also correlated with epithelial-mesenchymal transition, which Walter and colleagues show to be marked by DNA-methylation changes. If validated, these markers could help identify patients with wild-type EGFR who will benefit from EGFR therapy.


Syncope in a 14yo female with ventricular tachycardia; an atypical etiology.
Wide complex tachycardias are rare in the pediatric population and may be due to ventricular tachycardia, aberrant conduction or antidromic tachycardia each with multiple underlying etiologies. We present a 14 yo female in extremis with syncope at rest witnessed by her mother, found in ventricular tachycardia by EMS who challenged with IVF hydration and amiodarone. Consecutive adequate fluid challenges and antiarrhythmics in the emergency department failed requiring synchronized cardioversion for stabilization. Subsequent viral panels, imaging, genetic testing and cardiac biopsy confirmed a diagnosis of arrhythmogenic right (and left) ventricular dysplasia.


Phrenic nerve injury due to thoracentesis for TPN effusion in a preterm newborn: consecutive two unusual complications.
Central venous catheters ara commonly used in neonatal intensive care units as routes of parenteral nutrition. Pleural effusions caused by extravasation of parenteral alimentation fluid are a rare complication of central venous catheters in the newborn. Diaphragmatic paralysis due to phrenic nerve injury is a rare respiratory condition which may be life-threatening in infants.


Selective up-regulation of claudin-1 and claudin-2 in colorectal cancer.
To understand the molecular and morphological alterations in the tight junction in colorectal cancer (CRC) tissues, the expression of eight tight junction proteins in normal and cancer colorectal tissues were compared. Adenocarcinoma tissues and paired normal mucosa were resected from surgical specimens of CRC patients. The expression of occludin, ZO-1, ZO-2, and claudin-1 -5 was analyzed at the mRNA level by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and at the protein level by immunohistochemistry. The expression of claudin-1 and claudin-2 in cancer tissues was upregulated 40- and 49.2-fold, respectively, at the mRNA level, as compared with that in normal tissues. The up-regulation of these two claudins was also observed at the protein level and it appeared to depend on the depth of tumor invasion. Claudin-1 and claudin-2 were found to be overexpressed in CRC tissues. They may be useful as tumor markers and targets for the treatment of colorectal cancer.


Pulmonary toxicity in mice after high-dose methotrexate administration with and without leucovorin rescue.
Interstitial lung lesions were induced in mice by high-dose methotrexate with high frequency. They appeared early after treatment; their onset, evolution and recovery parallelled those of lesions to the hemopoietic tissues and the intestine. The pathogenesis of methotrexate lung toxicity in mice is discussed. Leucovorin rescue was ineffective in preventing the lung lesions induced by high-dose methotrexate.


Spontaneous apoptosis in murine free-floating neurospheres.
We have shown successful in vitro expansion of rodent and human neural precursor cells (NPC) derived from fetal midbrain and forebrain. Here, we show that mouse neural precursor cells growing in neurospheres proliferate, but also undergo spontaneous apoptosis in vitro. On average, 30.7 +/- 3.4% cells of midbrain-derived neural precursors and 32.1 +/- 2.5% of forebrain-derived neural precursors were found apoptotic within neurospheres. Spontaneous apoptosis involved mitochondrial cytochrome c release and activation of effector caspase-3. Caspase-3 was activated in 26.9 +/- 3.4% of mesencephalic neural precursor cells. Virtually all nuclei with morphological signs of apoptosis belong to caspase-3-positive cells. The great majority of dying cells within neurospheres was positive for CNS precursor cell marker nestin. Pro-apoptotic proteins of the Bcl-2 family, Bax and Bak, exhibited conformational changes in neural precursors expanding in vitro. Key molecules such as executioner caspase-3 may be useful targets to reduce the amount of apoptosis.


Nosocomial infections and antimicrobial susceptibility patterns among patients admitted to intensive care unit of Imam Khomeini hospital in Ilam, Iran.
Nosocomial infections (NIs) are a major challenge worldwide. Identification of antibiotic resistance pattern extended spectrum beta-lactamases (ESBLs) and carbapenem-resistant Enterobacteriaceae (CRE) were the objectives of this study. In this cross-sectional study, the antimicrobial susceptibility pattern of bacterial isolates collected from patients with NIs in ICU was determined. Overall, 42 Escherichia coli and Klebsiella pneumoniae isolates from different infection sites were used to determine phenotypic tests of ESBLs, Metallo-β-lactamases (MBLs) and CRE. Detection of ESBLs, MBLs and CRE genes were performed by the polymerase chain reaction (PCR) method. From 71 patients with NIs, 103 different bacterial strains were isolated. The most frequently isolated bacteria were E. coli (n = 29; 28.16%), Acinetobacter baumannii (n = 15; 14.56%), and K. pneumoniae (n = 13; 12.26%). Also, the rate of multidrug-resistant (MDR) isolates was 58.25% (60/103). Based on phenotypic confirmation tests, 32 (76.19%) isolates of E. coli and K. pneumoniae produced ESBLs, and 6 (14.28%) isolates were identified as CRE producers. PCR showed the high prevalence of the blaCTX-M (n = 29; 90.62%) in ESBL genes. In addition, blaNDM was detected in 4 (66.66%), blaOXA-23 in 3 (50%), and blaOXA-48 gene in 1 (16.66%) isolates. The blaVIM, blaKPC, and blaIMP genes were not detected in any of the isolates. The Gram-negative bacteria E. coli, A. baumannii, and K. pneumoniae with high resistance levels were the most common bacteria causing NIs in the ICU. This study for the first time identified blaOXA-11, blaOXA-23, and blaNDM-1 genes in E. coli and K. pneumoniae in Ilam city of Iran.


Prognostic value of epicardial fat volume measurements by computed tomography: a systematic review of the literature.
To perform a systematic review of the growing body of literature evaluating the prognostic value of epicardial fat volume (EFV) quantified by cross-sectional imaging. Two independent reviewers performed systematic searches on both PubMed and Scopus using search terms developed with a medical librarian. Peer-reviewed articles were selected based on the inclusion of outcome data, utilization of epicardial fat volume and sufficient reporting for analysis. A total of 411 studies were evaluated with nine studies meeting the inclusion criteria. In all, the studies evaluated 10,252 patients. All nine studies were based on CT measurements. Seven studies evaluated the prognostic value of EFV unadjusted for calcium score, and six of these studies found a significant association between EFV and clinical outcomes. Seven studies evaluated the incremental value of EFV beyond calcium scoring, and six of these studies found a significant association. The majority of studies suggest that EFV quantification is significantly associated with clinical outcomes and provides incremental prognostic value over coronary artery calcium scoring. Future research should use a binary cutoff of 125 mL for evaluation of EFV to provide consistency with other research. • Epicardial fat volume (EFV) has prognostic value for adverse cardiac events • Establishment of standardized quantitative categories for EFV is needed • Quantification of EFV could improve risk assessment with calcium scoring.


Vascular cell adhesion molecule-1 (VCAM-1) and leukocyte activation in pre-eclampsia and eclampsia.
To evaluate the levels of VCAM-1 in pre-eclampsia/eclampsia as a possible marker of leukocyte activation and endothelial damage. We performed a case-control study on 25 healthy pregnant women and 35 patients diagnosed as pre-eclampsia or eclampsia which were randomly selected. Peripheral venous blood samples were obtained and serum levels of VCAM-1 were measured by enzyme-linked immunoassay (ELISA). In pre-eclampsia/eclampsia, VCAM-1 levels were higher than in normal pregnancy. Serum concentrations of VCAM-1 were significantly higher in severe pre-eclampsia and eclampsia compared to mild pre-eclampsia or healthy controls. ROC analysis detected that VCAM-1 > or = 450 ng/ml had a sensitivity of 0.79 and a specificity of 0.90 in detecting severe pre-eclampsia and eclampsia. This is the first study to correlate VCAM-1 levels with severity of disease in pre-eclampsia. Our findings indicate that increasing levels of soluble VCAM-1 are present in the circulation of patients with severe pre-eclampsia/eclampsia compared to mild pre-eclampsia or healthy pregnant women. Elevated VCAM-1 levels may represent a possible mechanism by which endothelial cells attract leukocytes and cause endothelial cell damage.


Proteasome-dependent inactivation of Akt is essential for 12-O-tetradecanoylphorbol 13-acetate-induced apoptosis in vascular smooth muscle cells.
Apoptosis of vascular smooth muscle cells (SMCs) is a prominent feature of blood vessel remodeling. Here we investigated the effect of 12-O-tetradecanoylphorbol 13-acetate (TPA) on SMC apoptosis. We found that TPA treatment induced SMC apoptosis through the rapid downregulation of Akt phosphorylation. The inhibition of Akt activation by TPA was markedly reduced by inhibitors of protein phosphatase 2A and proteasome. Moreover, TPA promoted the ubiquitination of p-Akt, whereas inhibition of TPA-induced PKC activation suppressed the downregulation and ubiquitination of p-Akt. Taken together, these results demonstrate that TPA triggers inactivation of Akt, at least in part, through PKC and Ubiquitin-proteasome degradation, thereby contributing to SMC apoptosis.


Organisational design for health integrated delivery systems: theory and practice.
Integrated delivery systems (IDS) are worldwide emerging as the dominant organizational form in the healthcare sectors. This article, drawing from international comparisons, focuses on organizational design of IDS. The analysis derives from an extensive literature review, which shows over the last years a significant lack of works on design issues, and from a number of experiences in community care settings, which provide useful insights on changes taking place in governance and delivery of health services at the local level. The frameworks discussed depict the major options of reorganization that can be observed in local integrated health systems of industrialized countries.


Techniques of radiofrequency-assisted precoagulation in laparoscopic liver resection.
Although radiofrequency-assisted (RF) precoagulation has been described for open resections, there is little data evaluating precoagulation options in laparoscopic liver resection. The purpose of this study is to provide an algorithm for the use of monopolar and bipolar RF devices in laparoscopic liver resection. Patients undergoing laparoscopic liver resection utilizing precoagulation during the period 2007-2009 were identified from a prospectively maintained, institutional review board-approved database. RF-assisted precoagulation was performed using a second-generation monopolar RF ablation catheter (Starburst XL, AngioDynamics) or bipolar RF device (Habib 4X, AngioDynamics). Precoagulation was utilized in 31cases (monopolar, n = 19, and bipolar, n = 12). Procedures performed included segmentectomy/wedge resection in 19 patients and bisegmentectomy in 12 patients. The bipolar RF device was used for left lateral sectionectomies (90%) in which there was linear transaction, whereas the monopolar RF catheter was used for nonlinear segmental and wedge resections involving the right lobe (95%). Time required for precoagulation was 22.5 ± 7.2 min for the bipolar and 33.6 ± 15.9 min for the monopolar device. No patient developed postoperative bleeding, bile duct injury, or liver abscess. At follow-up, one patient in the monopolar group developed a suspected local recurrence. We have suggested an algorithm to select a given device based on tumor location and type of resection. With approximately 30 min of time spent for precoagulation, the blood loss and rate of local recurrence were favorable. There also could be an oncologic benefit due to additional functional margin obtained with the RF effect.


Yucca leaf protein (YLP) stops the protein synthesis in HSV-infected cells and inhibits virus replication.
Yucca leaf protein (YLP), an inhibitor of tobacco mosaic virus isolated from the leaves of Yucca recurvifolia Salisb., exhibited potent activity against herpes simplex virus type 1 (HSV-1) with no cytotoxicity below 300 micrograms/ml. The inhibitory dose was varied with the time of addition; 50% effective concentrations (ED50) of YLP were 3, 19 and 95 micrograms/ml when YLP exposure was begun 3 h before virus infection, 0 h and 3 h after infection, respectively. This protein also inhibited the multiplication of herpes simplex virus type 2 and human cytomegalovirus. YLP has been shown to have a weak virucidal activity at higher concentrations. Analysis of early events following infection showed that YLP affected viral penetration in HeLa cells but did not interfere with adsorption to the cells. YLP was found to exert strong inhibition of protein synthesis in virus-infected cells but not in uninfected cells. This selective effect can be considered to attribute mainly to the antiviral activity of YLP.


Fate of a giant {Mo72Fe30}-type polyoxometalate cluster in an aqueous solution at higher temperature: understanding related Keplerate chemistry, from molecule to material.
When the giant icosahedral {Mo72Fe30} cluster containing compound [Mo72Fe30O252(CH3COO)12{Mo2O7(H2O)}2{H2Mo2O8(H2O)}(H2O)91]·150H2O (1) is refluxed in water for 36 h, it results in the formation of nanoiron molybdate, Fe2(MoO4)3, in the form of a yellow precipitate; this simple approach not only generates nanoferric molybdate at a moderate temperature but also helps to understand the stability of {Mo72Fe30} in terms of the linker-pentagon complementary relationship.


p53 protein expression in cutaneous T-cell lymphomas.
p53 is an oncosuppressor gene located on chromosome 17p. Point mutations of the p53 gene are seen frequently in human malignancies, and are closely associated with malignant transformation under in vitro conditions. Mutated p53 protein shows a slow cell turnover rate, and accumulates in cells at the nuclear and/or cytoplasmic level. As a result, mutated p53 protein can be detected more readily by immunohistology than the wild-type protein. In this study, we used a monoclonal anti-p53 antibody (clone DO7) to examine the expression of p53 protein in 25 cutaneous T-cell lymphomas (CTCL) of low- and high-grade malignancy, i.e. mycosis fungoides (n = 6), Sézary's syndrome (n = 2), and large cell lymphomas of pleomorphic (n = 14) or anaplastic (n = 3) subtype. The results showed that easily detectable p53 protein was present in many of the neoplastic cells in half of the high-grade lymphomas. In contrast, in the low-grade lymphomas no, or only very few, p53-positive neoplastic cells could be detected. These findings suggest that molecular and/or genetic alterations of p53 may be implicated in the pathogenesis of high-grade CTCL, but are unlikely to be of critical importance in low-grade CTCL.


Emergency laparoscopic sigmoid colectomy with primary anastomosis for Hinchey stages III and IV diverticulitis.
For patients with perforated diverticulitis, many reports have focused on laparoscopic surgery without primary anastomosis. We performed laparoscopic surgery with primary anastomosis in three patients (two with Hinchey stage III, one with IV), with a median age of 53 years, all female, and no prior medical history. They all were hemodynamically stable. The median operation time was 91 minutes (range: 56-227 minutes) and the median blood loss was 50 mL (range: 0-200 mL). Their post-operative course was uneventful, and patients commenced oral intake at a median of 5 post-operative days and were discharged at a median of 12 post-operative days. This procedure may be an option for Hinchey stages III and IV diverticulitis.


Estimating the minimum sample size for interventional and observational studies using the lung clearance index as an endpoint✰.
With the increasing availability of highly effective modulators for people living with cystic fibrosis (CF), there is a need to re-design research studies to reflect the changing epidemiology of the CF population. The lung clearance index (LCI), a sensitive physiological measure of lung function, may be ideally suited as an endpoint in the era of CF modulator therapies. In this study we describe study design considerations for implementing LCI into interventional and observational research. Simulations were used to estimate the required sample size to detect a range of treatment effects for interventional studies (including cross-over trials) and to track lung disease progression in observational studies. Using published treatment effects to inform the design of prospective studies can lead to inefficient study designs. Large improvements in LCI for a few individuals can skew results and can influence interpretations of treatment effects. Adjusting for baseline LCI can help to improve the efficiency of a study. Compared to the forced expiratory volume in 1 second (FEV1), analysis using LCI as an endpoint requires as little as one third of the total sample size. Planning of prospective studies that include LCI as an endpoint need to consider baseline LCI and disease severity of the study population; whereas interpretation of results needs to consider whether a few individuals skew the overall treatment effect.


Sinonasal Inverted Papilloma and Squamous Cell Carcinoma: Contemporary Management and Patient Outcomes.
Inverted papillomas (IP) are the most common sinonasal tumor with a tendency for recurrence, potential attachment to the orbit and skull base, and risk of malignant degeneration into squamous cell carcinoma (SCC). While the overall rate of recurrence has decreased with the widespread adoption of high-definition endoscopic optics and advanced surgical tools, there remain challenges in managing tumors that are multiply recurrent or involve vital neurovascular structures. Here, we review the state-of-the-art diagnostic tools for IP and IP-degenerated SCC, contemporary surgical management, and propose a surveillance protocol.


The Mott-Hubbard insulating state and orbital degeneracy in the superconducting C60(3-) fulleride family.
Electron correlation controls the properties of important materials such as superconducting and magnetoresistive transition metal oxides and heavy fermion systems. The role of correlation in driving metal-to-insulator transitions assumes further importance because many superconducting materials are located close to such transitions. The nature of the insulating ground state often reveals the dominant interactions in the superconductor, as shown by the importance of the properties of La2CuO4 in understanding the high-temperature-superconducting cuprates. The A3C60 alkali metal fullerides are superconducting systems in which the role of correlation in both the normal state and the superconducting pairing mechanism is controversial, because no magnetic insulator comparable to the superconducting materials has been identified. We describe the first example of a cubic C60(3-) system with degenerate orbitals that adopts the Mott-Hubbard insulating localized electron ground state. Electron repulsion is identified as the interaction that is suppressed on the transition to metallic and superconducting behaviour in the fullerides. This observation is combined with ab initio calculations to demonstrate that it is the orbital degeneracy that allows the superconducting cubic A3C60 fullerides to remain metallic while provoking electron localization in systems with lower symmetry.


Disinfection byproduct regulatory compliance surrogates and bromide-associated risk.
Natural and anthropogenic factors can alter bromide concentrations in drinking water sources. Increasing source water bromide concentrations increases the formation and alters the speciation of disinfection byproducts (DBPs) formed during drinking water treatment. Brominated DBPs are more toxic than their chlorinated analogs, and thus have a greater impact on human health. However, DBPs are regulated based on the mass sum of DBPs within a given class (e.g., trihalomethanes and haloacetic acids), not based on species-specific risk or extent of bromine incorporation. The regulated surrogate measures are intended to protect against not only the species they directly represent, but also against unregulated DBPs that are not routinely measured. Surrogates that do not incorporate effects of increasing bromide may not adequately capture human health risk associated with drinking water when source water bromide is elevated. The present study analyzes trihalomethanes (THMs), measured as TTHM, with varying source water bromide concentrations, and assesses its correlation with brominated THM, TTHM risk and species-specific THM concentrations and associated risk. Alternative potential surrogates are evaluated to assess their ability to capture THM risk under different source water bromide concentration conditions. The results of the present study indicate that TTHM does not adequately capture risk of the regulated species when source water bromide concentrations are elevated, and thus would also likely be an inadequate surrogate for many unregulated brominated species. Alternative surrogate measures, including THM3 and the bromodichloromethane concentration, are more robust surrogates for species-specific THM risk at varying source water bromide concentrations.


Pharmacological natures of caffeine-induced endothelium-dependent and -independent contraction in canine mesenteric artery.
The present experiments were carried out to elucidate whether pharmacological nature of caffeine (1 mM)-induced endothelium-dependent contraction (EDC) is different from that of caffeine (10 mM)-induced endothelium-independent contraction (EIC) in canine mesenteric artery. Caffeine (1 mM)-induced EDC was abolished when arterial strips were incubated in Ca(++)-free medium for 20 min, but EIC was not abolished. EGTA and EDTA (0.5 and 1 mM) attenuated the EDC, and at the concentration of 2.5 mM completely abolished the EDC. Nifedipine (10(-6) and 3 x 10(-6) M), diltiazem (10(-6) M) and verapamil (10(-6) M) did not affect the caffeine (1 mM)-induced EDC. Lemakalim (10(-8), 3 x 10(-8) and 10(-7) M) attenuated the caffeine (1 mM)-induced EDC in a concentration-dependent manner. Lemakalim (10(-7) M) nearly abolished the EDC. The inhibitory effect of lemakalim (10(-7) M) on the EDC was antagonized in the presence of glibenclamide (3 x 10(-6) M). In contrast, caffeine (10 mM)-induced EIC was resistant to lemakalim at higher concentration (3 x 10(-7) M). Forskolin (10(-7), 3 x 10(-7) and 10(-6) M) significantly attenuated both the caffeine (1 mM)-induced EDC and caffeine (10 mM)-induced EIC. The inhibitory effect of forskolin on the EDC was augmented in the presence of rolipram (10(-6) M). Nitroglycerin (10(-5) M) attenuated significantly caffeine-induced both EDC and EIC. The inhibitory effect of nitroglycerin on the EDC was augmented in the presence of zaprinast (10(-5) M). The present experiments demonstrate that caffeine-induced EDC is due to nifedipine-resistant and lemakalim-sensitive Ca++ mobilization and the EIC is due to both nifedipine- and lemakalim-resistant Ca++ mobilization in canine mesenteric artery.


Biomechanical analysis of fibular graft techniques for nontraumatic osteonecrosis of the femoral head: a finite element analysis.
Free vascularized fibula graft (FVFG) techniques have most consistently demonstrated beneficial effects in young patients diagnosed with nontraumatic osteonecrosis of the femoral head (NONFH), and the core track technique (CTT) in particular is the most commonly used technique. As an alternative to CTT, the modified light bulb technique (LBT) has been reported to have a higher success rate. However, its biomechanical outcomes are poorly understood. This study aimed to compare the biomechanical properties of modified LBT with those of CTT in treating NONFH. Two types (C1 and C2) of NONFH finite element models were established on the basis of a healthy subject and the Japanese Investigation Committee (JIC) classification system, and the CTT and LBT procedures were simulated in each type of model. The average von Mises stresses and stiffness of the proximal femur were calculated by applying a load of 250% of the body weight on the femoral head to simulate walking conditions. In addition, two patient-specific models were built and simulated under the same boundary conditions to further validate the LBT. In the healthy subject-derived models, both the LBT and CTT resulted in reduced stresses in the weight-bearing area, central femoral head, femoral neck, and trochanteric and subtrochanteric regions and increased structural stiffness after surgery. In the weight-bearing area, the CTT reduced the stress more than the LBT did (36.19% vs 31.45%) for type C1 NONFH and less than the LBT did (23.63% vs 26.76%) for type C2 NONFH. In the patient-specific models, the stiffness and stresses also increased and decreased, respectively, from before to after surgery, which is consistent with the results of healthy subject-derived models. The biomechanical effects of the LBT and CTT differ by the JIC type of NONFH. In terms of preventing the collapse of the femoral head, the LBT may be more effective for JIC type C2 NONFH and may be a suitable alternative to the CTT, while for JIC type C1 NONFH, the CTT is still a better choice. Both techniques can improve the biomechanical properties of NONFH by reducing the proximal femoral stress and increasing the structural stiffness.


Quantification of Cell Division Angles in the Arabidopsis Root.
In many plant tissues, division plane orientation within cell files is highly predictable since all cells divide almost perpendicular to the cell file axis. Many mutations can affect division plane orientation, and the quantification of the deviation from the expected transverse orientation in various genetic backgrounds is thus an important issue.While several software tools have been proposed for the quantification of cellular morphology in plant tissues, none of them allowed investigating division plane orientation. We propose here a complete method for measuring orientation of division planes in 2D, using an open-source ImageJ plugin named "Cell File Angles." The method comprises the staining of cell wall within whole mount roots with the calcofluor dye, the acquisition of 3D Z-stacks of the stained roots, and the measurement of cell wall orientation using image processing algorithms and semi-automated analysis.


New treatment strategies: ipriflavone, strontium, vitamin D metabolites and analogs.
Drugs used to treat osteoporosis can be grouped in two main categories: those that decrease bone resorption and those that increase bone formation. Antiresorptive drugs are active in preventing bone fractures in patients characterized by a negative calcium balance. However, because antiresorptive agents are often coupled to inhibition of bone formation, inhibitors of bone resorption may not be candidates as potential curative drugs in osteoporosis. Conversely, drugs that act by increasing bone formation produce an increase in bone mass above the fracture threshold; therefore, these agents are good candidates for the treatment of osteoporosis. The ideal curative drug in osteoporosis should have the ability both to decrease bone resorption and to maintain a relatively high rate of bone formation, thus inducing a favorable uncoupling of bone remodeling.


Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group.
The Early Treatment Diabetic Retinopathy Study (ETDRS) has recently shown that argon laser photocoagulation treatment is beneficial in reducing the risk of visual loss from clinically significant diabetic macular edema. The ETDRS treatment consisted of a combination of focal treatment to individual-leaking microaneurysms and grid treatment to areas of diffuse leakage and capillary nonperfusion. These techniques are described in detail, and the concepts of "clinically significant macular edema" and "treatable lesions" are defined. Guidelines for the application of ETDRS findings to clinical practice are discussed.


Nicotine self-administration acutely activates brain reward systems and induces a long-lasting increase in reward sensitivity.
Nicotine is a major component of tobacco smoke contributing to the initiation and persistence of the harmful tobacco habit in human smokers. The reinforcing effects of nicotine likely arise through its ability to stimulate brain circuitry mediating the detection and experiencing of natural rewards. Nevertheless, remarkably little is known concerning the acute or long-lasting actions of nicotine on brain reward systems in vivo. Here, we investigated the effects of intravenously self-administered nicotine (0.03 mg/kg/infusion, free base) on the sensitivity of brain reward systems, reflected in alterations of intracranial self-stimulation (ICSS) thresholds in rats. Rats self-administered nicotine during 1 or 12 h daily sessions, with reward thresholds assessed 1 h before and 15 min after each self-administration session. Control rats remained nicotine naïve throughout. Nicotine self-administration increased the sensitivity of brain reward systems, detected by post-nicotine lowering of reward thresholds in 1 and 12 h rats. This nicotine-enhanced sensitivity of reward systems was reversed by the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg). Surprisingly, nicotine-induced excitation of reward systems persisted for at least 36 days after nicotine self-administration had ceased. Overall, these data demonstrate that rats can voluntarily consume quantities of nicotine sufficient to increase the sensitivity of brain reward systems, an action likely crucial in establishing and maintaining the nicotine habit. Moreover, self-administered nicotine resets the sensitivity of reward systems to a new increased level, thereby imprinting an indelible 'memory' of its effects in reward systems, an action that so far appears unique to nicotine among drugs of abuse.


Prepyloric antral diaphragm: delays in treatment.
Six cases of prepyloric antral diaphragm were encountered at Children's Hospital Medical Center of Akron between 1965 and 1985, with approximately 150 cases reported in the literature during this time. In our series, a delay from onset of symptoms to treatment existed for a period of 4 months to 6 years. We suggest that prompt endoscopic confirmation and surgical therapy for this lesion, when suspected by clinical and radiologic abnormalities, would decrease the physical and psychologic morbidity of unexplained recurrent vomiting in these children.


Dose-dependent protective effect of connexin43 mimetic peptide against neurodegeneration in an ex vivo model of epileptiform lesion.
Epileptic seizures typically result in delayed neuronal loss secondary to the initial damage and an up-regulation in connexin43 (Cx43). This study investigated the role of Cx43 gap junctions in lesion spread and cell loss following epileptiform activity. Epileptiform injury in hippocampal slice cultures was induced by 48 h exposure to 100 μM bicuculline methochloride (BMC). During the 24h recovery period following BMC treatment, lesion spread was observed in the CA1. A Cx43 mimetic peptide, applied during either the BMC treatment or recovery periods, produced concentration- and exposure time-dependent neuroprotection, as measured by propidium iodide uptake at the end of the recovery period. During the BMC period, peptide concentrations between 5 and 50 μM (sufficient to block hemichannels) had a protective effect while a substantial gap junction blockade with 500 μM peptide exacerbated the lesion. By contrast, all doses applied during the recovery period protected the CA1 region from further damage. The results indicate that while the slices are undergoing excessive neuronal firing and epileptic stress, gap junction communication appears to be essential for tissue survival but hemichannel opening may be damaging. Following epileptiform insult, however, gap junction communication plays a crucial role in the spread of neuronal damage. The findings from this study identify gap junction communication as a potential therapeutic target for epilepsy.


Neuromorphic Model of Reflex for Realtime Human-Like Compliant Control of Prosthetic Hand.
Current control of prosthetic hands is ineffective when grasping deformable, irregular, or heavy objects. In humans, grasping is achieved under spinal reflexive control of the musculotendon skeletal structure, which produces a hand stiffness commensurate with the task. We hypothesize that mimicking reflex on a prosthetic hand may improve grasping performance and safety when interacting with human. Here, we present a design of compliant controller for prosthetic hand with a neuromorphic model of human reflex. The model includes 6 motoneuron pools containing 768 spiking neurons, 1 muscle spindle with 128 spiking afferents, and 1 modified Hill-type muscle. Models are implemented using neuromorphic hardware with 1 kHz real-time computing. Experimental tests showed that the prosthetic hand could sustain a 40 N load compared to 95 N for an adult. Stiffness range was adjustable from 60 to 640 N/m, about 46.6% of that of human hand. The grasping velocity could be ramped up to 14.4 cm/s, or 24% of the human peak velocity. The complaint control could switch between free movement and contact force when pressing a deformable beam. The amputee can achieve a 47% information throughput of healthy humans. Overall, the reflex-enabled prosthetic hand demonstrated the attributes of human compliant grasping with the neuromorphic model of spinal neuromuscular reflex.


Solid phase extraction as a cleanup step before microextraction of diclofenac and mefenamic acid using nanostructured solvent.
A new pretreatment method, solid-phase extraction combined with supramolecular solvents, was proposed for the first time for extraction of diclofenac (DIC) and mefenamic acid (MEF) from urine and water samples. Supramolecular solvent (SUPRAS) is a nano-structured liquid, generated from the amphiphiles through a sequential self-assembly process occurring on two scales, molecular and nano. SUPRAS tested were generated from solutions of reverse micelles of decanoic acid (DeA) in tetrahydrofuran (THF) by addition of water, which acted as the coacervating agent. In the present study, due to matrix effect, drugs were first extracted from the samples by SPE. The extracted analytes were then eluted from the sorbent with THF, and the eluate was subjected to SUPRAS formation (SUPRASF) process. Finally, the analytes in the SUPRAS were separated and determined by HPLC-UV. Several parameters affecting the SPE-SUPRASF process were investigated and optimized. The new method provides enrichment factors in the range of 431-489 for MEF and DIC, respectively. Calibration plots are linear in the range of 2-200 μg L(-1) for MEF and 1-200 μg L(-1) for DIC, with correlation of determination (r(2)) ranging from 0.996 to 0.999. The method was successfully applied for extraction and determination of analytes in urine and water samples and relative recoveries of the studied compounds were obtained in the range of 90.4-103.8%.


Prediction of the attenuation of the ascending aorta using bolus-tracking parameters and heart rate in coronary computed tomography angiography.
The purpose of this study was to evaluate the correlation between bolus-tracking parameters and heart rate (HR) with attenuation of the ascending aorta and create a linear regression model for predicting coronary attenuation in coronary computed tomography angiography (CCTA). A total of 50 patients (31 men, 19 women; mean age, 67.2±10.8 y) underwent CCTA using a 320-detector CT scanner. A bolus-tracking scan was performed to optimize the scan timing. The average HR under normal breathing for 10s was recorded just before the bolus-tracking scan started. Attenuation values of the pulmonary artery at 7s (PA7) and 10s (PA10) after the beginning of the injection were recorded during the bolus-tracking scan and the ascending aortic attenuation (CEAAo) was measured during the diagnostic scan. A positive correlation was observed between PA7 and CEAAo (r=0.41, P=0.003) and PA10 and CEAAo (r=0.66, P<0.0001), and weak negative correlation was observed between HR and CEAAo (r=-0.46, P=0.15). A multivariable linear regression model for predicting CEAAo was evaluated, and the residual error between the predicted and the measured CEAAo was within approximately ±100 HU. Coronary attenuation could be predicted using HR and pulmonary artery attenuation during the bolus-tracking method.


Flow-controlled ventilation and hi-flow nasal oxygen in laser surgery for a grade III subglottic stenosis patient.
A 49-year old patient (BMI 29.4kg/m2 and ASA III) with grade III subglottic stenosis (> ventilator in flow controlled ventilation mode, which allowed us to regulate both inspiratory and expiratory flow without compromising gas exchange despite maintaining peak FIO2 at 0.3 due to the risk of ignition. Before proceeding with endoscopic dilation, the 4.5mm laser endotracheal tube was withdrawn and high flow nasal cannula oxygenation was started in order to prolong apnoeic oxygenation. Total apnoea time was 11min, maintaining SpO2>70%) underwent laser resection followed by dilation. During resection he was ventilated by the Evone>ventilator; high flow nasal cannula therapy; apnoeic oxygenation-98% and peak EtCO2 60mmHg throughout the procedure.


Hybrid methods of chemical-shift imaging.
We propose a family of hybrid chemical-shift sequences which combines two physical principles for water/lipid separation to minimize artifacts introduced by B0 and B1 inhomogeneities. Hybrid sequences provide improved species discrimination over earlier methods without resorting to postprocessing while maintaining a multislice/multiecho capability.


Changes in the cognitive function of Chinese college students with a clinical high risk of psychosis.
The purpose of our study was to explore the value of measuring cognitive functions for predicting the conversion to psychosis in Chinese college students with a clinical high risk (CHR). A total of 115 CHR students and 99 healthy controls were enrolled. All included participants were recruited from colleges in Wuhan, China. The MATRICS Consensus Cognitive Battery was used to evaluate cognitive function. CHR individuals were followed for 2 years, and the cognitive function of CHR individuals who later converted to psychosis (CHR-C) was compared to CHR individuals who did not convert (CHR-NC). Of the 107 CHR individuals that completed the 2- year follow-up, 29 (27.1%) developed a psychotic disorder. CHR individuals demonstrated poorer performance on all cognitive function tests compared to controls. CHR-C participants exhibited poorer performance on all cognitive tests except the Trail Making Test A and Continuous Performance Test-Identical Pairs compared to CHR-NC participants. The most significant differences displayed between CHR-C and CHR-NC groups were in visual learning, working memory, and reasoning and problem solving. The degree of cognitive impairment in visual learning and working memory may be a predictive marker for individuals who are at risk of developing psychosis.


In-cell structural dynamics of an EGF receptor during ligand-induced dimer-oligomer transition.
The epidermal growth factor receptor (EGFR) is a membrane protein that regulates cell proliferation, differentiation and survival, and is a drug target for cancer therapy. Ligand-induced activation of the EGFR kinase is generally regarded to require ligand-bound-dimers, while phosphorylation and down-stream signalling is modulated by oligomers. Recent work has unveiled changes in EGFR dynamics from ligand-induced dimerization in membranes extracted from cells, however, less is known about the changes in EGFR dynamics that accompany the ligand-induced oligomerization in a live cell environment. Here, we determine the dynamics of a c-terminal GFP tag attached to EGFR in the unliganded dimer and in the liganded oligomers. By means of the single-frequency polarized phasor ellipse approach we extracted two correlation times on the sub-nanosecond and super-nanosecond timescales, respectively. EGF binding to the EGFR-GFP dimer lengthened the sub-nanosecond correlation time (from 0.1 to 1.3 ns) and shortened the super-nanosecond correlation time (from 210 to 56 ns) of the c-terminal GFP probe. The sub-nanosecond depolarization processes were assigned to electronic energy migration between proximal GFPs in the EGFR dimer or oligomer, while the super-nanosecond correlation times were assigned to nanosecond fluctuations of the GFP probe in the EGFR complex. Accordingly, these results show that ligand binding increased the average separation between the c-terminal tags and increased their rotational mobility. We propose that the dynamics are linked to an inhibitory function of the c-terminal tail in the un-liganded dimer and to the requirement of facile stochastic switching between kinase activation and cytoplasmic adaptor/effector binding in the active oligomers.


Comparison of Ancylostoma caninum worm counts acquired by endoscopy and necropsy.
Many regulatory agencies require that the efficacy of veterinary anthelmintic medications be evaluated by enumerating parasites in treated and untreated animals after necropsy. Current ethical considerations, i.e., the 3 Rs of research, call for the replacement of this method with less invasive techniques that would not require animal sacrifice. This study tested standard gastrointestinal endoscopy as an in vivo method of quantifying the intestinal hookworm, Ancylostoma caninum. Worm counts were compared with those from gold standard necropsy. Thirteen dogs inoculated with third-stage A. caninum larvae underwent endoscopy 4-6 weeks post-infection, just prior to necropsy. Two-thirds of the adult hookworms were located in the middle section of the small intestine that could not be reached for endoscopic examination. Not surprisingly, the total worm counts obtained by endoscopy did not correlate with those from necropsy (R(2)=0.05, p=0.464). One method to increase small intestinal access would be to use specialized balloon or spiral endoscopes developed for this purpose in human gastroenterology. Based on the results of this study, standard endoscopy alone is unsuitable for quantification of A. caninum in the small intestine. Parasites in more accessible sites, such as whipworms in the cecum and colon, might be more appropriate targets for endoscopic counting.


Trends and Characteristics of Global Initiative for Chronic Obstructive Lung Disease Guidelines-Discordant Prescribing of Triple Therapy Among Patients with COPD.
Triple therapy (long-acting muscarinic antagonist [LAMA] plus long-acting beta2-agonist [LABA] plus inhaled corticosteroid [ICS]) is recommended by the Global initiative for chronic Obstructive Lung Disease (GOLD) for moderate-to-severe chronic obstructive pulmonary disease (COPD) with a history of frequent and/or severe exacerbation(s) and dyspnea while using dual bronchodilators. However, many patients receive triple therapy contrary to these recommendations. This study describes factors associated with GOLD-discordant triple therapy initiation. This retrospective analysis included patients aged 40 and above, with ≥1 COPD diagnosis, who initiated triple therapy (initiation=index date) during the period January 1, 2014 to December 31, 2018 and had ≥12 months pre-index continuous enrollment (baseline). Triple therapy comprised ≥30 days of overlapping LAMA, LABA, and ICS treatments (open triple therapy), or single-inhaler fluticasone furoate/umeclidinium/vilanterol (closed triple therapy). Cohorts were defined based on the absence of baseline maintenance medication use ("maintenance-naïve"), and/or exacerbations ("exacerbation-discordant"), or "dual-discordant" (discordant on both measures). All triple therapy initiators, overall and for each cohort, were described, and predictors of GOLD-discordant triple therapy initiation were identified. Among 21,711 triple therapy initiators, 34.4% were maintenance-naïve, 61.9% exacerbation-discordant, and 22.2% dual-discordant. Triple therapy initiation appeared to increase during the period 2016 to 2018. In 2018 alone, 31.9% and 58.3% of open triple therapy patients were maintenance-naïve and exacerbation-discordant, respectively, versus 37.6% and 64.4% of closed triple therapy patients. Closed triple therapy initiators had 1.65 times greater risk of dual discordance than open triple therapy initiators. Exacerbation-discordant patients initiating closed triple therapy were 1.61 times more likely to be maintenance-naïve than those initiating open triple therapy. A substantial proportion of COPD patients initiating triple therapy do not meet GOLD recommendations regarding exacerbation history and/or prior maintenance therapy. Compared with open triple therapy, closed triple therapy initiators were more likely to be dual discordant.


Characterization of extracellular polymeric substances of Bacillus amyloliquefaciens SQR9 induced by root exudates of cucumber.
Bacillus amyloliquefaciens SQR9 is a plant growth-promoting rhizobacterium (PGPRs) that forms biofilm on the roots of plants and protects them from a variety of pathogens. In this study, we reported the effect of root exudates produced by cucumber (Cucumis sativus L.) at different developmental stages on the biochemical composition of the biofilm matrix of SQR9. The results showed that the amino acids present in the root exudates of cucumber were responsible for triggering biofilm formation of SQR9. In addition, when root exudates harvested at different growth phases of cucumber were used as carbon sources for biofilm formation, the resulting biofilm matrixes differed both quantitatively and qualitatively. The biofilm matrix was mostly composed of amino groups observed by confocal laser scanning microscope (CLSM) hence the proteins formed the major component of the resulting extracellular polymeric substances (EPS). The potential use of amino acid-based dietary supplements to control biofilm formation in the plants may be a viable option to improve agricultural productivity by recruiting beneficial association with PGPRs in the manufacture of bio fertilizers or bio controls.


Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade.
The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of "molecular response" using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease. SIGNIFICANCE: In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A "molecular response" metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.This article is highlighted in the In This Issue feature, p. 1775.


Nicotine dependence among clients receiving publicly funded substance abuse treatment.
Smoking and nicotine dependence (ND) are prevalent among substance abusers but little is known about characteristics of ND in this population. This information would help identify those most in need of smoking cessation programs. This study evaluated the associations of socio-demographic, tobacco- and substance use-related, and health/mental health factors to ND in adults receiving publicly funded substance abuse treatment in Tennessee. All Tennessee residents who received federal block grant-funded substance abuse treatment during July-December, 2004 were invited to participate in a 6 month post-intake telephone follow-up interview. Socio-demographic characteristics, perceived health and mental health, tobacco use history and patterns, and ND, assessed by the Fagerstrom Test of Nicotine Dependence (FTND), were obtained at follow-up. Alcohol and illicit drug use and smoking status prior to treatment were assessed at intake. This paper analyzes data for 855 clients who were current cigarette smokers at both intake and follow-up. Sixty three percent of smokers were ND (FTND score ≥ 4). Correlates of ND included older age, poorer self-rated overall health, earlier age of onset of cigarette smoking and substance abuse, fewer smoking quit attempts in past year, single substance use (alcohol or illicit drug, vs. multiple substances) at intake, use of opiates/narcotics and sedatives, and past month self-reported depression. ND was highly prevalent and correlated with specific types and patterns of substance abuse and depression. These results suggest that intensive smoking cessation interventions, involving behavioral support, pharmacotherapy, and mood management, are needed to effectively assist this population.


Saturated long-chain fatty acids activate inflammatory signaling in astrocytes.
This study describes the effects of long-chain fatty acids on inflammatory signaling in cultured astrocytes. Data show that the saturated fatty acid palmitic acid, as well as lauric acid and stearic acid, trigger the release of TNFα and IL-6 from astrocytes. Unsaturated fatty acids were unable to induce cytokine release from cultured astrocytes. Furthermore, the effects of palmitic acid on cytokine release require Toll-like receptor 4 rather than CD36 or Toll-like receptor 2, and do not depend on palmitic acid metabolism to palmitoyl-CoA. Inhibitor studies revealed that pharmacologic inhibition of p38 or p42/44 MAPK pathways prevents the pro-inflammatory effects of palmitic acid, whereas JNK and PI3K inhibition does not affect cytokine release. Depletion of microglia from primary astrocyte cultures using the lysosomotropic agent l-leucine methyl ester revealed that the ability of palmitic acid to trigger cytokine release is not dependent on the presence of microglia. Finally, data show that the essential ω-3 fatty acid docosahexaenoic acid acts in a dose-dependent manner to prevent the actions of palmitic acid on inflammatory signaling in astrocytes. Collectively, these data demonstrate the ability of saturated fatty acids to induce astrocyte inflammation in vitro. These data thus raise the possibility that high levels of circulating saturated fatty acids could cause reactive gliosis and brain inflammation in vivo, and could potentially participate in the reported adverse neurologic consequences of obesity and metabolic syndrome.


[The role of tracking in the perception of objects, moving toward each other in a narrow vertical slit line].
It has been shown by means of calculation and device modeling that the observed subjective pressure of two objects moving toward one another behind a narrow vertical slit corresponds to the pressure of objects retinal projections, induced in its turn by a slowed down tracing. 180e turn of one of the moving objects is also explained by tracing.


An ELISA for the measurement of VP16 (etoposide) in unextracted plasma.
An ELISA for the anti-cancer drug VP16 in unextracted plasma has been developed using VP16-thyroglobulin-coated microtitre plates, a sheep anti-VP16 serum, and a donkey anti-sheep HRPO-labelled second antibody. The sensitivity of the assay was 0.5 ng/ml, providing a detection limit of 0.1 microgram VP16/ml plasma. Plasma interference effects were negligible and therefore the standard curve could be set up in assay buffer. A good correlation was obtained between the ELISA and established HPLC and RIA methods. No evidence was found of significant levels of cross-reacting metabolites in plasma samples obtained from patients receiving VP16 therapy. The antiserum did not cross-react with the epiaglycone of VP16.


Isolation of Newcastle disease virus from a non-avian host (sheep) and its implications.
Newcastle disease virus (NDV) is an avian virus that has not been isolated from naturally infected non-avian and non-human hosts except for one report in which it was isolated from cattle in 1952. We report here for the first time the isolation and identification of NDV from sheep and suggest that this virus be included in the screening of viruses from non-avian hosts.


Do patients with hypospadias and cryptorchidism share a common phenotype? Case-control study of an Italian paediatric population.
A large number of children affected by hypospadias and undescended testis (UDT) are characterized facially by a large forehead with frontal bossing, telecanthus and broad flat nasal bridge. These traits are classically part of the clinical spectrum of the Opitz-GBBB and other syndromes. The aim of this study was to test the hypothesis that the presence of these features in isolated hypospadias and UDT is not correlated with chromosomal anomalies and/or syndromes, but defines a distinct morphology. Two hundred patients affected by isolated hypospadias and 100 presenting with a UDT were evaluated for facial biometric indices. An age-matched group of patients was used as control. The parameters inter-pupillary/inner canthal ratio and glabella-nose tip/nasion distance were then calculated. The glabella-nose tip/nasion distance was significantly different between hypospadias and control groups, but was not different between UDT and control groups. There was no difference in inter-pupillary/inner canthal ratio. Children affected by hypospadias and/or UDT frequently present peculiar phenotypic features making it possible to recognize them 'at first glance'. This association needs to be explained in future studies.


[The influence of exogen and endogen factors on the moulting of Pygnogonum litorale (Ström)].
Pycnogonum litorale has a terminal anecdysis. After attaining maturity it does not moult again. Maturity can be attained at different body size, the female usually being larger than the male.The pre-adult instar can also be entered at various body sizes. The duration of the pre-adult instar depends upon body size: At 19°C its mean duration was 86 days, that of the preceding instar 71 days.The freshly moulted animal is transparent. It feeds soon after each moult, which is essential for hardening the integument. Hardening and stretching of the integument continue for about three weeks.Photoperiods differing from those at which the animal was collected, delay moulting. Long day favours adult development.Temperatures of 2-3° C block the moults.The adult moult is not so easily influenced by these factors as the juvenile moults. Possibly a critical phase aster which moulting can no longer be prevented occurs sooner during the pre-adult instar than in earlier instars.After loss of leg parts the rest of the leg is not automomized. The limbs of juvenile animals regenerate at the following moult. Moulting is not accelerated but rather delayed.With Ecdyson and Ecdysterone moults have not yet been evoked.


Harnessing solar power: photoautotrophy supplements the diet of a low-light dwelling sponge.
The ability of organisms to combine autotrophy and heterotrophy gives rise to one of the most successful nutritional strategies on Earth: mixotrophy. Sponges are integral members of shallow-water ecosystems and many host photosynthetic symbionts, but studies on mixotrophic sponges have focused primarily on species residing in high-light environments. Here, we quantify the contribution of photoautotrophy to the respiratory demand and total carbon diet of the sponge Chondrilla caribensis, which hosts symbiotic cyanobacteria and lives in low-light environments. Although the sponge is net heterotrophic at 20 m water depth, photosynthetically fixed carbon potentially provides up to 52% of the holobiont's respiratory demand. When considering the total mixotrophic diet, photoautotrophy contributed an estimated 7% to total daily carbon uptake. Visualization of inorganic 13C- and 15N-incorporation using nanoscale secondary ion mass spectrometry (NanoSIMS) at the single-cell level confirmed that a portion of nutrients assimilated by the prokaryotic community was translocated to host cells. Photoautotrophy can thus provide an important supplemental source of carbon for sponges, even in low-light habitats. This trophic plasticity may represent a widespread strategy for net heterotrophic sponges hosting photosymbionts, enabling the host to buffer against periods of nutritional stress.


Refractive lens exchange in modern practice: when and when not to do it?
Cataract surgery due to advances in small incision surgery evolved from a procedure concerned with the primary focus on the safe removal of cataractous lens to a procedure focused on the best possible postoperative refractive result. As the outcomes of cataract surgery became better, the use of lens surgery as a refractive modality in patients without cataracts has increased in interest and in popularity. Removal of the crystalline lens for refractive purposes or refractive lens exchange (RLE) presents several advantages over corneal refractive surgery. Patients with high degrees of myopia, hyperopia and astigmatism are still not good candidates for laser surgery. Moreover, presbyopia can currently only be corrected with monovision or reading spectacles. RLE supplemented with multifocal or accommodating intraocular lenses (IOLs) in combination with corneal astigmatic procedures might address all refractive errors including presbyopia, and eliminate the future need for cataract surgery.


Polyamine metabolism in carcinoma of the oral cavity compared with adjacent and normal oral mucosa.
In this study, polyamine biosynthesis required for cellular proliferation showed elevated levels in neoplastic cells. Putrescine, spermidine, and spermine, as well as the rate-limiting enzyme ornithine decarboxylase, were measured to evaluate differences in tissue concentration in squamous cell carcinoma of the oral cavity, and in the normal adjacent, buccal, and retromolar trigone tissues. Mean polyamine levels (nanomoles per gram of tissue +/- standard error of the mean) were significantly elevated in tumor tissue at 136 +/- 42 nmol/g for putrescine compared with 41 +/- 9 nmol/g in adjacent, 25 +/- 5 nmol/g in buccal, and 41 +/- 14 nmol/g in retromolar trigone tissues. Tumor spermidine was 415 +/- 41 nmol/g compared with 192 +/- 34 nmol/g in adjacent, 184 +/- 34 nmol/g in buccal, and 214 +/- 63 nmol/g in retromolar trigone tissues. Tumor spermine was 461 +/- 41 nmol/g compared with 236 +/- 30 nmol/g in adjacent, 233 +/- 35 nmol/g in buccal, and 269 +/- 59 nmol/g in retromolar trigone samples. Ornithine decarboxylase activity was highly variable in tumor tissues. High levels of polyamines appear to be specific for this malignancy, whereas ornithine decarboxylase activity is not. Measurement of polyamine content may be useful in evaluating epithelial changes in the oral cavity.


Shedding of Endogenous Interleukin-6 Receptor (IL-6R) Is Governed by A Disintegrin and Metalloproteinase (ADAM) Proteases while a Full-length IL-6R Isoform Localizes to Circulating Microvesicles.
Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation.


Role of hypobromous acid in the transformation of polycyclic aromatic hydrocarbons during chlorination.
Hypobromous acid (HOBr), a highly reactive active species, can be formed and impact reaction processes with organic pollutants in source water during chlorination disinfection of the water containing bromide (Br-). In this study, we investigated the transformation kinetics of 10 parent polycyclic aromatic hydrocarbons (PAHs) and formation mechanisms of transformation products in the presence of Br- during chlorination. The results indicated that HOBr can accelerate the processes of electrophilic substitution (ES) and single electron transfer (ET) reactions in PAHs, and the second-order rate constants of HOBr are 102-103 times higher than those of hypochlorous acid (HOCl) with PAHs. HOBr was more conductive to induce ES reactions than HOCl. In water containing Br-, HOBr and HOCl dominate the reaction processes with PAHs, although other active bromine species may still affect reaction processes. In terms of transformation products, higher reactivity of HOBr results from faster formation of oxygenated PAHs (OPAHs) and halogenated PAHs (HPAHs) than HOCl. As an example of 3 model PAHs, anthracene transforms faster to its oxygenated products at a higher concentration, while pyrene and fluorene transform faster to halogenated products. These fundamental results were essential to understanding the transformation kinetics of PAHs and the formation of toxic disinfection by-products in the presence of Br-.


Treatment of Susac's Syndrome.
Susac's syndrome (SS) consists of the triad of encephalopathy, branch retinal artery occlusions (BRAO), and hearing loss. It usually affects women aged 20 to 40, but men are also affected, and the age range extends from 9 to 72 years. It tends to be unrecognized, even in major academic centers. The complete triad may not be present at the onset, which makes diagnosis more difficult. However, since this disorder is treatable, early diagnosis is important. The encephalopathy is usually associated with headaches, multifocal neurologic manifestations, and psychiatric features (particularly paranoia). MRI shows a white matter disturbance that is frequently confused with multiple sclerosis and acute disseminated encephalomyelitis. During the encephalopathy, the corpus callosum is always affected and shows central involvement--small to large "snowballs" and linear defects, "spokes." As the acute changes (microinfarcts) resolve, central callosal "holes" develop, a pathognomonic finding. The deep gray matter (70%) and leptomeninges (33%) also may be involved. Dilated fundus examination will reveal branch retinal artery occlusions. Fluorescein angiography may disclose pathognomonic staining of the arterioles proximal to the occlusions and of nonoccluded arterioles. The cochlear hearing loss, sometimes associated with vertigo, is usually bilateral, and deafness becomes a major disabling problem. Brain biopsies, anatomic observations, and responses to immunosuppressive therapy suggest that SS represents an autoimmune endotheliopathy in the microvasculature of the brain, retina, and cochlea. Treatment requires immunosuppression. High-dose corticosteroid therapy is the mainstay, but additional therapies such as intravenous immunoglobulin, mycophenolate mofetil, and cyclophosphamide are often necessary. Rituximab is the newest therapy to consider. Treatment should be prompt, aggressive, and sustained to avoid the dreaded residuals of dementia, deafness, and blindness.


A microfluidic approach to studying the injection flow of concentrated albumin solutions.
Subcutaneous injection by means of prefilled syringes allows patients to self-administrate high-concentration (100 g/L or more) protein-based drugs. Although the shear flow of concentrated globulins or monoclonal antibodies has been intensively studied and related to the injection force proper of SC processes, very small attention has been paid to the extensional behavior of this category of complex fluids. This work focuses on the flow of concentrated bovine serum albumin (BSA) solutions through a microfluidic "syringe-on-chip" contraction device which shares some similarities with the geometry of syringes used in SC self-injection. By comparing the velocity and pressure measurements in complex flow with rheometric shear measurements obtained by means of the "Rheo-chip" device, it is shown that the extensional viscosity plays an important role in the injection process of protinaceous drugs. A microfluidic "syringe on chip" device mimicking the injection flow of protinaceous drugs has been developed.The velocity field of concentrated BSA solutions through the "syringe on chip" is Newtonian-like.The extensional viscosity of concentrated protein solutions should also be considered when computing injection forces through needles.