A consequence of immature breathing induces persistent changes in hippocampal synaptic plasticity and behavior: a role of prooxidant state and NMDA receptor imbalance.
Underdeveloped breathing results from premature birth and causes intermittent hypoxia during the early neonatal period. Neonatal intermittent hypoxia (nIH) is a condition linked to the increased risk of neurocognitive deficit later in life. However, the mechanistic basis of nIH-induced changes to neurophysiology remains poorly resolved. We investigated the impact of nIH on hippocampal synaptic plasticity and NMDA receptor (NMDAr) expression in neonatal mice. Our findings indicate that nIH induces a prooxidant state that leads to an imbalance in NMDAr subunit composition favoring GluN2B over GluN2A expression and impairs synaptic plasticity. These consequences persist in adulthood and coincide with deficits in spatial memory. Treatment with an antioxidant, manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin (MnTMPyP), during nIH effectively mitigated both immediate and long-term effects of nIH. However, MnTMPyP treatment post-nIH did not prevent long-lasting changes in either synaptic plasticity or behavior. In addition to demonstrating that the prooxidant state has a central role in nIH-mediated neurophysiological and behavioral deficits, our results also indicate that targeting the prooxidant state during a discrete therapeutic window may provide a potential avenue for mitigating long-term neurophysiological and behavioral outcomes that result from unstable breathing during early postnatal life.


Tracking the evolution of crossmodal plasticity and visual functions before and after sight restoration.
Visual deprivation leads to massive reorganization in both the structure and function of the occipital cortex, raising crucial challenges for sight restoration. We tracked the behavioral, structural, and neurofunctional changes occurring in an early and severely visually impaired patient before and 1.5 and 7 mo after sight restoration with magnetic resonance imaging. Robust presurgical auditory responses were found in occipital cortex despite residual preoperative vision. In primary visual cortex, crossmodal auditory responses overlapped with visual responses and remained elevated even 7 mo after surgery. However, these crossmodal responses decreased in extrastriate occipital regions after surgery, together with improved behavioral vision and with increases in both gray matter density and neural activation in low-level visual regions. Selective responses in high-level visual regions involved in motion and face processing were observable even before surgery and did not evolve after surgery. Taken together, these findings demonstrate that structural and functional reorganization of occipital regions are present in an individual with a long-standing history of severe visual impairment and that such reorganizations can be partially reversed by visual restoration in adulthood.


Effects of orthodontic force on enamel formation in normal and hypocalcemic rats.
Maxillary incisors of young rats fed a diet deficient in calcium and vitamin D for 4 weeks developed hypoplastic enamel surfaces. In the enamel of maxillary incisors of deficiently fed rats as well as in normal rats, an orthodontic force (50 gm) acting on their incisors for 3-7 days induced foldings in the enamel, globular projections from the surface and marked hypoplastic defects. However, the orthodontic force produced clusters of free-lying enamel matrix only in the nutritionally deficient rats. In view of these observations, it might be concluded that disturbances in enamel formation which cause hypoplasias can be caused both by mechanical trauma and hypocalcemia. Furthermore, it seems that hypocalcemia increases the susceptibility to mechanical trauma of ameloblasts in their secretory stage. Whether the changes in enamel formation noted in the hypocalcemic rats is a direct effect of lowered serum calcium or due to the increase in parathyroid hormone is not known at present.


A Review of Biologically Active Natural Products from a Desert Plant Cistanche tubulosa.
An Orobanchaceae plant Cistanche tubulosa (SCHENK) WIGHT (Kanka-nikujuyou in Japanese), which is one of the authorized plant resources as Cistanches Herba in both Japanese and Chinese Pharmacopoeias, is a perennial parasitic plant growing on roots of sand-fixing plants. The stems of C. tubulosa have traditionally been used for treatment of impotence, sterility, lumbago, and body weakness as well as a promoting agent of blood circulation. In recent years, Cistanches Herba has also been widely used as a health food supplement in Japan, China, and Southeast Asian countries. Here we review our recent studies on chemical constituents from the stems of C. tubulosa as well as their bioactivities such as vasorelaxtant, hepatoprotective, and glucose tolerance improving effects.


A multicenter study of radiologically isolated syndrome in children and adolescents: Can we predict the course?
To evaluate clinical characteristics, imaging features and etiological profile of Radiologically Isolated Syndrome (RIS) along with clinical and radiological follow-up. Demographic, clinical and radiological data of patients younger than 18 years fulfilling the criteria for RIS were retrospectively analyzed. RIS was defined by the detection of lesions meeting the revised 2010 McDonald Criteria for dissemination in space on magnetic resonance imaging (MRI) in the absence of any symptoms of demyelinating disease or an alternative cause for the MRI findings. There were total 69 patients (38 girls, 31 boys). The median age at index MRI was 15.7 years, and median follow-up time was 28 months. The most common reason for neuroimaging was headache (60.9%). A first clinical event occurred with median 11 months in 14/69 (20%) of cases. Those with oligoclonal bands (OCB) in cerebrospinal fluid (CSF) and follow-up longer than 3 years were more likely to experience a clinical event (p<0.05): 25% of those with OCB manifested clinical symptoms within the first year and 33.3% within the first two years compared to 6.3% and 9.4%, respectively in those without OCB. Radiological evolution was not associated with any variables: age, sex, reason for neuroimaging, serum 25-hydroxyvitamin D level, elevated IgG index, OCB positivity, total number and localization of lesions, presence of gadolinium enhancement, achievement of 2005 criteria for DIS and duration of follow-up. Children and adolescents with RIS and CSF OCB should be followed-up for at least 3 years in order to detect any clinical symptoms suggestive of a demyelinating event. Because disease-modifying treatments are not approved in RIS and no consensus report justifies their use especially in pediatric RIS, close follow-up of OCB-positive patients is needed for early recognition of any clinical event and timely initiation of specific treatment.


The usefulness of a biosensor controlled perfusion cell culture for the investigation of new drugs demonstrated with the marine fungus Kirschsteiniothelia maritima.
The investigation of new biological active substances from limited sources for example from marine organisms needs sensitive and evident test systems. Such a system is the glucose biosensor controlled perfusion cell culture. The glucose consumption of cells is a very sensitive parameter which allows the continuous measurement of external effects of test substances on the cells under in vivo-like conditions. Cytotoxic concentrations of active substances as well as a virus infection lowers the glucose consumption of continuously perfused cells. This effect can be monitored using a glucose biosensor. The influence of drugs and the virus infection can be observed simultaneously in the same system continuously over several days. With two substances isolated from the marine fungus Kirschsteiniothelia maritima investigations for cytotoxic and for antiviral effects are demonstrated.


Self-catalyzed VLS grown InAs nanowires with twinning superlattices.
We report on the self-catalyzed growth of InAs nanowires by molecular beam epitaxy on GaAs substrates covered by a thin silicon oxide layer. Clear evidence is presented to demonstrate that, under our experimental conditions, the growth takes place by the vapor-liquid-solid (VLS) mechanism via an In droplet. The nanowire growth rate is controlled by the arsenic pressure while the diameter depends mainly on the In rate. The contact angle of the In droplet is smaller than that of the Ga droplet involved in the growth of GaAs nanowires, resulting in much lower growth rates. The crystal structure of the VLS grown InAs nanowires is zinc blende with regularly spaced rotational twins forming a twinning superlattice.


Genetic analysis of drinking behavior in World War II veteran twins.
The objective of the present study was to investigate longitudinal changes in drinking behaviors of adult male twins and model these changes as a function of genetic and environmental influences. Alcohol data available for World War II veteran twins, first surveyed in 1967-69 and followed up during 1983-85, were used to examine components of variability in measures of alcohol consumption. Multivariate biometric analysis of these data indicated 1) longitudinal stability of drinking behaviors in this cohort, 2) a significant contribution of genetic factors to the observed stability that accounted for more than 80% of the stable variation in frequency and in quantity of alcohol consumed per drinking occasion, and 3) evidence for a significant contribution of shared environmental influences to drinking of specific beverages (e.g., wine). The implications of these results for issues of health in the elderly are considered.


Variant pectoralis minor muscle: a case study with clinical relevance.
The pectoralis minor (PMn) muscle originates from the third, fourth, and fifth ribs near the costochondral junctionusually and gets inserted on the medial margin and upper surface of the coracoid process of the scapula. To look at the morphological insertion patterns and sites of attachment of the PMn muscle in the donated cadavers. Over all 19 limbs were included in the study (9 right and 10 left). Out of 19 limbs, 10 belonged to female and 9 belonged to male cadavers. The cadavers were meticulously dissected to determine the morphological insertion types and location of the attachment of the muscle. Unusual pattern of insertion was observed in 6 limbs (31.6%) out of total 19 limbs included in the study. The variations we observed does not fall completely in the classification by Le Double, hence variations we observed can be considered as new and rare variant which to our knowledge is not reported in literature. We propose this new variant to be type 4 of Le Double classification. The potential of ectopic PMn tendon should be taken into consideration and tested out, especially in patients with shoulder discomfort and stiffening who have ruled out the more frequent diseases. For proper surgical planning, a preoperative magnetic resonance imaging or USG examination of the shoulder joint is required considering the prevalence of variation in the insertion pattern of PMn muscle. Preoperative identification of any abnormal PMn insertion can help to reduce the risk of iatrogenic tendon injury and post-operative problems.


Thermotherapy v. antimonials: what happens after the healing of cutaneous leishmaniasis lesions?
The long-term effects of meglumine antimoniate (chemotherapy) or exposure to an environmental temperature of 37 degrees C (thermotherapy) on the evolution of Leishmania mexicana infections and on the response to challenge infections six months after treatment were compared in susceptible (BALB/c) and partially resistant (C57BL/6) mice. Thermotherapy was better than chemotherapy in that it healed lesions quicker and prevented relapses in the partially resistant mice during the observation period. However, both treatments appeared equally effective in terms of clinical cure. Neither treatment cleared all parasites from the hosts and both impaired the hosts' immune response to a challenge infection. The results indicate that specific immunity fades with time post-infection and that the persistence of the parasite in a clinically cured host does not maintain protective immunity against challenge infections.


An immunofluorescence study of warts.
An investigation of the incidence of wart virus-specific antibody and of virion antigens in patients with single or multiple warts taken from different anatomical sites showed that all warts did not contain antigen. The incidence was identical using either rabbit antiserum or human sera known to contain virus-specific antibody. The warts from sole, heel and toe had a much higher incidence of stainable virus antigen. Virus-specific staining was mainly found in the keratinized and granular layers of the wart but occasional synthesis in prickle cell layer was observed. All the patients who had virus antigens in their warts did not have virus-specific antibodies but no patient who had antibody lacked antigen. Of the virus-specific antibodies, the IgM class was predominant; a smaller number also contained virus-specific IgG antibody; none had virus antigens and both classes of virus-specific antibody. A wart cell-specific IgM was also found along with virus-specific antibodies and independent of them. An IgM producing fibrillar Staining in human embryonic lung cells was noted in some sera.


[Hematopoietic reconstitution in the allogeneic bone marrow chimeric mice].
Hematopoietic reconstitution in the allogeneic chimera is an important issue because its failure causes fatal infection in the host. Although graft-versus-host disease (GVHD) often occurs and is a major obstacle for successful bone marrow transplantation (BMT), it does not always play an unfavorable role in the host. It has been suggested that GVHD may show some effects on the hematopoietic reconstitution. In order to elucidate mechanism of the influence of GVHD on the hematopoiesis, I have studied kinetics of the hematopoietic progenitor cells in the bone marrow chimeric mice and the effects of spleen cells on it using in vitro CFU-GM assay. The number of CFU-GM in the bone marrow obtained from the allogeneic chimeras were reduced in the very early phase after BMT compared to that of syngeneic bone marrow chimeras. After then, the CFU-GM number in the allogeneic chimeras increased rapidly, especially in the chimeras showing a sign of severe GVHD. Addition of spleen cells from syngeneic chimeras to the bone marrow cell cultures showed no influence on the CFU-GM number observed. However, addition of spleen cells from allogeneic chimeras at 14 days after BMT to the bone marrow cells increased the CFU-GM number. By contrast, the chimeric spleen cells at 21 days after BMT decreased the number. These biphasic effects of spleen cells from allogeneic chimeras on the CFU-GM were considered to be mediated by some kinds of colony stimulating and inhibiting factors. Intraperitoneal injections of recombinant granulocyte-colony stimulating factors into bone marrow chimeras increased the number of granulocyte.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and correlation of OXIS contacts using Cone Beam Computed Tomography (CBCT) images and photographs.
The contact areas in between primary teeth are broader, flatter, and located further cervically when compared with the contact areas of permanent molars. We investigated the prevalence of interproximal contact area types of primary molars using CBCT images in children aged 3-10 years. Our second objective was to correlate OXIS contact areas when observed with CBCT images and clinical photographs. A retrospective cross-sectional study was performed with 367 CBCT images of children, aged 3-10 years, obtained from Children's Dental Centre, South Korea. The type of contacts in between primary molars was scored at various levels, specifically, occlusal, middle, and cervical thirds, according to OXIS criteria. Following this, the same patient's records were checked for the presence of clinical photographs and scored according to the same criteria. Prevalence was stated as percentages along with numbers. Chi-square test was applied to determine association of contact areas across genders and arches. The correlation between the two methods was done by Cohen's Kappa correlation test. The prevalence of the OXIS contacts obtained from CBCT images was as follows: I (79.7%), followed by X (10.0%), S (6.6%), and, finally, O (3.7%). The overall score of all the 1343 contact areas matched with the score observed at the occlusal third. All included contacts were of O (open) type at cervical third, and 1,231 contacts were of O (open) type at the middle third. Significant results were observed with respect to arches (P < .001). The correlation between the two methods was found to be 0.958. The contact area observed at the occlusal level determined the overall type of contact based on OXIS criteria. Thus, reports in the literature concluded that contact areas are broad, flat, and extend further gingivally should be revised. The study also concluded almost perfect agreement between CBCT images and clinical photographs.


Rethinking McKeown: the relationship between public health and social change.
Thomas McKeown was a rhetorically powerful critic, from the inside, of the medical profession's mid-20th-century love affair with curative and scientific medicine. He emphasized instead the importance of economic growth, rising living standards, and improved nutrition as the primary sources of most historical improvements in the health of developed nations. This interpretation failed to emphasize the simultaneous historical importance of an accompanying redistributive social philosophy and practical politics, which has characterized the public health movement from its 19th-century origins. Consequently, the current generation of public health practitioners are having to reconstruct such a politics and practice following its virtual dismantlement during the last 2 decades of the 20th century.


Is there an association between Helicobacter pylori infection and irritable bowel syndrome? A meta-analysis.
Irritable bowel syndrome (IBS) is a prevalent and debilitating gastrointestinal condition. Research has reported persistent, low-grade mucosal inflammation and significant overlaps between patients with IBS and those with dyspepsia, suggesting a possible pathogenic role of Helicobacter pylori (H. pylori) in IBS. This study therefore aimed to provide the first systematic review and meta-analysis on the association between H. pylori infection and IBS. To investigate the association between H. pylori infection and IBS. Using the keywords "H. pylori OR Helicobacter OR Helicobacter pylori OR infection" AND "irritable bowel syndrome OR IBS", a preliminary search of PubMed, Medline, Embase, Cochrane Database of Systematic Reviews, Web of Science, Google Scholar and WanFang databases yielded 2924 papers published in English between 1 January 1960 and 1 June 2018. Attempts were also made to search grey literature. A total of 13 clinical studies were systematically reviewed and nine studies were included in the final meta-analysis. Random-effects meta-analysis found a slight increased likelihood of H. pylori infection in patients with IBS, albeit this was not statistically significant (pooled odds ratio 1.47, 95% confidence interval: 0.90-2.40, P = 0.123). It must also be acknowledged that all of the available studies reported only crude odd ratios. H. pylori eradication therapy also does not appear to improve IBS symptoms. Although publication bias was not observed in the funnel plot, there was a high degree of heterogeneity amongst the studies included in the meta-analysis (I 2 = 87.38%). Overall, current evidence does not support an association between IBS and H. pylori infection. Further rigorous and detailed studies with larger sample sizes and after H. pylori eradication therapy are warranted.


[HIV and other sexually transmitted infections among migrant population in Spain: a scoping review].
Migration flows have the ability to disperse infectious agents and alter local epidemiologies. The aim of the study is to describe the socio-epidemiological, clinical and microbiology / molecular epidemiology of HIV / AIDS infection in the immigrant population. Review of the literature following the methodology Scoping review. A literature search in Medline and MEDES, original items made in Spain, published between 1998-2012, with people from Latin America, sub-Saharan Africa, North Africa, Asia and / or Eastern Europe was conducted. 41 articles were selected. The most studied population was from Latin America (48.8%). Higher HIV prevalence than in native was observed in men who have sex with men from Latin America (18.1%), transvestite and transsexual sex workers from Latin America (23.3%), pregnant women (0.9%) and men and women from sub-Saharan Africa (9.1% and 7.5%). Risk behaviors were different depending on the country of origin and sex. The diagnostic delay of HIV infections reached 43%, with higher prevalence in immigrants from sub-Saharan Africa, which showed delayed diagnosis in 41% and resistance to anti-retroviral treatment in 13%. Immigrant women had more losses to follow up, worse immunological response to antiretroviral treatment and shorter time treatment failure. Higher prevalence of HIV is presented by subjects from sub-Saharan Africa, men who have sex with men and transgender and transvestite sex workers from Latin America. Also pregnant women. Delayed diagnosis and resistance to treatment are more common in individuals from sub-Saharan Africa. Immigrant women presented poorer response to antiretroviral treatment.


HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications.
Uterine papillary serous carcinoma (UPSC) is a highly aggressive variant of endometrial cancer with features similar to high-grade ovarian cancer. Patients tend to be elderly, thin, have a high grade tumor with extensive extrauterine disease at the time of diagnosis. The transmembrane receptor encoded by the HER-2 cellular oncogene is amplified in several types of human carcinomas and provides an attractive therapeutic target. HER-2/neu, the transmembrane receptor encoded by the c-erbB2 gene, is overexpressed by immunohistochemistry in <25% of ovarian cancers and 20-30% of breast cancers, and <10% of endometrial cancer. There are prognostic and therapeutic implications associated with the overexpression of this transmembrane protein. Herceptin, a humanized murine monoclonal antibody directed against the extracellular domain of the HER-2/neu protein, is being used to treat breast cancer that overexpresses HER-2/neu. We reviewed all patients diagnosed with UPSC between 1999-2001. Twenty-six patients were identified, and 19 patients had specimens available for evaluation. We performed immunohistochemical analysis (Herceptest, Dako, Carpinteria, CA) on 19 paraffin embedded blocks of UPSC tumors looking for HER-2/neu over expression. Five out of 19 (26%) stained heavily (3+) for HER-2/neu receptor protein. Four of these five patients had advanced disease at diagnosis. Two of these patients were subsequently treated with Herceptin; one with complete response and one with stable disease based on CT scan and CA-125 findings. Targeting HER-2/neu may be beneficial for a select group of patients with UPSC. We are continuing to evaluate samples for HER-2/neu over expression by fluorescence in situ hybridization (FISH).


[Severe postmenopausal hyperandrogenism due to an ovarian lipoid cell tumor: a case report].
The case of a 62-year-old woman with severe post-menopausal hirsutism is described. Her clinical history revealed regular menstrual periods until menopause at the age of 50, hysterectomy for fibromatosis at 58 years, non-insulin dependent diabetes mellitus, hypertension, obesity, severe hirsutism, which had developed in the previous 3 years, with a deeping of the voice. Examination showed android obesity, hypertension and severe hirsutism involving the face and the trunk. Endocrine evaluation pointed out regular adrenal function, serum total and free-testosterone in the adult male range, with normal androstenedione, DHEAS and 17OHP levels. Estradiol was slightly increased and LH and FSH were inappropriately low for her post-menopausal age. Computed tomography of the abdomen showed regular adrenal glands, and a radio-labeled cholesterol scan was negative. A further pelvic transvaginal ultrasonography revealed a small cystic formation near the right ovary and a slight increase in the size of the left ovary. The patient underwent bilateral ovariectomy. Histological examination showed a lipoid cell tumor within the left ovary. Immunohistochemical studies were positive for inhibin and cytokeratin. After surgery, serum testosterone fell to normal levels, gonadotropins increased to menopausal levels, confirming that the tumor was able to produce both LH, and FSH-inhibiting factors, and hirsutism greatly improved. Periodic hormonal tests remained normal and CT of the abdomen and pelvic ultrasonography did not show alterations at a 3 years follow-up.


Point of Care Testing of Serum Electrolytes and Lactate in Sick Children.
To evaluate the electrolyte and lactate abnormalities in hospitalized children using a point of care testing (POCT) device and assess the agreement on the electrolyte abnormalities between POCT and central laboratory analyzer with venous blood. This observational study recruited hospitalized children aged 1 month to 12 years within two hours of admission. A paired venous sample and heparinized blood sample were drawn and analyzed by the central laboratory and POCT device (Stat Profile Prime Plus-Nova Biomedical, Waltham, MA, USA) for sodium and potassium. Lactate was measured on the POCT device only. The clinical and outcome parameters of children with electrolyte abnormalities or elevated lactate (>2mmol/L), and the agreement between POCT values and central laboratory values were assessed. A total of 158 children with median (IQR) age 11 (6-10) months and PRISM score 5 (2-9) were enrolled. The proportion of children with abnormal sodium and potassium levels, and acidosis on POCT were 87 (55.1%), 47 (29.7%) and 73 (46.2%), respectively. The interclass coefficient between POCT and laboratory values of sodium and potassium values was 0.74 and 0.71 respectively; P<0.001. Children with hyperlactatemia (81, 51.3%) had higher odds of shock (OR 4.58, 95% CI: 1.6-12.9), mechanical ventilation (OR 2.7, 95% CI 1.1-6.6, P=0.02) and death (OR 3.1, 95% CI 1.3-7.5 P=0.01) compared to those with normal lactate. POCT can be used as an adjunct for rapid assessment of biochemical parameters in sick children. Lactate measured by POCT was a good prognostic indicator.


GR and HMGB1 interact only within chromatin and influence each other's residence time.
Most nuclear proteins reside on a specific chromatin site only for seconds or less. The hit-and-run model of transcriptional control maintains that transcription complexes are assembled in a stochastic fashion from freely diffusible proteins; this contrasts to models involving stepwise assembly of stable holo complexes. However, the chances of forming a productive complex improve if the binding of one factor promotes the binding of its interactors. We prove here that in living cells, the glucocorticoid receptor and HMGB1 interact only within chromatin and not in the nucleoplasm and decrease each other's mobility. Thus, the formation of a GR-HMGB1-chromatin complex is more likely than one would expect from independent binding to chromatin of GR and HMGB1. Remarkably, this complex is potentially stable, and its disassembly is effected by active, ATP-consuming processes. We propose that kinetic cooperativity among transcription factors in chromatin binding may be a common feature in transcription and DNA transactions.


Bronchiectasis following treatment for high-risk neuroblastoma: A case series.
High-risk (HR) neuroblastoma remains a very challenging disease to treat and long-term cure is only possible with intensive, multimodal treatment including chemotherapy, high-dose therapy, radiotherapy, surgery, and immunotherapy. As a result, treatment-related morbidity and late effects are common in survivors. This report outlines a case series of six patients who developed a chronic productive cough following treatment for HR neuroblastoma. High-resolution computed tomography scanning confirmed the diagnosis of bronchiectasis. Two of the patients who have undergone immunological testing demonstrate hypogammaglobulinaemia and impaired vaccine response. Persistent cough in patients treated for neuroblastoma warrants investigation and consideration of immunological referral.


Identification, nucleotide sequence and expression of the regulatory region of the histidine operon of Escherichia coli K-12.
A restriction fragment has been isolated and its nucleotide sequence determined. This fragment contains sites for RNA polymerase binding, initiation and termination of transcription of the Escherichia coli histidine operon. In vitro transcription of plasmids containing this region generates one single histidine-specific, attenuated, small RNA: the leader RNA. This RNA is more efficiently transcribed when the template DNA is supercoiled. Another promoter was identified on the same fragment of deoxyribonucleic acid by in vitro transcription, DNA sequencing and RNA polymerase binding. Both promoters, transcribing in opposite direction, are very A-T rich and are separated by a G-C rich region containing a palyndromic structure.


Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity.
Copper is essential for the growth and development of mammalian cells. The key role in the intracellular distribution of copper belongs to the recently discovered family of metallochaperones and to copper-transporting P-type ATPases. The mutations in the ATPase ATP7B, the Wilson's disease protein (WNDP), lead to intracellular accumulation of copper and severe hepatic and neurological abnormalities. Several of these mutations were shown to disrupt the protein-protein interactions between WNDP and the metallochaperone Atox1, suggesting that these interactions are important for normal copper homeostasis. To understand the functional consequences of the Atox1-WNDP interaction at the molecular level, we produced recombinant Atox1 and characterized its effects on WNDP. We demonstrate that Atox1 transfers copper to the purified amino-terminal domain of WNDP (N-WNDP) in a dose-dependent and saturable manner. A maximum of six copper atoms can be transferred to N-WNDP by the chaperone. Furthermore, the incubation of copper Atox1 with the full-length WNDP leads to the stimulation of the WNDP catalytic activity, providing strong evidence for the direct effect of Atox1 on the function of this transporter. Our data also suggest that Atox1 can regulate the copper occupancy of WNDP. The incubation with apo-Atox1 results in the removal of copper from the metalated N-WNDP and apparent down-regulation of WNDP activity. Interestingly, at least one copper atom remains tightly bound to N-WNDP even in the presence of excess apo-Atox1. We suggest that this incomplete reversibility reflects the functional non-equivalency of the metal-binding sites in WNDP and speculate about the intracellular consequences of the reversible Atox1-mediated copper transfer.


Hybrid male sterility in rice controlled by interaction between divergent alleles of two adjacent genes.
Sterility is common in hybrids between divergent populations, such as the indica and japonica subspecies of Asian cultivated rice (Oryza sativa). Although multiple loci for plant hybrid sterility have been identified, it remains unknown how alleles of the loci interact at the molecular level. Here we show that a locus for indica-japonica hybrid male sterility, Sa, comprises two adjacent genes, SaM and SaF, encoding a small ubiquitin-like modifier E3 ligase-like protein and an F-box protein, respectively. Most indica cultivars contain a haplotype SaM(+)SaF(+), whereas all japonica cultivars have SaM(-)SaF(-) that diverged by nucleotide variations in wild rice. Male semi-sterility in this heterozygous complex locus is caused by abortion of pollen carrying SaM(-). This allele-specific gamete elimination results from a selective interaction of SaF(+) with SaM(-), a truncated protein, but not with SaM(+) because of the presence of an inhibitory domain, although SaM(+) is required for this male sterility. Lack of any one of the three alleles in recombinant plants does not produce male sterility. We propose a two-gene/three-component interaction model for this hybrid male sterility system. The findings have implications for overcoming male sterility in inter-subspecific hybrid rice breeding.


Biochemical principles and inhibitors to interfere with viral capping pathways.
Messenger RNAs are decorated by a cap structure, which is essential for their translation into proteins. Many viruses have developed strategies in order to cap their mRNAs. The cap is either synthetized by a subset of viral or cellular enzymes, or stolen from capped cellular mRNAs by viral endonucleases ('cap-snatching'). Reverse genetic studies provide evidence that inhibition of viral enzymes belonging to the capping pathway leads to inhibition of virus replication. The replication defect results from reduced protein synthesis as well as from detection of incompletely capped RNAs by cellular innate immunity sensors. Thus, it is now admitted that capping enzymes are validated antiviral targets, as their inhibition will support an antiviral response in addition to the attenuation of viral mRNA translation. In this review, we describe the different viral enzymes involved in mRNA capping together with relevant inhibitors, and their biochemical features useful in inhibitor discovery.


Differential regional effects of ketamine on spontaneous and glutamate-induced activities of single CNS neurones in rats.
Ketamine and L-glutamate were applied microiontophoretically to neurones of several central nervous system (CNS) structures in urethane anaesthetized Wistar rats. The spontaneous single-unit activities of all the hippocampal CA1 and CA3 neurones were suppressed by ketamine in an iontophoretic current-dependent manner. The spontaneous single-unit activities of eight of nine neurones in the thalamus were not affected by ketamine and suppressed in one. Spontaneous neurone activities in the midbrain reticular formation were not significantly affected by ketamine. Spontaneous activities of the cerebellar Purkinje cell were suppressed by ketamine in four of eight neurones. L-Glutamate excited all 13 hippocampal and nine thalamic neurones in a current-dependent manner. L-Glutamate-induced excitation of all CA1, CA3 and thalamic neurones was inhibited by ketamine. The inhibitory effects of ketamine on L-glutamate-induced excitation were dependent on the injection current intensity, although the sensitivity of thalamic neurones to the injection current was approximately three times that of hippocampal neurones. We conclude that the effects of ketamine on spontaneous activities of neurones vary according to the brain region, probably because of the distribution of NMDA receptors. Moreover, the actions of the drug on NMDA receptors appear to differ between the hippocampus and thalamus. These regionally differential actions of ketamine may reflect characteristics of anaesthesia induced by this drug.


Region-specific Etv2 ablation revealed the critical origin of hemogenic capacity from Hox6-positive caudal-lateral primitive mesoderm.
Hematopoietic cells (HPCs) develop from hemogenic endothelial cells (ECs), a specialized type of ECs undergoing hematopoietic transition. However, the mesoderm origin for hemogenic ECs or HPCs has not been clarified. To examine the origin for hemogenic mesoderm, we inactivated Etv2, a master regulator for EC/HPC commitment, in specific regions. Region-specific Etv2 ablation in early mesoderm caused local EC differentiation block, resulting in the loss of specific vascular beds without compensatory migration of residual ECs into avascular area. This feature of local EC/HPC differentiation block was correlated to the hemogenic potential of each mesoderm subset. We found that caudal-lateral mesoderm of E7.5-8.5 embryos represent the pre-committed population critical for generating hemogenic ECs. Etv2 ablation in caudal-lateral mesoderm by Hoxb6 Cre or Hoxb6CreER transgene affected vitelline plexus formation and intra-aortic hematopoietic clusters. In differentiated embryonic stem cells, this mesoderm subset marked by Hoxb6-lateral mesoderm promoter showed enriched T lymphopoietic potential among Flk-1(+) cells, which could be regarded as a characteristic for definitive HPCs. These findings indicate that critical mesoderm precursors possibly for definitive type hemogenic ECs are regionally specified in primitive mesoderm, suggesting that Hoxb6(+) caudal-lateral mesoderm represents the critical source of HPCs, which are potentially useful to enrich definitive HPCs from embryonic stem cells.


Using spectral reflectance to distinguish between tracheal and oesophageal tissue: applications for airway management.
Proper placement of the tracheal tube requires confirmation, and the predominant method in addition to clinical signs is the presence of end-tidal carbon dioxide. Such is the importance of confirmation that novel methods may also have a place. We previously demonstrated using ex-vivo swine tissue a unique spectral reflectance characteristic of tracheal tissue that differs from oesophageal tissue. We hypothesised that this characteristic would be present in living swine tissue and human cadavers. Reflectance spectra in the range 500-650 nm were captured using a customised fibreoptic probe, compact spectrometer and white light source from both the trachea and the oesophagus in anesthetised living swine and in human cadavers. A tracheal detection algorithm using ratio comparisons of reflectance was developed. The existence of the unique tracheal characteristic in both in-vivo swine and cadaver models was confirmed (p < 0.0001 for all comparisons between tracheal and oesophageal tissue at all target wavelengths in both species). Furthermore, our proposed tracheal detection algorithm exhibited a 100% positive predictive value in both models. This has potential utility for incorporation into airway management devices.


Predictive value of FSH, testicular volume, and histopathological findings for the sperm retrieval rate of microdissection TESE in nonobstructive azoospermia: a meta-analysis.
We performed this meta-analysis to evaluate the predictive value of different parameters in the sperm retrieval rate (SRR) of microdissection testicular sperm extraction (TESE) in patients with nonobstructive azoospermia (NOA). All relevant studies were searched in PubMed, Web of Science, EMBASE, Cochrane Library, and EBSCO. We chose three parameters to perform the meta-analysis: follicle-stimulating hormone (FSH), testicular volume, and testicular histopathological findings which included three patterns: hypospermatogenesis (HS), maturation arrest (MA), and Sertoli-cell-only syndrome (SCOS). If there was a threshold effect, only the area under the summary receiver operating characteristic curve (AUSROC) was calculated. Otherwise, the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and the diagnostic odds ratio (DOR) were also calculated. Twenty-one articles were included in our study finally. There was a threshold effect among studies investigating FSH and SCOS. The AUSROCs of FSH, testicular volume, HS, MA, and SCOS were 0.6119, 0.6389, 0.6758, 0.5535, and 0.2763, respectively. The DORs of testicular volume, HS, and MA were 1.98, 16.49, and 1.26, respectively. The sensitivities of them were 0.80, 0.30, and 0.27, while the specificities of them were 0.35, 0.98, and 0.76, respectively. The PLRs of them were 1.49, 10.63, and 1.15, respectively. And NLRs were 0.73, 0.72, and 0.95, respectively. All the investigated factors in our study had limited predictive value. However, the histopathological findings were helpful to some extent. Most patients with HS could get sperm by microdissection TESE.


Single-Factor Comprehensive Reservoir Quality Classification Evaluation-Taking the Hala'alat Mountains at the Northwestern Margin of the Junggar Basin as an Example.
In the process of petroleum geology exploration and development, reservoir quality evaluation is an essential component. However, conventional reservoir quality evaluation methods are no longer able to provide accurate and comprehensive assessments for all types of reservoirs. Therefore, the comprehensive evaluation of reservoir quality using multiple single factors is of significant importance in improving the level of reservoir quality assessment and enhancing the effectiveness of oil and gas exploration techniques. Conventional reservoir quality evaluation methods can assess only the quality of individual reservoir properties, resulting in limited classification outcomes. Taking the Cretaceous formations in the southern margin of the Hala'alat Mountain in the Junggar Basin as the research object, preliminary classification criteria were established based on the principles of formation coefficient, storage coefficient, and flow unit index. Combining experimental data such as core observation, thin-section identification, pore permeability analysis, and scanning electron microscopy, a comprehensive set of reservoir quality classification and evaluation criteria were developed. Furthermore, the corresponding reservoir classification evaluation maps were generated to illustrate the spatial distribution of reservoir quality. The study reveals that the area can be classified into four types of reservoirs, namely, Class I, Class II, Class III, and Class IV, corresponding to the best reservoir, relatively good reservoir, relatively poor reservoir, and poor reservoir, respectively. Among them, the second (K1q2) and third (K1q3) members of the Cretaceous Qingshuihe Formation, as well as the first (K1h1) and third (K1h3) members of the Cretaceous Hutubi Formation, exhibit the best reservoir quality as Class II. On the other hand, the second member of the Cretaceous Hutubi Formation (K1h2) exhibits the best reservoir quality as Class III, with relatively poorer reservoir quality overall. The research findings of this study can provide an important theoretical basis for oil and gas exploration and development in the region.


[Alveolar hemorrhage and glomerulonephritis in two patients with anti-neutrophil cytoplasmic antibodies].
A 55-year-old woman and a 56-year-old woman were admitted to the hospital because of dyspnea on exertion and bloody sputum. Chest roentgenography and computed tomography showed bilateral infiltrative shadows. Examination of bronchoalveolar lavage fluid and of specimens obtained by transbronchial lung biopsy revealed alveolar hemorrhage and hemosiderin-laden macrophages. Examination of specimens obtained by needle biopsies of the kidneys showed glomerulonephritis. Test for anti-neutrophil cytoplasmic antibody (ANCA) were positive; alveolar hemorrhage and glomerulonephritis accompanied by ANCA-related vasculitis was diagnosed. The patients' condition improved with administration of prednisolone and cyclophosphamide. Measurement of ANCA was useful for monitoring the activity of the disease.


Optimize the Preparation of Novel Pyrite Tailings Based Non-sintered Ceramsite by Plackett-Burman Design Combined With Response Surface Method for Phosphorus Removal.
The large amount of untreated pyrite tailings has caused serious environmental problems, and the recycling of pyrite tailings is considered as an attractive strategy. Here, we reported a novel non-sintered ceramsite prepared with pyrite tailings (PTNC) as the main active raw material for phosphorus control, and the dosage effect of ingredients on total phosphorus (TP) removal ability was investigated. The results from Plackett-Burman Design (PBD) suggested the dosages of dehydrated sludge, sodium bicarbonate, and cement were the factors which significantly affect the TP removal ability. The Box-Behnken Design (BBD) based response surface methodology was further employed, and it indicated the interactions between different factors, and the optimized recipe for PTNC was 84.5 g (pyrite tailings), 10 g (cement), 1 g (calcined lime), 1 g (anhydrous gypsum), 3 g (dehydrated sludge), and 0.5 g (sodium bicarbonate). The optimized PTNC was characterized and which presented much higher specific area (7.21 m2/g) than the standard limitation (0.5 m2/g), as well as a lower wear rate (2.08%) rather than 6%. Additionally, the leaching metal concentrations of PTNC were far below the limitation of Chinese National Standard. The adsorption behavior of TP on PTNC was subsequently investigated with batch and dynamic experiments. It was found that the calculated max adsorption amount (qmax) was about 7 mg/g, and PTNC was able to offer a stable TP removal ability under different hydraulic retention time (HRT). The adsorption mechanism was discussed by model fitting analysis combined with XRD and SEM characterization, and cobalt phosphide sulfide was observed as the newly formed substance through the adsorption process, which suggested the existing of both physical and chemical adsorption effect. Our research not only offered an economic preparation method of ceramsite, but also broadened the recycling pathway of pyrite tailings.


The human muscle nicotinic acetylcholine receptor alpha-subunit exist as two isoforms: a novel exon.
Analysis of acetylcholine receptor clones isolated from a human leg muscle cDNA library, revealed that the alpha-subunit existed as two isoforms. A novel exon, coding for 25 amino acids, was located in the human genomic DNA sequence; its insertion into the alpha-subunit gives the new isoform of 462 amino acids. In addition, mRNAs for the two isoforms were found in equal proportions in poly(A)+ RNA obtained from three further sources including partially denervated and innervated human muscle and the rhabdomyosarcoma cell line TE671. Both protein isoforms can be expressed in E. coli. No evidence of a sequence related to that of the new exon was found in cDNA derived from poly(A)+ RNA isolated from fetal calf or embryonic chick muscle or Torpedo marmorata electric organ.


Bradykinin stimulates bone resorption and lysosomal-enzyme release in cultured mouse calvaria.
The effect of bradykinin on bone resorption was studied in cultures of newborn-mouse calvaria. Bradykinin (0.03 microM, 1 microM) stimulated the release of 45Ca2+ from bones dissected out from mice prelabelled in vivo with 45Ca. Bradykinin (1 microM) also augmented the release of stable calcium ( 40Ca ), Pi and the lysosomal enzyme beta-glucuronidase. The stimulatory effect of bradykinin on mineral mobilization and lysosmal -enzyme release could be blocked by indomethacin. It is speculated that concomitant generation of thrombin and bradykinin in areas of trauma and inflammation may induce resorption of nearby bone tissue.


Noncholesterol-lowering effects of statins.
Statins, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors, inhibit the rate-limiting enzyme in cholesterol synthesis and lead to a significant reduction of plasma lipid concentrations. As a clear correlation exists between serum cholesterol and cardiovascular risk, statins have become increasingly important in current preventive medicine. Studies prompted by the extraordinary benefits afforded by these drugs have reported minimal changes in the vasculature of hypercholesterolemic patients when compared with clinical benefits and have led to further investigations to determine the underlying reasons for these clinical benefits. The purpose of this review is to present the wide array of systems that HMG-CoA reductase inhibitors are known to influence, which range from adverse events due to coronary artery disease, stroke risk, platelet function, endothelial function, and inflammatory effects to intracellular signaling pathways that control vascular cell migration, proliferation, and differentiation.


Undertaking a Collaborative Rapid Realist Review to Investigate What Works in the Successful Implementation of a Frail Older Person's Pathway.
We addressed the research question "what factors enable the successful development and implementation of a frail older person's pathway within the acute setting". A rapid realist review (RRR) was conducted by adopting the RAMESES standards. We began with a sample of 232 articles via database searches supplemented with 94 additional records including inputs from a twitter chat and a hospital site visit. Our final sample consisted of 18 documents. Following review and consensus by an expert panel we identified a conceptual model of context-mechanism-(resources)-outcomes. There was overall agreement frailty should be identified at the front door of the acute hospital. Significant challenges identified related to organisational boundaries both within the acute setting and externally, the need to shift outcomes to patient orientated ones, to support staff to sustain the pathway by providing ongoing education and by providing role clarity. RRRs can support research such as the systematic approach to improving care for frail older adults (SAFE) study by producing accounts of what works based on a wide range of sources and innovative engagement with stakeholders. It is evident from our provisional model that numerous factors need to combine and interact to enable and sustain a successful frail older person's pathway.


[The effect of recombinant human erythropoietin during hemodialysis on the thrombocyte and erythrocyte functions of patients with chronic kidney failure].
To elucidate causes of thrombotic complications early in the course of RHE treatment, the authors studied platelet function (by aggregation of washed platelets), cAMP and cGMP as well as TxB2 levels in blood plasma, red cell function (by MDA content) in 16 patients suffering from chronic renal failure (CRF) on hemodialysis. 8 of them had been on RHE for 1.5 months. It appeared that plasma levels of TxB2 and cGMP increased, thrombin-induced platelet aggregation slightly decreased, MDA in red cells on treatment month 1.5 rose. The authors made the conclusion that early in the course of RHE treatment the conditions promoting active thrombogenesis may arise as a result of red cell induced platelet activation due to increased number of red cells with poor resistance to oxidant damage and hemolysis. Application of RHE in CRF patients should be combined with antioxidant therapy, especially in patients at high thrombogenesis risk.


Polyethylene glycol 400 enhances the bioavailability of a BCS class III drug (ranitidine) in male subjects but not females.
The aim of this study was to investigate the effects of different doses of polyethylene glycol 400 (PEG 400) on the bioavailability of ranitidine in male and female subjects. Ranitidine (150 mg) was dissolved in 150 ml water with 0 (control), 0.5, 0.75, 1, 1.25 or 1.5 g PEG 400 and administered to 12 healthy human volunteers (six males and six females) in a randomized order. The cumulative amount of ranitidine and its metabolites excreted in urine over 24 h was determined for each treatment using a validated HPLC method. In the male volunteers, the mean cumulative amount of ranitidine excreted in the presence of 0, 0.5, 0.75, 1, 1.25 and 1.5 g PEG 400 were 35, 47, 57, 52, 50 and 37 mg respectively. These correspond to increases in bioavailability of 34%, 63%, 49%, 43% and 6% over the control treatment. In the female subjects, the mean cumulative quantity of ranitidine excretion in the absence and presence of increasing amounts of PEG 400 were 38, 29, 35, 33, 33 and 33 mg, corresponding to decreases in bioavailability of 24%, 8%, 13%, 13% and 13% compared to the control. The metabolite excretion profiles followed a similar trend to the parent drug at all concentrations of PEG 400. All doses of PEG 400 enhanced the bioavailability of ranitidine in male subjects but not females, with the most pronounced effect in males noted with the 0.75 g dose of PEG 400 (63% increase in bioavailability compared to control, p < 0.05). These findings have significant implications for the use of PEG 400 in drug development and also highlight the importance of gender studies in pharmacokinetics.


Ataxia-telangiectasia: some historic, clinical and pathologic observations.
Although an isolated clinical case report was published in 1926 and another in 1941, ataxia-telangiectasia (A-T) was not established as a distinct entity until 1957, when it was first delineated clinicopathologically. Susceptibility to sinopulmonary infection was identified as the main cause of death and as the third major component of the syndrome; its heredofamilial nature was documented, and it was designated "ataxia-telangiectasia." In a later review of 101 published cases, lymphoreticular malignancy emerged as the second most frequent cause of death. Although the thymus was found to be absent in the first reported autopsy in 1957 and the serum IgA deficiency was first recorded in 1961, A-T was not established as an immunodeficiency disease until 1963. Thymic abnormality and dysgammaglobulinemia explain the 2 main causes of death, sinopulmonary and neoplastic, but the immunodeficiency is probably not the central defect. It does not appear to explain either of the 2 main clinical diagnostic keys, the ataxia and the telangiectasia, or any of the other seemingly unrealted multisystemic facets of this complex disorder. Some of our most provocative long-term clinical observations and recent pathologic findings in our series of 9 autopsies are discussed.


Screening of Natural Lead Molecules Against Putative Molecular Targets of Drug-resistant Cryptococcus spp: An Insight from Computer-aided Molecular Design.
Cryptococcosis is one of the major invasive fungal infections distributed worldwide with high mortality rate. C. neoformans and C. gattii are the major organisms that cause various types of infections. Anti-fungal resistances exhibited by the mentioned species of Cryptococcus threaten their effective prevention and treatment. There is limited information available on human to human transmission of the pathogen and virulent factors that are responsible for Cryptococcus mediated infections. Hence, there is high scope for understanding the mechanism, probable drug targets and scope of developing natural therapeutic agents that possess high relevance to pharmaceutical biotechnology and medicinal chemistry. The proposed review illustrates the role of computer-aided virtual screening for the screening of probable drug targets and identification of natural lead candidates as therapeutic remedies. The review initially focuses on the current perspectives on cryptococcosis, major metabolic pathways responsible for the pathogenesis, conventional therapies and associated drug resistance, challenges and scope of structure-based drug discovery. The review further illustrates various approaches for the prediction of unknown drug targets, molecular modeling works, screening of natural compounds by computational virtual screening with ideal drug likeliness and pharmacokinetic features, application of molecular docking studies and simulation. Thus, the present review probably provides AN insight into the role of medicinal chemistry and computational drug discovery to combat Cryptococcus infections and thereby open a new paradigm for the development of novel natural therapeutic against various drug targets for cryptococcal infections.


The effect of proprioceptive knee bracing on knee stability during three different sport related movement tasks in healthy subjects and the implications to the management of Anterior Cruciate Ligament (ACL) injuries.
Proprioceptive knee braces have been shown to improve knee mechanics, however much of the work to date has focused on tasks such as slow step down tasks rather than more dynamic sporting tasks. This study aimed to explore if such improvements in stability may be seen during faster sports specific tasks as well as slower tasks. Twelve subjects performed a slow step down, single leg drop jump and pivot turn jump with and without a silicone web brace. 3D kinematics of the knee were collected using a ten camera Qualisys motion analysis system. Reflective markers were placed on the foot, shank, thigh and pelvis using the Calibrated Anatomical Systems Technique. A two way ANOVA with repeated measures was performed with post-hoc pairwise comparison to explore the differences between the two conditions and three tasks. Significant differences were seen in the knee joint angles and angular velocities in the sagittal, coronal and transverse planes between the tasks. The brace showed a reduction in knee valgum and internal rotation across all tasks, with the most notable effect during the single leg drop jump and pivot turn jump. The transverse plane also showed a significant reduction in the external rotation knee angular velocity when wearing the brace. The brace influenced the knee joint kinematics in coronal and transverse planes which confirms that such braces can have a significant effect on knee control during dynamic tasks. Further studies are required exploring the efficacy of proprioceptive braces in athletic patient cohort.


Extent of Atrial Deformation in Catheter Ablation of Atrial Fibrillation.
Anatomical atrial distortion during catheter mapping and ablation has not been elucidated in atrial fibrillation (AF) ablation. This study aimed to characterize the regional anatomical distortion in common ablation areas according to different contact forces (CFs) with radiofrequency and cryoballoon catheters.Ten patients underwent distortion mapping with low (5-10 g) and high CFs (10-30 g) at the pulmonary vein (PV) antra, left atrial (LA) roof line, mitral isthmus line, cavotricuspid isthmus line, and superior vena cava (SVC)-right atrial (RA) junction. Fifteen patients underwent distortion mapping with a 28-mm second-generation cryoballoon surrounded by a decapolar catheter at each PV antrum following creating the LA geometry. High CFs distorted the PV antra as compared to low CFs and the extent was greater at the anterior PV aspect, and the catheter was located more inside the PVs. The inflated cryballoon stretched the PV surface in the postero-superior direction in the upper PVs and posterior direction in the lower PVs. High CFs as compared to low CFs distorted the LA roof and cavotricuspid isthmus in the postero-inferior and inferior directions, respectively, but not the mitral isthmus line even with deflectable sheaths. High CFs distended the SVC-RA junction as compared to low CFs, and the extent was greatest at the lateral side and smallest at the antero-septal side.Human atria significantly distend during radiofrequency and cryoballoon ablation, and there are regional heterogeneities of the extent of the distortion. This information might aid operators in performing safe and effective AF ablation procedures.


[The Situation of Psychiatric Medicine and the System of Dispatching Medical Doctors Half a Century Ago in Okinawa].
This article describes the situation of psychiatric medicine and the system of dispatching medical doctors half a century ago in Okinawa, based on the author's knowledge and experi- ence gained as an expert participating in the mental health survey of Okinawa in 1966 (herein- after referred to as the Okinawa survey) and as the responsible officer of the Ministry of Health and Welfare in Japan in charge of dispatching medical personnel from mainland Japan to Okinawa. The Okinawa survey adopted the same high-level statistical methods as its counterpart mental health surveys in Japan. The survey clearly illustrated the situation of psychiatric dis- orders and psychiatric medicine in Okinawa, and influenced subsequent psychiatric medicine in Okinawa. After rejoining mainland Japan in 1972, the situation of psychiatric medicine in Okinawa changed markedly. In the Okinawa survey, the prevalence of mental disorders was 25.7 per 1,000 of the popu- lation, and the number of persons with mental disorders was estimated to be 24,060. Approximately 17,000 persons (71%) with mental disorders did not receive treatment or guidance. In 1966, mental institutions in Okinawa consisted of five mental hospitals and one clinic. The num- ber of psychiatric beds was 915. The Ryukyu Mental Health Law came into effect in Okinawa before rejoining mainland Japan. The characteristics of this law were the confinement of per- sons with mental disorders in private residences and the waiver of psychiatric medical fees using public resources. After rejoining mainland Japan, the confinement of persons with mental disorders in private residences was discontinued, but the waiver of psychiatric medical fees was continued. The Okinawa Mental Health Association contributed to psychiatric medicine and mental health services in Okinawa before rejoining mainland Japan. Taking the opportunity of the Okinawa survey, officers in charge of mental health services and public health nurses started mental health activities in public health centers. The dispatch of medical doctors is one of the medical supports for Okinawa. Psychiatrists are dispatched mainly from public mental hospitals such as the Shimofusa National Mental Hospital. Compared with 1966, the present situation regarding the quantity of psychiatric medicine, in Okinawa, such as the number of beds, has improved. It is expected hereafter that comprehensive psychiatric rehabilitation and stress care sys- tems will improve psychiatric medicine in Okinawa.


Laparoscopic Colectomy Versus Open Colectomy for Treatment of Transverse Colon Cancer: A Systematic Review and Meta-Analysis.
The surgical management of transverse colon cancer (TCC) is still not standardized. The aim of this meta-analysis was to evaluate the effect of laparoscopic colectomy (LC) for treatment of TCC in terms of short-term and long-term outcomes compared with open colectomy. A systematic literature search with no limits was performed in PubMed and Embase. The last search was performed on September 15, 2016. The short-term outcomes included intraoperative outcomes, postoperative outcomes, and oncological surgical quality. The long-term outcomes included overall survival (OS) and disease-free survival (DFS). Thirteen articles and one conference abstract published between 2010 and 2016 with a total of 1728 patients were enrolled in this meta-analysis. LC was associated with significant less estimated blood loss, fewer total postoperative complications, and shorter time to first flatus, time to liquid diet, length of hospital stay, and length of postoperative hospital stay. However, longer operative time was needed in LC. There was no statistically significant difference between the groups concerning the intraoperative complications, mortality, ileus, anastomotic leakage, bleeding, wound infection, abdominal infection, lymph nodes harvested, proximal resection margin, distal resection margin, OS, or DFS. Our meta-analysis suggests that LC is a safe and feasible technique for TCC associated with less estimated blood loss, fewer total postoperative complications, quicker recovery of intestinal function, shorter length of hospital stay, and equivalent long-term outcomes. Furthermore, a large-scaled, prospective randomized controlled study is warranted to verify those results.


A comparison of CA125, HE4, risk ovarian malignancy algorithm (ROMA), and risk malignancy index (RMI) for the classification of ovarian masses.
Differentiation between benign and malignant ovarian neoplasms is essential for creating a system for patient referrals. Therefore, the contributions of the tumor markers CA125 and human epididymis protein 4 (HE4) as well as the risk ovarian malignancy algorithm (ROMA) and risk malignancy index (RMI) values were considered individually and in combination to evaluate their utility for establishing this type of patient referral system. Patients who had been diagnosed with ovarian masses through imaging analyses (n = 128) were assessed for their expression of the tumor markers CA125 and HE4. The ROMA and RMI values were also determined. The sensitivity and specificity of each parameter were calculated using receiver operating characteristic curves according to the area under the curve (AUC) for each method. The sensitivities associated with the ability of CA125, HE4, ROMA, or RMI to distinguish between malignant versus benign ovarian masses were 70.4%, 79.6%, 74.1%, and 63%, respectively. Among carcinomas, the sensitivities of CA125, HE4, ROMA (pre-and post-menopausal), and RMI were 93.5%, 87.1%, 80%, 95.2%, and 87.1%, respectively. The most accurate numerical values were obtained with RMI, although the four parameters were shown to be statistically equivalent. There were no differences in accuracy between CA125, HE4, ROMA, and RMI for differentiating between types of ovarian masses. RMI had the lowest sensitivity but was the most numerically accurate method. HE4 demonstrated the best overall sensitivity for the evaluation of malignant ovarian tumors and the differential diagnosis of endometriosis. All of the parameters demonstrated increased sensitivity when tumors with low malignancy potential were considered low-risk, which may be used as an acceptable assessment method for referring patients to reference centers.


Design of cell-permeable, fluorescent activity-based probes for the lysosomal cysteine protease asparaginyl endopeptidase (AEP)/legumain.
Asparaginyl endopeptidase (AEP), also known as legumain, is a cysteine protease that has been ascribed roles in antigen presentation yet its exact role in human biology remains poorly understood. We report here, the use of a positional scanning combinatorial library of peptide AOMKs containing a P1 aspartic acid to probe the P2, P3, and P4 subsite specificity of endogenous legumain. Using inhibitor specificity profiles of cathepsin B and legumain, we designed fluorescent ABPs that are highly selective, cell-permeable reagents for monitoring legumain activity in complex proteomes.


Surgical management of ascending aortic disease.
Two cases of aortic pathology have been presented--namely, ascending aortic aneurysm and ascending aortic dissection. These entities are distinct, but can be superimposed. Surgical resection is the procedure of choice for both these entities, in contradistinction to descending aortic dissections. Although dealing with these entities can indeed be a humbling experience, lifesaving treatment can be delivered by a combination of a high index of suspicion, early diagnosis, and prompt surgical therapy.


Loss of olfactory receptor function in hominin evolution.
The mammalian sense of smell is governed by the largest gene family, which encodes the olfactory receptors (ORs). The gain and loss of OR genes is typically correlated with adaptations to various ecological niches. Modern humans have 853 OR genes but 55% of these have lost their function. Here we show evidence of additional OR loss of function in the Neanderthal and Denisovan hominin genomes using comparative genomic methodologies. Ten Neanderthal and 8 Denisovan ORs show evidence of loss of function that differ from the reference modern human OR genome. Some of these losses are also present in a subset of modern humans, while some are unique to each lineage. Morphological changes in the cranium of Neanderthals suggest different sensory arrangements to that of modern humans. We identify differences in functional olfactory receptor genes among modern humans, Neanderthals and Denisovans, suggesting varied loss of function across all three taxa and we highlight the utility of using genomic information to elucidate the sensory niches of extinct species.


Functional Differentiation among the Arabidopsis Phosphatidylinositol 4-Phosphate 5-Kinase Genes PIP5K1, PIP5K2 and PIP5K3.
Phosphatidylinositol 4-phosphate 5-kinase (PIP5K) is involved in regulating various cellular processes through the signaling function of its product, phosphatidylinositol (4,5)-bisphosphate. Higher plants encode a large number of PIP5Ks forming distinct clades in their molecular phylogenetic tree. Although biological functions of PIP5K genes have been analyzed intensively in Arabidopsis thaliana, it remains unclear how those functions differ across clades of paralogs. We performed comparative functional analysis of the Arabidopsis genes encoding PIP5K1, PIP5K2 and PIP5K3, of which the first two and the last belong to closely related but distinct clades, to clarify their conserved and/or differentiated functions. Genetic analysis with their single and multiple mutants revealed that PIP5K1 and PIP5K3 have non-overlapping functions, with the former in total plant growth and the latter in root hair elongation, whereas PIP5K2 redundantly functions in both phenomena. This pattern of functional redundancy is explainable in terms of the overlapping pattern of their promoter activities. In transformation rescue experiments, PIP5K3 promoter-directed PIP5K1-YFP completely rescued the short-root-hair phenotype of pip5k3. However, PIP5K3-YFP could substitute for PIP5K1-YFP only partially in rescuing the severe dwarfism of pip5k1pip5k2 when directed by the PIP5K1 promoter. Phylogenetic analysis of angiosperm PIP5Ks revealed that PIP5K3 orthologs have a faster rate of diversification in their amino-acid sequences compared with PIP5K1/2 orthologs after they arose through a eudicot-specific duplication event. These findings suggest that PIP5K3 specialized to promote root hair elongation and lost some of the protein-encoded functions retained by PIP5K1 and PIP5K2, whereas PIP5K1 differentiated from PIP5K2 only in its promoter-directed expression pattern.


Neuropathological study of chorea-acanthocytosis.
Neuropathological studies of a woman with chorea-acanthocytosis were reported. The patient clinically showed generalized epileptic seizures, choreatic involuntary movements, hypotonia , areflexia, neurogenic muscular atrophy, tongue-biting and acanthocytosis of the peripheral blood and died from asphyxia at the age of 34. Autopsy revealed atrophy of the caudate nucleus but the cerebral cortex was well preserved. Histological examination showed severe neuronal loss associated with moderate fibrous gliosis of the caudate. The putamen was similarly but less markedly affected. The small striatal neurons were more severely depopulated than the large neurons, although the latter were not spared. Cytometrical study of the caudate head revealed that the remaining small neurons were significantly larger in size than the normal small neurons of the same area. The anatomical substratum of the choreatic involuntary movements in chorea-acanthocytosis is thought to be the degeneration of the striatum, especially the caudate nucleus. Neuropathological differentiation of chorea-acanthocytosis from Huntington's chorea which shows similar pathology was discussed.


Investigating spiritual care perceptions and practice patterns in Hong Kong nurses: results of a cluster analysis.
Nurses' spiritual care perceptions and practices are explored by identifying profiles of nurses studying in a part-time baccalaureate course in a local Hong Kong university. Relationships between nurses' spiritual care perceptions and their practices are explored. Hundred and ninety three nurses completed a structured questionnaire. Spiritual care perceptions and practices. Two-step cluster analysis yielded three clusters. Clusters A, B, and C consisted of 15.0% (n = 29), 44.6% (n = 86), and 40.4% (n = 78), respectively. Cluster A nurses were characterized by relatively negative spiritual care perceptions and practices. Cluster C nurses reported positive perceptions, but negative practices; they mainly chose 'uncertain' for most items on both scales. Cluster B was a large group of nurses holding both positive spiritual care perceptions and practices. Significant differences towards spiritual care were found among clusters. Nurses' perceptions were significant positively correlated with practices (r = 0.62). High positive correlations were found between the two scales (r = 0.83) for nurses in Cluster A, for nurses in Clusters B and C, low positive correlations (r = 0.37) were found. Three clusters of Hong Kong nurses were differentiated. They showed differences in the level of their spiritual care perceptions and practices. Despite their level of spiritual care perceptions, nurses seldom incorporated spiritual care practices into their daily nursing care, and the level of spiritual care awareness of some nurses was low. Findings may be used to improve support of nurses, to ensure sensitive spiritual care in their daily practices, and to enhance nursing curricula.


Perioperative Management of Rheumatoid Medications in Orthopedic Surgery.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder known to cause progressive joint destruction. Over time, untreated RA can lead to pain and increasing disability, making orthopedic intervention necessary. The treatment of RA revolves around a variety of medications that blunt the overall immune response. However, this may increase the risk of infection and impair wound healing. Given the nature of this disease, orthopedists frequently encounter patients with RA in the operative setting. To optimize surgical outcomes, orthopedists must carefully manage and pay special attention to the adverse side effects of the complicated medication regimens of these patients perioperatively. [Orthopedics. 2017; 40(5):282-286.].


Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis.
Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory properties. Epidemiological studies have suggested a link between VitD deficiency and risk of development of chronic lung diseases. Its role in lung fibrosis is largely unknown. The aim of our study was to investigate the role of VitD in experimental and human lung fibrosis. VitD (25-OH-D3, 2 μg/kg) was orally administered from day 3-day 13 following bleomycin-challenge, in 8-10 weeks-old C57/BL6 mice. Mouse Lung Fibroblasts (MLFs) were pre-treated with VitD (2 μM for 24 h) and then stimulated with TGFB1 (10 ng/ml). Serum samples from 93 patients with IPF and other forms of interstitial lung diseases (ILDs) were prospectively collected for VitD measurement. VitD administration prevented bleomycin-induced lung fibrosis, as assessed by reductions in hydroxyproline levels, mRNA levels of col1a1, col3a1 and a-SMA (1.4-, 3.1-, 2.25-, 2.5-fold, respectively) and Masson Trichrome staining compared to the untreated group and these changes were associated with restoration of the bleomycin-induced downregulation of vitamin D-receptor (Vdr) mRNA levels. Pre-treatment with VitD reduced the responsiveness of MLFs to pro-fibrotic stimuli, as indicated by significant decreases of col1a1, col3a1 and a-SMA (3.6-, 4.1- and 2.7-fold, respectively).These changes were associated with restoration of the TGFB1-induced downregulation of vitamin D-receptor (VDR) mRNA levels. VitD treatment deactivated TGFB1-induced Smad3 phosphorylation. Patients with IPF and other forms of ILDs displayed deficient VitD serum concentrations (mean VitD = 18.76 ± 8.36 vs. 18.54 ± 8.39 ng/ml, respectively, p = 0.9). VitD deficiency was correlated with baseline FVC%predicted (r = 0.47, p < 0.0001), DLCO%predicted (r = 0.6, p < 0.0001), GAP score (r = -0.4, p < 0.0001) and all-cause mortality in patients with IPF (HR: 3.7, p = 0.001). VitD could serve as a prognosticator and potential therapeutic target in patients with IPF. Further studies are sorely needed.


Occult thyroid carcinoma. A study of 160 autopsy cases. The first report for the region of Epirus-Greece.
Thyroid glands from 160 patients, aged 11 to 95 years, without known thyroid disease, collected from medicolegal autopsies, were sectioned at 3-5 mm slices and microscopically examined for occult disease. The glands were normal in 57.9%, while nodules were observed in 16.8% and adenomas in 10.6% of the cases. Carcinomas were found in 12 cases (7.7%) and occult papillary carcinomas in 5.6%. No carcinomas were found in the thyroids of patients less than 40 years of age. There were no significant differences in frequency of occult carcinomas between female and male patients. The diameter of these tumors was less than or equal to 5 mm, with one exception, which had a diameter more than 6 mm. The aim of this article is to provide data about the frequency of occult thyroid tumors in the population of Epirus, which is a district in the north west part of Greece.


Influence of colorant solutions in properties of indirect resin composites.
To evaluate the influence of colorant solutions on color stability and surface roughness of indirect resin composites submitted to prior immersion in mouthwashes. Five brands of indirect resin composites were assessed: Adoro, Resilab, Cristobal, Sinfony and Epricord. The specimens were immersed in five different solutions (n = 10): four mouthwashes (Listerine, Oral-B, Plax, Periogard) and artificial saliva (control). 60 hours after immersion in mouthwashes, the specimens were exposed to coffee solution. Shade stability and surface roughness were tested by a spectrophotometer and by a profilometer, respectively. A three-way repeated-measures ANOVA was performed. Differences between the values were compared by the Tukey-Kramer test (P < 0.05). The majority of the specimens showed human-perceptible color change. Greater color change was observed after immersion in coffee, except for Cristobal. The color change was even higher for specimens previously immersed in mouthwashes. The Epricord resin showed the lowest roughness value and the Cristobal showed the highest value, regardless of the period. The highest roughness change occurred after immersion in Listerine.


Preferences for prolonging life: a prospect theory approach.
Kahneman and Tversky's (1979) Prospect theory was tested as a model of preferences for prolonging life under various hypothetical health statuses. A sample of 384 elderly people living in congregate housing (263 healthy, 131 frail) indicated how long (if at all) they would want to live under each of nine hypothetical health conditions (e.g., limited to bed or chair in a nursing home). Prospect theory, a decision model which takes into account the individual's point of reference, would predict that frail people would view prospective poorer health conditions as more tolerable and express preferences to live longer in worse health than would currently healthy people. In separate analyses of covariance, we evaluated preferences for continued life under four conditions of functional ability, four conditions of cognitive impairment, and three pain conditions--each as a function of participant's current health status (frail vs. healthy). The predicted interaction between frailty and declining prospective health status was obtained. Frail participants expressed preferences for longer life under more compromised health conditions than did healthy participants. The results imply that such preferences are malleable, changing as health deteriorates. They also help explain disparities between proxy decision-makers' and patients' own preferences as expressed in advance directives.


In Wiskott-Aldrich syndrome, platelet count matters.
In a retrospective analysis of the French Registry of patients with Wiskott-Aldrich Syndrome (WAS), Mahlaoui et al have identified severe refractory thrombocytopenia (SRT) early in life as a major risk factor for poor outcome.


Treatment of late biliary stricture after blunt abdominal trauma.
Extrahepatic bile duct injury from blunt abdominal trauma is severe and very rare. However, no definitive treatment has been proposed for biliary strictures caused by blunt abdominal trauma. Four cases of late biliary stricture following the initial repair of the liver rupture because of the blunt abdominal trauma are described. The diagnosis, treatment, and outcome of the complications are discussed. One patient received bile drainage because of biliary peritonitis on admission. He underwent a right hepatectomy and a Roux-en-Y anastomosis on the left bile duct because of right lobar atrophy 3 months later. Cholangiojejunostomy was performed in the other three patients using the Hepp-Couinaud technique. The patients were followed for 5-37 months, yielding no recurrence of the biliary stricture or cholangitis. Surgical intervention should be used after the failure of repeating endoscopic stenting or percutaneous drainage. The Hepp-Couinaud technique could provide a wide and accurate leakproof mucosa-to-mucosa anastomosis that is responsible for excellent results.


[General practitioners in service for public health services].
After the publication of the Swiss plan for pandemic preparation, specific tasks for the general practitioners (GPs) in Switzerland in the case of a pandemic situation have been analysed. A comprehensive preparation of the GPs for the pandemic is essential, first because of the increasing number of sick people and second because of the experience and competence of GPs in recognising and treating people affected by influenza. This article underlines the importance of the GPs in public health services and assists the GPs in their preparation for a pandemic.


A role for effectors of cellular immunity in epimorphic regeneration of amphibian limbs.
Immune modulation of regeneration of amphibian appendages is suggested, but not proven, by previous studies. Earlier studies have not demonstrated effects of treatments on both epimorphic regeneration and immune responses or restoration of regeneration by specific reversal of immunomodulation. Cyclosporin A (CsA) and interleukin-2 (IL-2) were used in this study to demonstrate the effects of immune suppression and its reversal, on allograft rejection and forelimb regeneration. When administered alone, CsA suppressed rejection of skin allografts and induced a dose-dependent retardation of regeneration. IL-2, administered alone, did not affect allograft rejection or regeneration. However, when combined with CsA, IL-2 abrogated or reversed effects of CsA on both allograft rejection and forelimb regeneration, in a dose-dependent manner. The selective focus of CsA's action and the ability of IL-2 to overcome and reverse these effects strongly suggest that T-lymphocytes participate in or contribute to expression of epimorphic regeneration of amphibian appendages. Further studies are required to better characterize this role.


Specific binding sites for gonadotrophin-releasing hormone, LH/chorionic gonadotrophin, low-density lipoprotein, prolactin and FSH in homogenates of human corpus luteum. II: Concentrations throughout the luteal phase of the menstrual cycle and early pregnancy.
Corpora lutea were obtained from 52 women undergoing laparotomy during the luteal phase of the menstrual cycle. In addition, stromal, thecal and granulosa cell preparations were obtained from seven women undergoing ovariectomy during the late follicular-preovulatory phase of the cycle. The specific binding of a 125I-labelled gonadotrophin-releasing hormone (GnRH) agonist [D-Ser(But)6] GnRH(1-9)-ethylamide (buserelin) and of human chorionic gonadotrophin (hCG), human FSH (hFSH), human prolactin (hPRL) and human low-density lipoprotein (hLDL) to tissue homogenates was measured under optimal conditions. Bound LH/hCG was estimated by elution with acid-citrate buffer, followed by radioimmunoassay of released hormone. Binding of GnRH agonist, though variable, was highest in mid-luteal corpus luteum and high binding was also present in three out of four corpora lutea of pregnancy. Binding of LH/hCG increased significantly with luteinization, reaching maximal levels in the mid-luteal phase before falling significantly. Occupancy of LH receptors by bound LH was relatively constant throughout the luteal phase (10.7-35.3%), but occupancy increased to greater than 90% in corpora lutea from early pregnancy. Binding of hFSH was variable, with only five out of 50 corpora lutea having binding greater than 10 pg/micrograms DNA. Similarly, hPRL binding varied markedly with only six out of 44 having binding greater than 50 pg/micrograms DNA. Binding of LDL was highest in the early- to mid-luteal phases of the cycle. In corpora lutea from all stages of the menstrual cycle (excluding corpora albicantia), GnRH agonist binding was highly correlated with the levels of unoccupied and occupied LH receptors (P less than 0.001; n = 49 and n = 48 respectively) and with LDL receptors (P less than 0.002; n = 49). Binding of GnRH agonist was also correlated with PRL binding (P less than 0.05; n = 21) but not with FSH receptors (P greater than 0.4; n = 25). In addition, LDL binding was associated with PRL (P less than 0.005; n = 21) and FSH receptors (P less than 0.05; n = 25) and with endogenously bound LH (P less than 0.03; n = 48), but not with unoccupied LH receptors (P = 0.8; n = 49). Moreover, in corpora lutea from the mid-luteal phase, there was a strong association between GnRH agonist binding and LDL receptors (P less than 0.02; n = 23). The correlations between GnRH agonist binding and a number of important indices of luteal function suggest a physiological role for GnRH-like factors in the human corpus luteum.


Class I-restricted alloreactive cytotoxic T lymphocytes recognize a complex array of specific MHC-associated peptides.
A major issue in understanding alloreactive T cell responses is whether the Ags recognized reside in allogeneic MHC proteins themselves regardless of the structure of the associated peptides or whether specific peptides presented by allogeneic MHC proteins determine each epitope. We developed HLA-A*0201-specific alloreactive human CD8+ CTL lines and clones to address this issue. Acid treatment of HLA-A*0201+ target cells resulted in the loss of Ab-defined epitopes as well as recognition by all alloreactive CTL. In the presence of brefeldin A, no class I molecules were re-expressed at the surface of the acid-treated cells. Addition of a mixture of synthetic peptides corresponding to known, naturally processed, HLA-A*0201-associated peptides together with exogenous human beta2m restored binding by specific Ab but not recognition by alloreactive CTL. However, addition of a more complex mixture of peptides directly extracted from HLA-A*0201 reconstituted CTL recognition. This demonstrates that these alloreactive CTL recognize specific peptides and not a common peptide-dependent conformation of HLA-A*0201. Reverse phase HPLC fractionation of the extracted peptides resulted in the loss of recognition by CTL lines from three individuals. This was not due to the loss of specific peptide species because repooling of the HPLC fractions led to a recovery of recognition. Furthermore, three HLA-A*0201-alloreactive CTL clones recognized single distinct peptide peaks from the same HPLC fractionation. These data suggest that the epitopes recognized in allogeneic responses to HLA-A*0201 are complex, and the response is a result of recognition of multiple unique peptide-MHC complexes.


Regulation of prostacyclin generation by angiotensin converting enzyme related substances in cultured human vascular endothelial cells.
The regulation of prostacyclin (PGI2) generation by angiotensin I-converting enzyme (ACE) related substances was investigated using cultured human vascular endothelial cells. Angiotensin I (AI) or bradykinin (BK) increased PGI2 generation and ACE activity, while the ACE inhibitor, captopril decreased both of them, and angiotensin II (AII) did not show any effect. The increasing rate of PGI2 generation induced by AI or BK was not affected by the pretreatment with captopril. These results suggest that the accumulation of AI or BK via the inhibition of ACE by captopril did not cause the enhancement of PGI2 generation. Rather, it was proposed that the enhanced PGI2 generation by AI or BK might be regulated by ACE activation derived from these substances, as an autoregulation mechanism.


Enhanced inactivation of avian influenza virus at -20°C by disinfectants supplemented with calcium chloride or other antifreeze agents.
Avian influenza outbreaks have occurred during winter months, and effective disinfection of poultry premises at freezing temperatures is needed. The commercial disinfectants Virkon and Accel, supplemented with an antifreeze agent [propylene glycol (PG), methanol (MeOH), or calcium chloride (CaCl₂)], were evaluated for their effectiveness in killing avian influenza virus (AIV) at -20°C or 21°C. An AIV suspension was applied to stainless steel disks, air-dried, and covered with a disinfectant or antifreeze agent for 5 to 30 min. Virkon (2%) and Accel (6.25%) with 30% PG, 20% MeOH, or 20% CaCl₂ inactivated 6 log₁₀ AIV within 5 min at -20°C and 21°C. At these temperatures PG and MeOH alone did not kill AIV, but the 20% CaCl₂ solution alone inactivated 5 log10 AIV within 10 min. The results suggested that CaCl₂ is potentially useful to enhance the effectiveness of disinfection of poultry facilities after outbreaks of AIV infection in warm and cold seasons.


Development of natural soft tissue architecture and interdental papillae between adjacent implants in the aesthetic zone.
A classification of predicted vertical height of the interdental papillae has been developed based on whether a papilla has a tooth, a pontic, or an implant on either side of it. Based on this classification, it may be prudent to avoid the placement of adjacent implants in multiple-unit restorations. To further enhance the aesthetics of multiple-unit restorations, endodontically retained roots may be submerged between implant sites. Some patients, however, require adjacent implants due to limited bone support. Others request them for personal reasons. In these cases, additional efforts must be made to create naturally appearing soft tissue architecture with full and symmetrical papillae.


Evidence-based radiology: steps 1 and 2--asking answerable questions and searching for evidence.
Evidence-based medicine originated at McMaster University, Hamilton, Ontario, Canada, where it was defined as "the integration of current best evidence with clinical expertise and patient values" by the Evidence-based Medicine Working Group led by Drs Gordon Guyatt and David Sackett. From this developed the McMaster University and National Health Service Centre for Evidence-Based Medicine, University of Oxford, paradigm of evidence-based practice, which consists of five steps that can be used by ordinary practitioners: formulate answerable questions with which to search for evidence, search the literature, appraise the retrieved evidence by using explicit methods, apply results to a patient or patient group, and evaluate one's evidence-based practice and clinical performance and practice. This communication is about the first two steps of this process. Step 1 provides a framework for more effective question formulation that improves subsequent literature searches. It works equally well for questions about diagnostic and interventional radiology. A clinical scenario for a diagnostic question is used to illustrate the formulation of an answerable question. This question is then used to illustrate step 2-how and where to search for evidence.


Hypo-Oestrogenaemia in retinal vasculopathy due to primary antiphospholipid antibody syndrome.
To report hypo-estrogenemic state in a case of recurrent vitreous hemorrhages due to primary antiphospholipid antibody syndrome. Interventional case report. A 40-year-old woman presented with recurrent vitreous hemorrhages. Treated initially with laser photocoagulation followed by hormone replacement therapy. Cessation of vitreous hemorrhage since starting hormone replacement therapy (twenty months ago). This is the first documented case of hypo-estrogenemia in lupus anticoagulant retinopathy. The response of this condition to estrogen is worth exploring. (Eur J Ophthalmol 2003; 13: 819-21).


Acrodermatitis enteropathica: the need for sustained high dose zinc supplementation.
Acrodermatitis enteropathica (AE) is a rare congenital disorder owing to an abnormality with intestinal absorption and/or transportation of zinc. We describe two male siblings, who presented with evidence of both acute and chronic zinc deficiency, despite being diagnosed with AE very early in life. We wish to highlight the importance of sustained high-dose zinc supplementation and regular monitoring in AE cases. Proper counselling of parents about the need for life long supplementation and increasing requirements with age is essential.


Computerized Dual-Task Testing of Gait and Visuospatial Cognitive Functions; Test-Retest Reliability and Validity.
The common occurrence of age decline in mobility and cognition does cause a decrease in the level of physical activity and an increased falls risk. Consequently, dual -task (DT) assessment that simultaneously addresses both mobility skills and cognitive functions are important because, continued difficulties and fall injuries will have a sizable impact in this population. The first objective of the present study was to assess test-retest reliability of a computerized DT treadmill walking protocol and concurrent outcome measures of gait and visuospatial executive function in a group of healthy older adults. Secondly, discriminative validity was evaluated by examining the effect of DT conditions (single task vs. dual-task) on; (a) spatiotemporal gait measures (average and coefficient of variation) and (b) visuomotor and visuospatial executive performance measures. Twenty-five community-dwelling individuals median age 65 (range 61-67) were recruited from a Fitness Facility. Participants performed a computerized visuomotor tracking task and a visuospatial executive game task in standing and while treadmill walking. Testing was conducted on two occasions, 1 week apart. Moderate to high test-retest reliability (ICC values of 0.65-0.88) were observed for spatiotemporal gait variables. No significant differences between the group means were observed between test periods in any gait variable. Moderate test-retest reliability (ICC values of 0.6-0.65) was observed for measures of visuomotor and visuospatial executive performance during treadmill walking. Significant DT effects were observed for both spatiotemporal gait variables and visuospatial executive performance measures. This study demonstrates the reliability and reproducibility of the computer-based assessment tool for dual task treadmill walking. The high to moderate ICC values and the lack of systematic errors in the measures indicate that this tool has the ability to repeatedly record reliable data from community-dwelling older adults. The present computerized dual-task protocols broaden the types of standardized visuomotor and visuospatial executive activities for use with DT treadmill walking that has previously been reported.


Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2).
Tissue transglutaminase (TG2) is a multifunctional enzyme involved in the cross-linking of extracellular matrix proteins, formation of complexes with fibronectin (FN) and integrins, and GTP hydrolysis. TG2 is activated in several pathological conditions, including cancer. We recently described a novel series of ligands that bind to TG2 and inhibit its interaction with FN. Because TG2 acts via multiple mechanisms, we set out to pursue a targeted protein degradation strategy to abolish TG2's myriad functions. Here, we report the synthesis and characterization of a series of VHL-based degraders that reduce TG2 in ovarian cancer cells in a proteasome-dependent manner. Degradation of TG2 resulted in significantly reduced cancer cell adhesion and migration in vitro in scratch-wound and migration assays. These results strongly indicate that further development of more potent and in vivo efficient TG2 degraders could be a new strategy for reducing the dissemination of ovarian and other cancers.


Physical impairment and social life goals among adult long-term survivors of childhood cancer: a population-based study from the childhood cancer registry of Piedmont, Italy.
The study describes the health status and the attainment of life goals in the adult survivors of childhood cancer recorded at the Childhood Cancer Registry of Piedmont. A postal questionnaire was sent to the general practitioner of the 690 cases born before 1976 and alive in 1991 after at least 5 years from diagnosis. The answer was received for 485 (72.9%) included in the analyses. Items in the questionnaire were: sequelae related to cancer and its treatment, health-related quality of life (according to Bloom's criteria), educational level attained, and employment status. Vital and marital status were obtained for all 690 cases at the offices of the town of residence. No medical condition was reported for 309 cases (63.7%). The overall proportion with a high school or university education was compared to corresponding figures for Piedmont in 1991, adjusted by age, and was as high as in the general population. Similar results are observed for occupation. Patients of both genders were married less than expected. Patients with leukemia (112 cases), non-Hodgkin's lymphoma (34) or Hodgkin's lymphoma (52) were reported to have the highest quality of life. In contrast, patients with tumors of the central nervous system (151) had the highest frequency of sequelae and the lowest score for health-related quality of life. They-also presented the lowest educational achievement, the lowest proportion of employment and, among males, the lowest frequency of marriage. Our study shows a good social adjustment of adult survivors from childhood cancer, with the exception of central nervous system tumors. From the methodologic point of view, the present study shows the feasibility of surveillance surveys on health-related quality of life with the contribution of general practitioners.