Characterization of kidney cell-specific, non-major histocompatibility complex alloantigen using antibodies eluted from rejected human renal allografts.
Previous studies from our laboratories (1) have indicated that eluates prepared from rejected kidneys have antibodies not only reactive to MHC class I and class II antigens but also to antigens unique for monocytes, endothelial cells, and kidney cells. To further define the serological and biochemical nature of antigens detected by the antibodies eluted from rejected kidneys, 13 eluates prepared from rejected renal allografts and two eluates from normal kidneys were absorbed with pooled platelets, normal splenic leukocytes and/or B cells from chronic lymphocytic leukemia patients. All of the eluates failed to react with normal T and B lymphocytes by microcytotoxicity and immunofluorescence assays. However, the eluates from rejected kidneys, but not normal kidneys, reacted with peripheral blood monocytes, endothelial cells cultured from umbilical cord as well as primary kidney cells. Detailed immunohistochemical analysis of frozen kidney sections showed that the eluates from rejected kidneys reacted with structures of the cortex while sparing the structures in the medullary region. All eluates bound to the glomerulus with intense fluorescence, but not to the mesangium and Bowman's capsule, while binding to interstitial capillaries, venous endothelium, and tubular epithelium varied. More significantly, none of the eluates reacted with frozen sections of the liver, spleen, or lymph node including the endothelial lining of blood vessels in these organs. Thus, the data indicate that the eluates prepared from rejected kidneys are recognizing organ-specific antigens expressed on the kidney cells. To identify the alloantigen(s) recognized by the eluted antibodies, an immunoblot analysis was performed against phase separated membrane proteins isolated from cortical kidney cells solubilized in 2X precondensed Triton X-114. A protein of Mr. 90,000-100,000 was identified as the target non-MHC antigen to which the eluates prepared from rejected allografts were reactive. Furthermore, our results suggest a possible polymorphism among these antigens.


Release of Cell-Free Tumor DNA in the Plasma of Uveal Melanoma Patients Under Radiotherapy.
Uveal melanoma (UM) is a tumor of the eye that metastasizes in approximately half of cases. Prognostic testing requires accessibility to tumor tissue, which is usually not available with eye-preserving therapies. Noninvasive approaches to prognostic testing that provide valuable information for patient care are therefore needed. The aim of this study was to evaluate the use of circulating cell-free plasma DNA analysis in UM patients undergoing brachytherapy. The study recruited 26 uveal melanoma patients referred to the department between February and October 2020. Blood samples were collected at various time points before, during, and after treatment, and deep amplicon sequencing was used to identify oncogenic variant alleles of the GNAQ and GNA11 genes, which serve as indicators for the presence of circulating tumor DNA (ctDNA). The results showed that all patients were ctDNA negative before brachytherapy. In 31% of patients, ctDNA was detected during therapy. The variant allele fraction of GNAQ or GNA11 alleles in ctDNA positive samples ranged from 0.24% to 2% and correlates with the largest basal diameter and thickness of the tumor. The findings suggest that brachytherapy increases the presence of tumor DNA in the plasma of UM patients. Thus ctDNA analysis may offer a noninvasive approach for prognostic testing. However, efforts are still required to lower the limit of detection for tumor-specific genetic alterations.


BK virus-specific antibodies and BKV DNA in renal transplant recipients with BKV nephritis.
We evaluated twenty renal transplant subjects at various stages of BKV nephritis (BKVN) for BKV-specific IgG and IgM antibodies using ELISA technique and BKV-DNA using PCR. They were divided as early onset (n = 7), stabilizing (n = 3), resolved (n = 8) and late onset (n = 2) BKVN. BKV-specific antibodies and BKV-DNA were simultaneously determined. The mean BKV-specific IgG level in early onset and stabilizing BKVN were 64 and 39 EIA units, and were significantly lower than 138 EIA units seen in resolved BKVN, P = 0.007, P = 0.008. The mean BKV-specific IgM levels in stabilizing BKVN was higher than resolved BKVN (130 vs 51 EIA units), P = 0.006. Mean plasma BKV loads for each group were 955,925, 5642 and 42 copies/mL of plasma, respectively. Prospective study in six BKVN cases revealed mean IgG, IgM levels and BKV-DNA at the time of diagnosis of BKVN as 39, 110 EIA units and 586,758 copies/mL of plasma, respectively. After a mean period of 5.2 months, IgG level increased to 120 EIA units (p = 0.0058) and had no detectable viral copies in circulation. Recovery from BKVN and elimination of BKV is associated with the development of BKV-specific IgG antibodies and this provides insight into the role of humoral immunity to BKV in the pathogenesis of BKVN.


The fate of E. coli lipopolysaccharide after the uptake of E. coli by murine macrophages in vitro.
The fate of bacterial lipopolysaccharide (LPS) after the uptake of Escherichia coli by macrophages in vitro was studied. The LPS of the galactose epimerase-deficient E. coli J5 mutant was specifically radiolabeled with [3H]galactose by growing the organism in a basic salts medium containing galactose. Control bacteria were uniformly radiolabeled by growth in [14C]glucose and unlabeled galactose-containing medium. Surface constituents of E. coli were also labeled with 125I. After in vitro phagocytosis of labeled E. coli by murine peritoneal exudate macrophages, the rate of exocytosis of LPS, as assessed by release of 3H over a 72-hr period, was considerably reduced in comparison with other bacterial constituents (14C and 125I release). The [3H]galactose-labeled material exocytosed from macrophages and that remaining intracellularly (obtained from macrophage lysates) were isolated by cesium chloride (CsCl) density gradients and were shown to have altered density profiles as compared with purified E. coli LPS. The macrophage-"processed" [3H] galactose-containing fractions from CsCl density gradients of culture supernatants or macrophage lysates were capable of clotting Limulus amebocyte lysate. The [3H]galactose material obtained from 48-hr macrophage lysates and culture supernatants could also induce a lethal response in actinomycin D-treated mice. These data suggest that bacterial LPS may be selectively retained by the macrophage and that the post-phagocytic events that result in bacterial degradation are not accompanied by the degradation of LPS. Furthermore, although the LPS may be modified by the macrophage, it retains its biologic activity.


Development of radioimmunoassay for measurement of serum digoxin in digitalized patients using novel anti-digoxin antiserum.
There is an antiserum elicited by digoxin 3'-hemisuccinate-bovine serum albumin (BSA) conjugate possessing high specificity for digoxin. Our study focused on development of RIA using this novel antiserum for measurement of digoxin in serum from digitalized patients. The property of the new antiserum was investigated by RIA with digoxin 3'-hemisuccinyl-[3H]leucine. The separation of bound and free fractions was performed using a dextran-coated charcoal suspension. The new antiserum bound approximately 50% of digoxin 3'-hemisuccinyl-[3H]leucine with a final dilution of 1:30000. The intra- and inter-assay coefficients of variation were <9% in the range of 0.52-4.17 ng/ml. The mean digoxin concentration in serum samples (n=35) from digitalized patients was estimated to be 0.68 ng/ml, which was lower than its measurement of digoxin with the commercial antidigoxin BSA serum and monoclonal anti-digoxin. It is apparent that the RIA described here has sufficient precision. The RIA system was available for the measurement of digoxin in serum from digitalized patients.


Are children's grief camps effective?
Bereavement camps are one form of popular grief intervention for children. A review of the existing literature on child bereavement camps was conducted to examine effectiveness of these camps. An initial database search led to 187 entries. Selection criteria employed resulted in a total of eight studies for an in-depth examination. While camps had differences in their lengths, camper acceptance, restrictions, and theoretical frameworks used; many shared similar camp goals and objectives, activities, and outcome measures. Emerging evidence shows camps are promising venues to help bereaved children develop and build resilience in dealing with loss.


Human cortical responses to the speech envelope.
To evaluate the response of the human auditory cortex to the temporal amplitude-envelope of speech. Responses to the speech envelope could be useful for validating the neural encoding of intelligible speech, particularly during hearing aid fittings--because hearing aid gain and compression characteristics for ongoing speech should more closely resemble real world performance than for isolated brief syllables. The speech envelope comprises energy changes corresponding to phonemic and syllabic transitions. Envelope frequencies between 2 and 20 Hz are important for speech intelligibility. Human event-related potentials were recorded to six different sentences and the sources of these potentials in the auditory cortex were determined. To improve the signal to noise ratio over ongoing electroencephalographic recordings, we averaged the responses over multiple presentations, and derived source waveforms from multichannel scalp recordings. Source analysis led to bilateral, symmetrical, vertical, and horizontal dipoles in the posterior auditory cortices. The source waveforms were then cross-correlated with the low frequency log-envelopes of the sentences. The significance and latency of the maximum correlation for each sentence demonstrated the presence and latency of the brain's response. The source waveforms were also cross-correlated with a simple model based on a series of overlapping transient responses to stimulus change (the derivative of the log-envelope). Correlations between the log-envelope and vertical dipole source waveforms were significant for all sentences and for all but one of the participants (mean r = 0.35), at an average delay of 175 (left) to 180 (right) msec. Correlations between the transient response model (P1 at 68 msec, N1 at 124 msec, and P2 at 208 msec) and the vertical dipole source waveforms were detected for all sentences and all participants (mean r = 0.30), at an average delay of 6 (right) to 10 (left) msec. These results show that the human auditory cortex either directly follows the speech envelope or consistently reacts to changes in this envelope. The delay between the envelope and the response is approximately 180 msec.


On the role of Ca, Mg-dependent nuclease in the postirradiation degradation of chromatin in lymphoid tissues.
The characteristics of the postirradiation degradation of chromatin in thymocytes in vivo were compared with the features of chromatin fragmentation in isolated thymocyte nuclei in vitro by endogenous chromatin-bound nucleases. Nuclease which degrades chromatin produces in vivo fragments of nucleosomal size; the double-strand breaks appear as the result of the accumulation of single-strand breaks with 3'-OH ends; the nuclease is inhibited by Zn2+ and DTNB and its activity is depressed by cycloheximide pretreatment. In experiments on in vitro degradation of chromatin in isolated thymocyte nuclei similar properties were observed for the Ca, Mg-dependent, but not for acid nuclease. The results bring further evidence of the involvement of an enzyme of the Ca, Mg-dependent nuclease-type in chromatin degradation in irradiated thymocytes.


Novel clinical associations with specific C9ORF72 transcripts in patients with repeat expansions in C9ORF72.
The loss of chromosome 9 open reading frame 72 (C9ORF72) expression, associated with C9ORF72 repeat expansions, has not been examined systematically. Three C9ORF72 transcript variants have been described thus far; the GGGGCC repeat is located between two non-coding exons (exon 1a and exon 1b) in the promoter region of transcript variant 2 (NM_018325.4) or in the first intron of variant 1 (NM_145005.6) and variant 3 (NM_001256054.2). We studied C9ORF72 expression in expansion carriers (n = 56) for whom cerebellum and/or frontal cortex was available. Using quantitative real-time PCR and digital molecular barcoding techniques, we assessed total C9ORF72 transcripts, variant 1, variant 2, variant 3, and intron containing transcripts [upstream of the expansion (intron 1a) and downstream of the expansion (intron 1b)]; the latter were correlated with levels of poly(GP) and poly(GA) proteins aberrantly translated from the expansion as measured by immunoassay (n = 50). We detected a decrease in expansion carriers as compared to controls for total C9ORF72 transcripts, variant 1, and variant 2: the strongest association was observed for variant 2 (quantitative real-time PCR cerebellum: median 43 %, p = 1.26e-06, and frontal cortex: median 58 %, p = 1.11e-05; digital molecular barcoding cerebellum: median 31 %, p = 5.23e-10, and frontal cortex: median 53 %, p = 5.07e-10). Importantly, we revealed that variant 1 levels greater than the 25th percentile conferred a survival advantage [digital molecular barcoding cerebellum: hazard ratio (HR) 0.31, p = 0.003, and frontal cortex: HR 0.23, p = 0.0001]. When focusing on intron containing transcripts, analysis of the frontal cortex revealed an increase of potentially truncated transcripts in expansion carriers as compared to controls [digital molecular barcoding frontal cortex (intron 1a): median 272 %, p = 0.003], with the highest levels in patients pathologically diagnosed with frontotemporal lobar degeneration. In the cerebellum, our analysis suggested that transcripts were less likely to be truncated and, excitingly, we discovered that intron containing transcripts were associated with poly(GP) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.33, p = 0.02, and (intron 1b): r = 0.49, p = 0.0004] and poly(GA) levels [digital molecular barcoding cerebellum (intron 1a): r = 0.34, p = 0.02, and (intron 1b): r = 0.38, p = 0.007]. In summary, we report decreased expression of specific C9ORF72 transcripts and provide support for the presence of truncated transcripts as well as pre-mRNAs that may serve as templates for RAN translation. We further show that higher C9ORF72 levels may have beneficial effects, which warrants caution in the development of new therapeutic approaches.


Association of cucumovirus and potyvirus with betelvine (Piper betle L.) as evidenced by ELISA and RT-PCR.
An attempt was made to detect various viruses of Piper betle grown at Mahoba and Banthara in India. DAC-ELISA and RT-PCR tests were performed in leaf sap samples of betelvine for detection of a cucumovirus (Cucumber mosaic virus) and potyvirus (Bean yellow mosaic virus) using specific antibodies and universal primers of respective viruses. DAC-ELISA could detect only CMV. However, RT-PCR detected both cucumovirus and potyvirus infection in betelvine samples. Association of CMV with betelvine was observed for the first time in the present study.


Back to the Drawing Board.
A misunderstanding of what 'human factors' means often leads organisations to try to change their people rather than the processes that could transform patient safety, finds Claire Read.


Extended biotic ligand model for predicting combined Cu-Zn toxicity to wheat (Triticum aestivum L.): Incorporating the effects of concentration ratio, major cations and pH.
Current risk assessment models for metals such as the biotic ligand model (BLM) are usually applied to individual metals, yet toxic metals are rarely found singly in the environment. In the present research, the toxicity of Cu and Zn alone and together were studied in wheat (Triticum aestivum L.) using different Ca2+ and Mg2+ concentrations, pH levels and Zn:Cu concentration ratios. The aim of the study was to better understand the toxicity effects of these two metals using BLMs and toxic units (TUs) from single and combined metal toxicity data. The results of single-metal toxicity tests showed that toxicity of Cu and Zn tended to decrease with increasing Ca2+ or Mg2+ concentrations, and that the effects of pH on Cu and Zn toxicity were related not only to free Cu2+ and Zn2+ activity, respectively, but also to other inorganic metal complex species. For the metal mixture, Cu-Zn interactions based on free ion activities were primarily additive for the different Ca2+ and Mg2+ concentrations and levels of pH. The toxicity data of individual metals derived by the BLM, which incorporated Ca2+ and Mg2+ competition and toxicity of inorganic metal complexes in a single-metal toxicity assessment, could predict the combined toxicity as a function of TU. There was good performance between the predicted and observed effects (root mean square error [RMSE] = 7.15, R2 = 0.97) compared to that using a TU method with a model based on free ion activity (RMSE = 14.29, R2 = 0.86). The overall findings indicated that bioavailability models that include those biochemistry processes may accurately predict the toxicity of metal mixtures.


An update on mechanical circulatory support for heart failure therapy.
This article aims to review contemporary studies that utilized mechanical circulatory support (MCS) in the treatment of heart failure and to elaborate on prospective mechanical alternatives. There is a growing need for a well-tolerated, durable and effective MCS option in patients with refractory heart failure. In previous years, the primary indication for MCS therapy supported bridge to transplantation. These early left ventricular assist devices (LVADs) suffered significant adverse events, thereby limiting their prolonged use. With the introduction of newer continuous flow LVADs, with lower morbidity, neurological events, pump failure and the expanded indication use (i.e. destination therapy), the overall number of implanted patients has grown. There has been a dramatic advancement of durability found in the second and third-generation, continuous flow LVADs, along with improved survival rates in patients receiving these devices for destination therapy. MCS may soon become the treatment option of choice in refractory heart failure patients, especially with further evolution of less invasive approaches, smaller designs, and energy sources.


A prospective 10-year study on children who had severe infantile colic.
To evaluate the association between infantile colic and gastrointestinal, allergic and psychological disorders in childhood. A prospective study was conducted on 103 infants aged 31-87 d. After 10 y, between 2001 and 2003, the children were recalled and a paediatrician evaluated the selected disorders by anamnesis, medical examination, laboratory tests and parent interviews. Of the 103 infants enrolled, 96 completed the study. There was an association between infantile colic and recurrent abdominal pain (p=0.001) and allergic disorders: allergic rhinitis, conjunctivitis, asthmatic bronchitis, pollenosis, atopic eczema and food allergy (p<0.05). Sleep disorders, fussiness, aggressiveness and feelings of supremacy are more frequent in children who suffered from colic during early infancy (p<0.05). A family history of gastrointestinal diseases and atopic diseases was significantly higher in infants with colic than in controls (p<0.05). Susceptibility to recurrent abdominal pain, allergic and psychological disorders in childhood may be increased by infantile colic. Our findings confirm that severe infantile colic might be the early expression of some of the most common disorders in childhood.


The Dark Side of the Moon: The Right Ventricle.
The aim of this review article is to summarize current knowledge of the pathophysiology underlying right ventricular failure (RVF), focusing, in particular, on right ventricular assessment and prognosis. The right ventricle (RV) can tolerate volume overload well, but is not able to sustain pressure overload. Right ventricular hypertrophy (RVH), as a response to increased afterload, can be adaptive or maladaptive. The easiest and most common way to assess the RV is by two-dimensional (2D) trans-thoracic echocardiography measuring surrogate indexes, such as tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and tissue Doppler velocity of the lateral aspect of the tricuspid valvular plane. However, both volumes and function are better estimated by 3D echocardiography and cardiac magnetic resonance (CMR). The prognostic role of the RV in heart failure (HF), pulmonary hypertension (PH), acute myocardial infarction (AMI), and cardiac surgery has been overlooked for many years. However, several recent studies have placed much greater importance on the RV in prognostic assessments. In conclusion, RV dimensions and function should be routinely assessed in cardiovascular disease, as RVF has a significant impact on disease prognosis. In the presence of RVF, different therapeutic approaches, either pharmacological or surgical, may be beneficial.


[Primary ovarian malignant melanoma].
Primary ovarian malignant melanoma is extremely rare. It usually appears in the wall of a dermoid cyst or is associated with another teratomatous component. Metastatic primary malignant melanoma to ovary from a primary melanoma elsewhere is well known and has been often reported especially in autopsy studies. We presented a case of primary ovarian malignant melanoma in a 45-year old woman, with no evidence of extraovarian primary melanoma nor teratomatous component. The tumor was unilateral, macroscopically on section presented as solid mass, dark brown to black color. Microscopically, tumor cells showed positive immunohistochemical reaction for HMB-45, melan-A and S-100 protein, and negative immunoreactivity for estrogen and progesteron receptors. Differentiate metastatic melanoma from rare primary ovarian malignant melanoma, in some of cases may be a histopathological diagnostic problem. Histopathological diagnosis of primary ovarian malignant melanoma should be confirmed by immunohistochemical analyses and detailed clinical search for an occult primary tumor.


A CRASH course in cultural competence for nurses.
Nurses are at the forefront of providing health care and need to be sensitive to the unique needs of all populations. Because urologic nurses care for individuals with sometimes embarrassing health care needs, we encourage urologic nurses to take a CRASH course in cultural competence, combining knowledge of Culture, Respect and Assessment of others' worldviews, Sensitivity to cultural differences, and providing care with Humility that can be integrated into urology. Resources for increasing cultural competence are also suggested.


Impact of inhaled and intranasal corticosteroids on glucose metabolism and diabetes mellitus: A mini review.
Inhaled corticosteroids (ICS) and intranasal corticosteroids (INS) are the mainstays of treatment for chronic respiratory diseases like asthma, chronic obstructive pulmonary disease, and allergic rhinosinusitis. In addition, these localized forms of steroid therapy are generally considered to have fewer systemic side effects compared to long-term oral corticosteroids. However, concern and controversy remain over the impact of ICS and INS on the incidence and control of diabetes mellitus (DM). Given the widespread use of ICS and INS, even small individual effects on DM could lead to large consequences for the global popu-lation. Multiple large observational studies suggest that high dose ICS is associated with increased incident DM and worsened DM control, though the contribution of other risk factors is less certain. In addition, only two studies were done to investigate the association of INS and DM, with both studies demon-strating a short-term association of INS use with hyperglycemia. While more research evaluating the risk of ICS/INS for DM-related adverse events is needed, high doses of ICS/INS should be avoided when possible. The following strategies for ICS/INS dose minimization can be considered: Use of non-pharmacological measures (trigger avoidance, smoking cessation, vaccination to avoid infection), control of comorbid conditions, use of non-ICS-containing medications, inter-mittent rather than regular ICS dosing, and appropriate de-escalation of high ICS doses.


Impact of etiology of chronic renal failure on growth in children.
A prospective study was carried out in the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from October, 2001 to October, 2003 to find out the impact of different etiology of chronic renal failure on growth in children. Fifty children of both sexes under 15 years of age with clinical and biochemical evidence of chronic renal failure (CRF) with creatinine clearance (Ccr) of <75 ml/min/1.73m2 were included in the study. On the basis of underlying causes of CRF, the children were divided into congenital (n=30) and acquired (n=20) groups. All patients' height, weight, radiographs of different bones was obtained to evaluate the presence of renal osteodystrophy (ROD) and for assessment of bone age. Serum intact parathormone (iPTH) level was also assayed in all patients. These parameters were evaluated in two groups. CRF children due to congenital anomalies had stunting and wasting in 23 (76.7%) and 20 (66.7%) cases respectively and the difference between two groups was highly significant (P<0.001). Alkaline phosphatase (467.70+/-218.55 U/L) and iPTH (91.43+/-33.42 pg/ml) were also significantly higher in the congenital group (P<0.001 and P<0.05 respectively). Radiographic features of ROD were present in 15 (50%) cases in congenital group in comparison to 4 (20%) in acquired group and the growth zone lesion was the commonest type of ROD in congenital group (66.7%). CRF should be diagnosed as early as possible to maintain growth potential.


[Early-onset epileptic encephalopathy caused by CDKL5 mutation].
Two girls suffering from early-onset epileptic encephalopathy are described. Both girls had changes involving the gene CDKL5. They both had seizures in the first weeks of life and normal EEG interictally. Both developed infantile spasms and severe developmental defect. The epilepsy was difficult to treat.


Saline infusion in excimer laser coronary angioplasty.
While the effects of high-intensity laser energy on tissue were studied early in the development of the laser, the interactions of laser radiation with immersion media have been the subject of more recent investigations. Prompted by reports of severe, morphologically unusual dissections occurring during 308 nm excimer laser angioplasty, several investigators have now demonstrated that both blood (haemoglobin) and angiographic contrast media strongly absorb excimer laser light at 308 nm. Upon absorption, this light energy is converted into rapidly expanding and imploding cavitation bubbles that generate intense pressure pulses. Subsequently, several techniques to remove contrast and dilute blood in the ablation field were evaluated. The application of saline infusion has resulted in improvements in both angiographic and clinical outcomes. The purpose of this paper is to review the development and application of the technique of saline infusion in the clinical practice of excimer laser coronary angioplasty.


Acute symptomatic hypocalcemia from immune checkpoint therapy-induced hypoparathyroidism.
Ipilimumab (a monoclonal antibody against CTLA-4) and nivolumab (a humanized antibody against PD-1) target these immune checkpoint pathways and are used for treatment of melanoma and an increasing number of other cancers. However, they may cause immune-related adverse effects (IRAEs). Although many endocrinopathies are known to be IRAEs, primary hypoparathyroidism with severe hypocalcemia has never been reported. This is the first case of hypoparathyroidism as an IRAE presenting to an Emergency Department with acute hypocalcemia. A 73-year-old man with metastatic melanoma presented to the Emergency Department for the chief complaints of imbalance, general muscle weakness, abdominal pain and tingling in extremities. He had wide spread metastasis, and begun immunotherapy with concurrent ipilimumab and nivolumab 1.5months ago. At presentation, he had ataxia, paresthesia in the hands and feet, and abdominal cramping. Magnetic resonance imaging of the brain was unremarkable. He was found to be hypocalcemic with undetectable plasma parathyroid hormone. He was admitted for treatment of symptomatic hypocalcemia and was diagnosed with primary hypoparathyroidism. Shortly afterwards, he had thyrotoxicosis manifesting as tachycardia and anxiety, followed by development of primary hypothyroidism. At 4months after the Emergency Department visit, his parathyroid function and thyroid function had not recovered, and required continued thyroid hormone replacement and calcium and vitamin D treatment for hypocalcemia. Primary hypoparathyroidism caused by ipilimumab and nivolumab may acute manifest with severe symptomatic hypocalcemia. Emergency care providers should be aware of hypoparathyroidism as a new IRAE in this new era of immuno-oncology.


Angiotensin II increases cardiac protein synthesis in adult rat heart.
This study examined the direct effect of angiotensin II (ANG II) on cardiac muscle atrophy previously observed in the denervated rat heart. Rats with transplanted hearts were infused with normal saline (1 microliter/h) or a subpressor dose of ANG II dissolved in saline (3 micrograms.kg-1.h-1) for 1 wk. Left ventricular (LV) mass of transplanted hearts decreased by 29 and 18% in the saline-infused and ANG II-infused groups, respectively (P < 0.05). Total LV protein synthesis of the transplanted heart was 1.4 +/- 0.1 mg.LV-1.day-1 in the saline compared with 2.2 +/- 0.2 mg.LV-1.day-1 in the ANG II (P < 0.05) group. Heart rate and carotid systolic arterial pressures were not affected by ANG II infusion, and the decrease in alpha-myosin heavy chain normally observed in this model was unchanged between the two groups (61 +/- 3 and 66 +/- 1%, saline vs. ANG II). These data demonstrate that ANG II increases total cardiac protein synthesis in the adult heart, leading to an attenuation in cardiac atrophy. The failure of ANG II to prevent the shift from alpha- to beta-myosin heavy chain may be related to its lack of an effect on heart rate, since other interventions that affect myosin isoenzyme distribution also increase heart rate.


Screening of non-alkaloidal natural compounds as acetylcholinesterase inhibitors.
Acetylcholinesterase (AChE) inhibitors are currently the only approved therapy for the treatment of Alzheimer's disease, only a limited number of drugs are commercially available. A library of non-alkaloidal natural compounds was investigated. To this end, a convenient microtitre plate method for assaying AChE inhibition, which allows a complete kinetic analysis of AChE inhibitors, was developed. Seven active compounds with Ki values in the micromolar range were identified, six of which were xanthones. This is the first report that a promising potential for AChE inhibition exists in such non-nitrogenous natural compounds. Furthermore, four xanthones among these xanthones had already been described as monoamine oxidase (MAO) inhibitors, making then dual AChE/MAO inhibitors of great interest.


Female germline expression of OVO transcription factor bridges Drosophila generations.
OVO is required for karyotypically female germ cell viability but has no known function in the male germline in Drosophila. ovo is autoregulated by two antagonistic isoforms, OVO-A and OVO-B. All ovo- alleles were created as partial revertants of the antimorphic ovoD1 allele. Creation of new targeted alleles in an ovo+ background indicated that disrupting the germline-specific exon extension of ovo-B leads to an arrested egg chamber phenotype, rather than germ cell death. RNA-seq analysis, including >1K full length cDNAs, indicates that ovo utilizes a number of unannotated splice variations in the extended exon and a minor population of ovo-B transcripts utilizes an alternative splice. This indicates that classical ovo alleles such as ovoD1rv23, are not truly null for ovo, and are likely to be weak antimorphs. To generate bonafide nulls, we deleted the ovo-A and ovo-B promoters showing that only ovo-B is required for female germ cell viability and there is an early and polyphasic developmental requirement for ovo-B in the female germline. To visualize OVO expression and localization, we endogenously tagged ovo and found nuclear OVO in all differentiating female germ cells throughout oogenesis in adults. We also found that OVO is maternally deposited into the embryo, where it showed nuclear localization in newly formed pole cells. Maternal OVO persisted in embryonic germ cells until zygotic OVO expression was detectable, suggesting that there is continuous nuclear OVO expression in the female germline in the transition from one generation to the next.


5-Hydroxydecanoate inhibits proliferation of hypoxic human pulmonary artery smooth muscle cells by blocking mitochondrial K(ATP) channels.
To study the effect of 5-hydroxydecanoate (5-HD) on the proliferation of 24 h hypoxic human pulmonary artery smooth muscle cells (HPASMC) and to explore the pharmacological mechanisms of 5-HD as an inhibitor of mitochondrial membrane ATP-sensitive potassium channel activation. Normoxic or hypoxic HPASMC in culture were stimulated by either diazoxide or 5-HD for 24 h. The proliferation of HPASMC was examined by 3- (4,5-dimethyl-2-thiazol-yl) -2,5-diphenyl- 2H-tetrazolium bromide (MTT) assay and proliferating cell nuclear antigen (PCNA) immunohistochemistry staining. The apoptosis of HPASMC was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and flow cytometric analysis. The relative changes in mitochondrial membrane potential (deltaPhi(m)) were measured using the rhodamine fluorescence (R-123) technique. Both hypoxia and diazoxide stimulation increased deltaPhi(m) value measured by the absorbance of MTT, PCNA-positive staining and decreased TUNEL-positive staining and apoptotic cells in HPASMC. Hypoxia and the concomitant stimulation of diazoxide obviously enhanced the effects of hypoxia or diazoxide alone. 5-HD significantly attenuated the effects in each of the above conditions. Additionally, 5-HD partially inhibited the effect of hypoxia on R-123 fluorescence intensity in HPASMC. 5-HD can inhibit the proliferation of hypoxic HPASMC by blocking mitochondrial K(ATP) channels.


Human enhancer of rudimentary is a molecular partner of PDIP46/SKAR, a protein interacting with DNA polymerase delta and S6K1 and regulating cell growth.
Enhancer of rudimentary (ER) is a small protein that has a unique amino acid sequence and structure. Its highly conserved gene has been found in all eukaryotic kingdoms with the exception of fungi. ER was proposed to be involved in the metabolism of pyrimidines and was reported to act as a transcriptional repressor in a cell type-specific manner. To further elucidate ER functions, we performed the yeast two-hybrid screen of the human lung cDNA library for clones encoding proteins interacting with the human ER protein. The screen yielded polymerase delta interacting protein 46 or S6K1 Aly/REF-like target (PDIP46/SKAR), a protein possessing one RNA recognition motif (RRM) and being a protein partner of both the p50 subunit of DNA polymerase delta and p70 ribosomal protein S6 kinase 1 (S6K1). This interaction was further confirmed in vitro by the glutathione S-transferase-ER pull-down of a protein of 46 kDa from a nuclear extract from human cells which was identified as PDIP46/SKAR by tandem mass spectrometry. The bipartite region of PDIP46/SKAR interacting with ER comprising residues 274-421 encompasses the docking site for S6K1 within the RRM and two serines phosphorylated by S6K1. ER and both isoforms of PDIP46/SKAR share the same nuclear localization in the mammalian cells and their genes display a ubiquitous pattern of expression in a variety of human tissues, so the interaction between ER and PDIP46/SKAR has an opportunity to occur universally in mammalian cells. Because PDIP46/SKAR is involved in the regulation of cell growth its interaction with ER may suggest some function for ER in that control.


Risk factors for posttraumatic stress disorder in persons with spinal cord injury.
Many of the events that cause spinal cord injury (SCI) are traumatic events that can result in posttraumatic stress disorder (PTSD). It therefore appears that most persons with SCI are at risk for developing PTSD. This study retrospectively examined risk factors for PTSD symptoms in a sample of 71 persons with SCI. The Structured Clinical Interview for DSM-IV was used to assess full and partial PTSD diagnoses. Self-administered questionnaires were used to measure potential risk factors. Results indicated that 11% of the participants met the criteria for full PTSD, and an additional 20% met the criteria for partial PTSD at some point after their SCI. Hierarchical linear regression analyses revealed that trauma history, peritraumatic reactions, and intolerance of uncertainty predicted the number of PTSD symptoms. This study highlights the importance of trauma history, peritraumatic reactions, and intolerance of uncertainty in the development of PTSD symptoms. Patients at risk for PTSD should be identified early in the rehabilitation process and could benefit from psychological interventions with the aim of preventing PTSD development.


Neuroleptic malignant syndrome with risperidone.
Neuroleptic malignant syndrome is thought to be a result of dopamine D2 receptor blockade in the striatum of the basal ganglia. Risperidone, a benzisoxazole derivative antipsychotic, has high serotonin 5-HT2 receptor blockade and dose-related D2 receptor blockade. The high ratio is believed to impart the low frequency of extrapyramidal symptoms with risperidone at low dosages. With this low frequency of extrapyramidal symptoms, it was thought the frequency of neuroleptic malignant syndrome might also be lowered. A 73-year-old woman developed neuroleptic malignant syndrome after monotherapy with risperidone. The syndrome reversed after discontinuing risperidone and starting treatment with dantrolene and bromocriptine. It appears that the protection from extrapyramidal side effects observed with risperidone does not ensure protection from neuroleptic malignant syndrome.


Residue pattern of polycyclic aromatic hydrocarbons during green tea manufacturing and their transfer rates during tea brewing.
Residues of polycyclic aromatic hydrocarbons (PAHs) in green tea and tea infusion were determined using gas chromatography-tandem mass spectrometry to study their dissipation pattern during green tea processing and infusion. Concentration and evaporation of PAHs during tea processing were the key factors affecting PAH residue content in product intermediates and in green tea. PAH residues in tea leaves increased by 2.4-3.1 times during the manufacture of green tea using the electric heating model. After correction to dry weight, PAH residue concentrations decreased by 33.5-48.4% during green tea processing because of PAH evaporation. Moreover, spreading and drying reduced PAH concentrations. The transfer rates of PAH residues from green tea to infusion varied from 4.6% to 7.2%, and PAH leaching was higher in the first infusion than in the second infusion. These results are useful for assessing exposure to PAHs from green tea and in formulating controls for the maximum residue level of PAHs in green tea.


Factors determining the smooth flow and the non-operative time in a one-induction room to one-operating room setting.
What factors determine the use of an anaesthesia preparation room and shorten non-operative time? A logistic regression is applied to 18 751 surgery records from AZ Sint-Jan Brugge AV, Belgium, where each operating room has its own anaesthesia preparation room. Surgeries, in which the patient's induction has already started when the preceding patient's surgery has ended, belong to a first group where the preparation room is used as an induction room. Surgeries not fulfilling this property belong to a second group. A logistic regression model tries to predict the probability that a surgery will be classified into a specific group. Non-operative time is calculated as the time between end of the previous surgery and incision of the next surgery. A log-linear regression of this non-operative time is performed. It was found that switches in surgeons, being a non-elective surgery as well as the previous surgery being non-elective, increase the probability of being classified into the second group. Only a few surgery types, anaesthesiologists and operating rooms can be found exclusively in one of the two groups. Analysis of variance demonstrates that the first group has significantly lower non-operative times. Switches in surgeons, anaesthesiologists and longer scheduled durations of the previous surgery increases the non-operative time. A switch in both surgeon and anaesthesiologist strengthens this negative effect. Only a few operating rooms and surgery types influence the non-operative time. The use of the anaesthesia preparation room shortens the non-operative time and is determined by several human and structural factors.


Three-Dimensional Graphene Foam-Filled Elastomer Composites with High Thermal and Mechanical Properties.
To meet the increasing demands for effective heat management of electronic devices, a graphene-based polymeric composite is considered to be one of the candidate materials owing to the ultrahigh thermal conductivity (TC) of graphene. However, poor graphene dispersion, low quality of exfoliated graphene, and strong phonon scattering at the graphene/matrix interface restrict the heat dissipation ability of graphene-filled composites. Here, a facile and versatile approach to bond graphene foam (GF) with polydimethylsiloxane (PDMS) is proposed, and the corresponding composite with considerable improvement in TC and insulativity is fabricated. First, three-dimensional GF was coated with polydopamine (PDA) via π-π stack and functional groups from PDA reacted with 3-aminopropyltriethoxysilane (APTS). Then, the modified GF was compressed (c-GF) to enhance density and infiltrated with PDMS to get the c-GF/PDA/APTS/PDMS composite. As a result, these processes endow the composite with high TC of in-plane 28.77 W m-1 K-1 and out-of-plane 1.62 W m-1 K-1 at 11.62 wt % GF loading. Besides, the composite manifests obvious improvement in mechanical properties, thermal stability, and insulativity compared to neat PDMS and GF/PDMS composite. An attempt to use the composite for cooling a ceramic heater is found to be successful. Above results open a way for such composites to be applied for the heat management of electronic devices.


Speed your diagnosis of this gallbladder disorder.
Fatty infiltration of the internal organs--and the inflammation associated with it--is an increasingly common cause of gallbladder dysfunction. Here's what to keep in mind to identify it without delay.


Tumor-Associated High Endothelial Venules: Inroads Enabling Immune Control of Cancer Progression.
Infiltration of lymphocytes into solid tumors represents a significant bottleneck to successful control of tumor growth. The nature of tumor blood vessels is an important factor governing both quantitative and qualitative features of the immune infiltrate. In this issue, Sawada and colleagues identify a genetic signature for blood vessels, most notably high endothelial venules, which are associated with tertiary lymphoid structures and improved clinical outcome. See related article by Sawada et al., p. 468 (4).


Anti-infective mode of action of EPs 7630 at the molecular level.
Clinical trials have shown that EPs 7630, an aqueous ethanolic extract from the roots of Pelargonium sidoides, is an efficacious treatment for respiratory tract infections. A large body of in vitro studies has provided evidence for an anti-infective principle associated with activation of the non-specific immune system. However, the mode of action at the cellular and molecular level is still insufficiently defined. This study, therefore, aimed to provide further insight into the underlying principles of the therapeutic benefits of EPs 7630 under these conditions. Using BMM phi experimentally infected with intracellular bacteria, Listeria monocytogenes, incubation with EPs 7630 (1 - 30 micro increased release of NO, production of membrane bound/intra- and extracellular IL-1, IL-12 and TNF-alpha and changed the expressions of the surface markers CD40 and CD119 at an early time point post infection (6 h) in a concentration-dependent manner in most experiments. Compared with non-infected cells, the effects were more pronounced. LPS + IFN-gamma served as positive and untreated cells as negative controls. Analyses were carried out at single cell levels using flow cytometry, while ELISA was additionally utilized for monitoring secreted cytokines. Although the current data provide additional valuable information for understanding the anti-infective effects of EPs 7630, the triggered signalling pathways associated with host immune responses appear even more complex than anticipated and are evidently not shared by 'classical' immunomodulators to this extent.


Convergent validity of the MCMI-III personality disorder scales and the MMPI-2 scales.
The MCMI-III personality disorder scales (Millon, 1994) were empirically validated in a sample of prisoners, psychiatric inpatients, and outpatients (N = 477). The scale intercorrelations were congruent with those obtained by Millon, Davis, and Millon (1997). We conclude that our Flemish/Dutch version shows no significant differences with the original version of the MCMI-III as far as intercorrelations are concerned. Convergent validity of the MCMI-III personality disorder scales was evaluated by the correlational data between the MCMI-III personality disorder scales and the MMPI-2 clinical (Butcher, Dahlstrom, Graham, Tellegen, & Kaemmer, 1989) and personality disorder (Somwaru & Ben-Porath, 1995) scales. Improved convergence was obtained compared with previous versions of the MCMI-I. Only the compulsive MCMI-III personality disorder scale remains problematic. The scale even showed negative correlations with some of the related clinical scales and with the corresponding personality disorder scales of the MMPI-2.


Association Between Body Mass Index and Mildly Decreased Estimated Glomerular Filtration Rate in Chinese Adults With Early Chronic Kidney Disease.
The magnitude of the influence that obesity contributes to the early stage of chronic kidney disease, especially among Asian population with higher obesity-related health risk, is unclear. The aim of this study was to investigate the association between body mass index (BMI) and mildly decreased estimated glomerular filtration rate (eGFR) among Chinese population. A cross-sectional study was conducted among 1,100 subjects under health screenings. BMI was used to classify overweight and obesity as a BMI greater than or equal to 23.0 kg/m2 and 25.0 kg/m2, respectively. Mildly decreased eGFR was defined as 60.0 to ≤89.0 mL/min/1.73 m2 based on modification of diet in renal disease Chinese equation. The prevalence of mildly decreased eGFR was increased significantly with increasing BMI categories. According to modification of diet in renal disease Chinese equation, obesity (odds ratio, 1.83; 95% confidence interval: 1.15-2.90) was positively associated with the odds of mildly decreased eGFR in the multivariate logistic regression model. BMI was significantly and negatively related to eGFR, and each increase in BMI (1.0 kg/m2) was associated with a decline in eGFR of 0.5 mL/min/1.73 m2. In subgroup analyses, BMI remained associated with an increased likelihood of mildly decreased eGFR independent of hypertension and diabetes. There was a positive relationship between BMI and mildly decreased eGFR among Chinese adults. Higher BMI may play a role in the onset and progression of renal damage, and maintaining a BMI in the healthy range may be contributed to the prevention of chronic kidney disease.


Use of standard diagnostic techniques to determine eradication of infection in experimental equine septic arthritis.
Septic arthritis is an important disease in horses, necessitating aggressive and prolonged therapy. In order to guide therapy, reliable methods of detecting the eradication of infection are needed. Therefore, the objective of this study was to investigate detection of eradication of infection in an experimental model of equine septic arthritis using standard diagnostic techniques. For this purpose, 17 adult horses were assigned to 3 experimental groups. The middle carpal joint of each horse was injected with Escherichia coli (Septic group, n = 8), lipopolysaccharide (LPS) (LPS group, n = 6), or sterile saline (Control group, n = 3) at day 0. Contralateral joints were not injected. Standard therapy was applied to all joints except non-injected joints in the Control group at day 1. Sequential samples of synovial fluid (SF) were collected for bacterial culture using 3 culture media [Columbia blood agar (CBA), brain heart infusion broth (BHI), and Signal blood culture medium] and for cytological evaluation [percentage neutrophils (PN), total nucleated cell count (TNCC), and total protein (TP)]. Escherichia coli-specific polymerase chain reaction (PCR) was carried out to detect E. coli DNA in synovial fluid. Culture and PCR were positive for E. coli in all joints injected with E. coli at day 1 and 1 joint was positive on BHI at day 4. Based on the results of bacterial culture, PCR, and TNCC, the elimination of infection in our experimental model occurred by day 4 post-infection in 6 out of 7 cases. Total protein (TP) and PN remained elevated at clinical threshold used for diagnosis of septic arthritis until day 14. In our experimental model of E. coli-induced arthritis, we conclude that TP and PN may not be good indicators for detecting the eradication of bacterial infection caused by E. coli from infected and subsequently treated joints.


Vape and Aviate: Electronic-Cigarette Use and Misuse in Naval Aviation.
Electronic cigarettes (EC) are an emerging form of nicotine replacement that has had a discernible increase in prevalence in the general population. Little is known regarding EC use among different military demographic groups or the extent of influence that social determinants of health may have on the behavior. The purpose of this study was to assess the prevalence and correlates of EC use in a select population of active duty U.S. Naval personnel. This study is unique in that it allows for EC behavior comparison between a traditionally healthy demographic (aviators, a subset of aircrew) and a representative general military population sample. Cross-sectional survey data were collected anonymously and analyzed in 2015-2016. Active duty Naval personnel (n = 977) were asked about ever trying ECs, frequency of use, and when was the last time an EC was used. Participants were assessed similarly regarding cigarette use. Descriptive and inferential statistics as well as multinomial logistic regression analyses were conducted using categorical and ordinal variables assigned to usage and demographic factors. This protocol was approved by the Institutional Review Board at Naval Hospital Portsmouth located in Portsmouth, Virginia. Within the study population, 31.4% have tried ECs, 9.3% were current users, and only 3.8% were dual (EC and cigarettes) users. EC use was significantly associated with paygrade (enlisted), primary job duty (non-aircrew), and education (less than a bachelor degree, p < 0.001, p < 0.01, and p < 0.001, respectively). ECs were used at some point as a smoking cessation tool for 43.6% of current EC users (p < 0.001), 21.6% of current smokers, and only 5.6% of former smokers. Continued EC use after ever trying ECs (30.0%) was only slightly more prevalent as continued cigarette use after ever trying cigarettes (27.3%). Smokers were nearly five times more likely to currently use ECs compared with non-smokers. Trying cigarettes was associated with nearly 12 times the risk for trying ECs compared with those who never tried cigarettes. No significant misuse of ECs was noted; however, several cases of drinking, tasting, and touching EC fluid were reported. This study is unique in that it examines the use of electronic cigarettes among selected healthy and baseline groups within the active duty U.S. Navy population. The current prevalence of EC use among active duty personnel is much higher than previously thought. Continued use of ECs after ever trying them appears to exceed that of cigarettes even among healthy populations such as aircrew. The findings of increased risk of EC use among those with lower income and less than a bachelor's degree suggest social determinants of health implications. This study sheds new light on EC use, characteristics of use, addiction implications, and highlights concerns for a growing health risk behavior.


Artificial spermatocele inserted onto the vas deferens: a clinical report.
This procedure was devised in an attempt to treat azoospermia caused by severe vas obstruction. An artificial spermatocele is prepared by resection of the vas slightly distal to the epididymal-deferential ansa and anastomosing onto its proximal stump a piece of Dardik's prosthesis sealed at the far end. During the partner's ovulatory period the spermatocele fluid is aspirated, mixed with fertile donor seminal plasma and used for artificial insemination. To date 8 subjects have had the operation: spermatocele fluids of 4 contained some highly motile spermatozoa with normal ability to penetrate cervical mucus for some months. Spermatocele implantation onto the vas apparently has the following advantages: the anatomic and functional integrity of the epididymis is maintained, the storage function of the epididymal-deferential ansa is preserved, and the risk of spermatocele collapse seems to be reduced by the high "vis a tergo" developed during ejaculation.


Older adults' help-seeking attitudes and treatment beliefs concerning mental health problems.
Older adults with mental health problems are especially unlikely to seek professional mental health services. It is not clear, however, whether their help-seeking attitudes and treatment beliefs contribute to this problem. The objectives of this study were to compare older adults' attitudes and beliefs to younger adults' and to examine the influence of age on these variables after controlling for other demographic variables, prior help-seeking, and mental disorders. The authors analyzed cross-sectional data from Part 2 of the National Comorbidity Survey Replication. This dataset includes 5,692 community-dwelling adults, including 1,341 adults who were 55 years of age and older. Participants responded to three questions assessing attitudes toward seeking professional mental health services and one question examining beliefs about the percentage of people with serious mental health concerns who benefit from professional help. The authors used logistic regression to predict positive versus negative attitudes and beliefs from age, gender, education, and race/ethnicity, as well as prior help seeking and mood and/or anxiety disorder diagnosis. Overall, more than 80% of participants exhibited positive help-seeking attitudes and more than 70% reported positive treatment beliefs. In contrast to the modest effect of age on beliefs, adults 55-74 years of age were approximately two to three times more likely to report positive help-seeking attitudes than younger adults. Older adults' positive attitudes and treatment beliefs are unlikely barriers to their use of mental health services. This finding, which is consistent with recent positive views of aging, suggests that enabling resources and need factors are more likely explanations for older adults' low rates of mental health service use.


New Insights in Gene Expression Alteration as Effect of Paclitaxel Drug Resistance in Triple Negative Breast Cancer Cells.
Triple negative breast cancer (TNBC) is a highly aggressive form of cancer which lacks targeted therapy options. Thus, TNBC patients have poor outcomes and a decreased survival rate than patients with other types of breast cancers. Due to the lack of surface receptors, TNBC needs a comprehensive investigation to provide more information regarding patient's therapy, as well as to understand the way how to counteract drug resistance mechanisms. Nowadays, chemotherapy remains an unsolved issue which rise a lot of questions in oncology field. In this article, we investigated the implication of paclitaxel in TNBC cell lines after a prolong administration, after 12, respectively 24 passages followed by evaluation of morphological alteration, mutational pattern by next generation sequencing and the altered gene expression pattern by microarray technology and validation by qRT-PCR of the resistance to therapy relevant genes. Using functional assays, we showed that paclitaxel exhibits antiproliferative activity on Hs578T/Pax and MDA-MB-231/Pax demonstrating the activation of cell death mechanisms. Confocal microscopy revealed significant modifications which occur in the morphological structure with a disruption of the actin-filaments and also mitotic catastrophe. The presence of these nuclear alterations is due to some modifications at the cellular and molecular levels. Important alterations at the transcriptomic and genomic levels were observed from this a common drug resistance signature (IL-6, CXCL8, VEGFA, EGR1, PTGS2 and TRIB1) for both cell lines at 24 passages was discovered. Also, an important mutation (TP53) linked with drug response was identified. These results might be used to furnish novel biomarkers in TNBC, as well as to find a strategy to counteract the resistance to therapy in order to increase survival rate and to enhance the prognosis of patients with TNBC.


Aetiological and epidemiological aspects of acute head injury in Malawi.
One hundred and four patients (88 males and 16 females) with acute head injuries admitted to the Queen Elizabeth Central Hospital, Blantyre from July 1st to December 31st 1995 were prospectively studied using a questionnaire. Forty seven (45.2%) of the injuries were caused by road traffic accidents, 42(40.4%) by assaults, nine (8.7%) resulted from falls from heights, two (1.9%) from occupational injuries and the remaining four (3.8%) were of miscellaneous origins. RTA associated head injuries involved 17 (36.2%) pedestrians; 14 (29.8%) vehicular passengers, 10 (21.3%) pedal cyclists; five (10.6%) drivers and one motor cyclist. Malawi males aged between 20 and 29 were mostly involved. Assault related head injuries occurred also in young adult males commonly at the weekend with more than 50% occurring on Saturday and Sunday. Fifty per cent were sustained at home, a quarter on the streets and surprisingly few at drinking houses making them the safest place to be in Malawi to avoid assaults! Alcohol usage was not statistically significant among those assaulted; it was not possible to define its aetiological role among assailants. The head injuries associated with falls from heights (FFH) involved eight males and one female; five were children. Strategies for the prevention of assaults, the various types of road traffic accidents and falls from heights are discussed.


Mosquito-Borne Diseases and Omics: Salivary Gland Proteome of the Female Aedes aegypti Mosquito.
The female Aedes aegypti mosquito is an important vector for several tropical and subtropical diseases such as dengue, chikungunya, and Zika and yellow fever. The disease viruses infect the mosquito and subsequently spread to the salivary glands after which the viruses can be transmitted to humans with probing or feeding by the mosquito. Omics systems sciences offer the opportunity to characterize vectors and can inform disease surveillance, vector control and development of innovative diagnostics, personalized medicines, vaccines, and insecticide targets. Using high-resolution mass spectrometry, we performed an analysis of the A. aegypti salivary gland proteome. The A. aegypti proteome resulted in acquisition of 83,836 spectra. Upon searches against the protein database of the A. aegypti, these spectra were assigned to 5417 unique peptides, belonging to 1208 proteins. To the best of our knowledge, this is the largest set of proteins identified in the A. aegypti salivary gland. Of note, 29 proteins were involved in immunity-related pathways in salivary glands. A subset of these proteins is known to interact with disease viruses. Another 15 proteins with signal cleavage site were found to be secretory in nature, and thus possibly playing critical roles in blood meal ingestion. These findings provide a baseline to advance our understanding of vector-borne diseases and vector-pathogen interactions before virus transmission in global health, and might therefore enable future design and development of virus-blocking strategies and novel molecular targets in the mosquito vector A. aegypti.


Contaminants in fish: risk-benefit considerations.
Fish provide a healthful source of dietary protein and are high in nutrients such as omega-3 fatty acids. There is evidence of beneficial effects of fish consumption in coronary heart disease, stroke, age-related macular degeneration, and growth and development. Yet, benefits may be offset by the presence of contaminants, such as methylmercury (MeHg), dioxins, polychlorinated biphenyls (PCBs) and several other halogenated persistent organic pollutants. MeHg is a known developmental neurotoxicant, as evidenced by several animal studies and episodes of human intoxication in Japan and Iraq. Fish represent the main source of exposure to MeHg for the general population, and large predatory fish (swordfish, tuna) have the highest levels of MeHg contamination. Provisional tolerable weekly intakes of 0.7 microg kg(-1) to 1.6 microg kg(-1) have been set by regulatory agencies. Concern for contamination of fish with dioxins and dioxin-like PCBs stems from their reported carcinogenicity, immunotoxicity, and reproductive and developmental toxicities. Farmed and wild-caught fish appear to have similar levels of contaminants. Advisories are in place that recommend limited consumption of certain fish in children, pregnant women and women of childbearing age. Careful risk-benefit considerations should foster fish consumption while minimizing exposure to toxic contaminants.


Permissive action of triiodothyronine on the long-term increase of glycolysis by insulin in cultured rat hepatocytes.
The long-term influence of triiodothyronine (T3) and insulin on glycolysis, some glycolytic/gluconeogenic enzymes and insulin responsiveness and sensitivity was investigated in rat hepatocytes cultured for 48 h without T3, with 10 microM T3, with 10nM insulin and with insulin plus T3. From 48 h-51 h basal glycolysis ([14C]lactate formation from [14C]glucose) was measured in the absence and short-term insulin-stimulated glycolysis in the presence of 100 nM insulin. 1) T3 addition for 48 h had no significant influence on basal or on insulin-stimulated glycolysis. 2) Insulin addition for 48 h increased basal glycolysis to 300%, and insulin-stimulated glycolysis to 160%. 3) T3 plus insulin addition for 48 h elevated basal glycolysis to 560% and insulin-stimulated glycolysis to 230%. 4) The 48-h treatment with T3 did not change glucokinase (GK) and pyruvate kinase (PK) activity, yet it increased phosphoenol-pyruvate carboxykinase (PEPCK) activity to 150%. 5) The 48-h treatment with insulin as well as T3 plus insulin enhanced GK to 200% and PK to 140% and decreased PEPCK to 65%. 6) The long-term effect of T3 on glycolysis was maximal at initial concentrations of 100 nM. 7) The long-term treatment with T3 did not alter the short-term responsiveness or sensitivity of glycolysis for insulin, neither in cells from euthyroid nor from hypothyroid rats. The present results allow the conclusion that T3 had a permissive effect on the long-term increase of glycolysis by insulin, and that T3 exerted this function by altering neither the cellular content of key enzymes nor the short-term insulin responsiveness and sensitivity.


Localization and Diagnostic Evaluation of Peripheral Nerve Disorders.
This article provides a framework for the initial evaluation of patients with suspected peripheral nerve disease. The key clinical elements of peripheral nerve diseases can help the practicing neurologist differentiate among peripheral neuropathies with similar presentations. The wide range of peripheral nerve diseases with similar clinical presentations can pose a diagnostic challenge. The large array of available testing modalities (including imaging and electrodiagnostic, autonomic, laboratory, biopsy, and genetic testing) further complicates clinical decision making. Recent developments (eg, discovery of new autoantibodies, genetic variations, and histopathologic techniques) across the peripheral neuropathy spectrum have resulted in an increased need to evaluate patients logically and with a tailored diagnostic approach. A careful approach that focuses on key clinical elements combined with an understanding of purposeful diagnostic testing can lead to a successful diagnosis of peripheral nerve diseases.


Repeated Aborted Sudden Cardiac Death with Long QT Syndrome in a Patient with Anomalous Origin of the Right Coronary Artery from the Left Coronary Cusp.
A 15-year-old female with a prior history of aborted cardiac death and surgical correction of anomalous origin of the right coronary artery (RCA) presented with polymorphic ventricular tachycardia. Her electrocardiogram after defibrillation was suggestive of congenital long QT syndrome (LQTS). The patient was treated with a β-blocker and remained free from ventricular arrhythmia during the follow-up of more than 6 months. Here, we present the case of a young female with repeated aborted cardiac death accompanied by anomalous origin of the RCA and congenital LQTS for the first time.


Diode Laser in the Management of Foliate Papillitis - Two Case Reports.
The human tongue consists of various kinds of papillae which form its characteristic morphology. Among these papillae, the foliate papillae may become enlarged and inflamed causing a condition called as foliate papillitis. The treatment of this disease includes relieving all causes of trauma such as sharp teeth, ill-fitting dentures, etc., to the region. However, for several patients, the symptoms of foliate papillitis remain even after the conservative treatment is done. For two of these patients, we have used IMDSL dental diode laser of 980 nm to ablate the enlarged foliate papillae to relieve the symptoms of pain. Both the patients were recalled after one month during which time they were free of symptoms with total healing of the ablated site. One year later, during follow-up, both the patients remained symptom free. We believe this is the first time that diode laser has been used for the treatment of foliate papillitis.


Neurotropic melanoma: an analysis of the clinicopathological features, management strategies and survival outcomes for 671 patients treated at a tertiary referral center.
Neurotropic cutaneous melanoma is a rare melanoma subtype that invades nerves and is often associated with desmoplastic melanoma. Limited data suggest that it has a greater propensity to recur locally, but it is unknown whether its behavior differs from that of other melanoma subtypes, including desmoplastic melanoma. We investigated clinicopathological predictors of outcome in a cohort of 671 patients with neurotropic melanoma to develop evidence-based management recommendations. Patients with primary neurotropic melanoma diagnosed from 1985 to 2013 were identified from the Melanoma Institute Australia database, along with a control cohort of 718 non-neurotropic melanoma patients. Features predictive of sentinel lymph node status, recurrence, melanoma-specific survival and response to adjuvant radiotherapy were sought. Neither local recurrence (hazard ratio: 1.28 (0.73-2.25) P=0.39) nor melanoma-specific survival (hazard ratio: 0.79 (0.55-1.15) P=0.22) were significantly affected by the presence of neurotropism on multivariate analysis. However, there was a markedly reduced likelihood of sentinel node positivity (hazard ratio: 0.61 (0.41-0.89) P=0.01) in neurotropic melanoma patients. Surgical margins ≥8mm halved the recurrence risk compared with <2 mm margins (hazard ratio: 0.46 (0.31-0.68) P<0.001). Additionally, in neurotropic melanoma patients with <8 mm margins, adjuvant radiotherapy halved the recurrence risk (hazard ratio: 0.48 (0.27-0.87) P=0.02). This, the largest study of neurotropic melanoma reported to date, has demonstrated that the presence of neurotropism does not alter the risk of melanoma recurrence or survival but does reduce the likelihood of sentinel node positivity. For successful treatment of neurotropic melanoma, adequate excision margins are of paramount importance. However, when adequate margins cannot be achieved, adjuvant radiotherapy reduces the risk of recurrence.


Mechanism of anode break stimulation in the heart.
Anodal stimulation is routinely observed in cardiac tissue, but only recently has a mechanism been proposed. The bidomain cardiac tissue model proposes that virtual cathodes induced at sites distant from the electrode initiate the depolarization. In contrast, none of the existing cardiac action potential models (Luo-Rudy phase I and II, or Oxsoft) predict anodal stimulation at the single-cell level. To determine whether anodal stimulation has a cellular basis, we measured membrane potential and membrane current in mammalian ventricular myocytes by using whole-cell patch clamp. Anode break responses can be readily elicited in single ventricular cells. The basis of this anodal stimulation in single cells is recruitment of the hyperpolarization-activated inward current I(f). The threshold of activation for I(f) is -80 mV in rat cells and -120 mV in guinea pig or canine cells. Persistent I(f) "tail" current upon release of the hyperpolarization drives the transmembrane potential toward the threshold of sodium channels, initiating an action potential. Time-dependent block of the inward rectifier, I(K1), at hyperpolarized potentials decreases membrane conductance and thereby potentiates the ability of I(f) to depolarize the cell on the break of an anodal pulse. Inclusion of I(f), as well as the block and unblock kinetics of I(K1), in the existing Luo-Rudy action potential model faithfully reproduces anode break stimulation. Thus active cellular properties suffice to explain anode break stimulation in cardiac tissue.


Temporal Trend of Transient Ischemic Attack Management over a 10-Year Period: Data from the Rhône County, France.
Timely recognition and management of transient ischemic attack (TIA) offer the greatest opportunity to prevent subsequent stroke. But variability of TIA management quality exists across hospitals. Under the impetus of national plans, measures were adopted to improve TIA management, including a structured local pathway. Our objective was to compare TIA management between two periods over 10 years, before and after the implementation of these measures. A before-and-after study was conducted with two identical population-based cohort studies in 2006-2007 (AVC69) and 2015-2016 (STROKE69) including all patients with TIA diagnosis over a 7-month period in six public and private hospitals in the Rhône county in France. The primary outcome was the adequate TIA management defined as brain and vessel imaging within 24 h of admission and the prescription of antithrombotic treatment at discharge. We identified 109 patients TIA patients in 2006-2007, and 458 over the same period in 2015-2016. A higher proportion of patients were adequately managed in 2015-2016 compared to 2006-2007 (14/96 [15%] in 2006-2007 vs. 306/452 [68%] in 2015-2016, p < 0.001). This difference was mainly driven by a marked increase of vessel imaging performed within 24 h of admission, most often by computed tomography angiography. Furthermore, patients called more often emergency medical dispatch before admission, were admitted with a shorter delay after symptom onset, and were more likely discharged to home in 2015-2016 compared to 2006-2007. Our study demonstrated an increasing rate of adequate TIA management, mainly driven by a marked increase of vessel imaging within 24 h of admission, over a 10-year period in the Rhône county in France.


Corneal changes after small-incision cataract surgery in patients with diabetes mellitus.
To evaluate functional impairment in the corneal endothelium of eyes in patients with diabetes mellitus, after small-incision cataract surgery. Evaluation was performed in 93 eyes in patients with type 2 diabetes mellitus (diabetic group) and 93 eyes in patients without diabetic mellitus (nondiabetic group) who underwent cataract surgery. Using a topography system, the corneal thickness in the central area was measured before surgery and 1 day, 1 week, and 1 month after surgery. Corneal endothelial cells were counted using a noncontact specular microscope. No significant differences in any preoperative measures were observed between the diabetic and nondiabetic groups. The increase in corneal thickness 1 month after surgery was significantly higher in the diabetic group than in the nondiabetic group (P =.03). The corneal endothelial cell losses 1 day and 1 week after surgery were significantly higher in the diabetic group than in the nondiabetic group (after 1 day, P =.03; and after 1 week, P =.04). Compared with nondiabetic eyes, eyes of patients with diabetes mellitus showed more damage in corneal endothelial cells due to cataract surgery and a delay in the postoperative recovery of corneal edema.


Influence of life event stress on physical illness: substantive effects or methodological flaws?
This study tests the hypothesis that the reported relationship between life event stress and physical illness is primarily a function of criterion and other content contamination in the stress measure. In particular, conventional life event measures include events related to physical health, which overlap with the criterion; events related to neuroticism, which influences the criterion; and events that are vague or subjective and could be affected by individual differences in psychological distress, response sets, and retrospective bias. In this study 386 adult males and females completed standard measures of life events and physical illness. Illness was significantly related to event subscales containing, respectively, health-related events, neuroticism-related events, and subjective events, but not to an "uncontaminated" event subscale. These results support the hypothesis of contamination and suggest that alternative approaches to the conceptualization and measurement of stress may need to be developed.


Synthesis and biological evaluation of new citrate-based siderophores as potential probes for the mechanism of iron uptake in mycobacteria.
Several iron chelators containing alpha,beta-unsaturated hydroxamic acid motifs appended to a citric acid platform were synthesized. Mycobacterium paratuberculosis was then challenged to grow in the presence of a panel of siderophores (mycobactin J, deferrioxamine B, acinetoferrin, and nannochelin A) and the new synthetic agents. Of the structures tested, those containing the trans 2-octenoyl motif were preferred over those with trans cinnamoyl groups. In addition, derivatives containing longer tether lengths between the iron binding ligands (C5) were more efficacious and led to higher growth index values. Perhaps most remarkable was the finding that at 2.4 microM a trans 2-octenoylated, citrate-containing imide 6 was nearly 5-fold more effective in stimulating growth than the native chelator, mycobactin J. In this regard, new structural elements were identified (e.g., an imide motif or 2-octenoyl side chain), whose presence stimulated mycobacterial growth.


Successful Virtual Delivery of a Group Childhood Healthy Weight Program.
Because of the COVID-19 pandemic, the Get Up & Go program, an established effective 10-week healthy weight program for children ages 6-14 years provided free to families, has offered the option of a synchronous virtual delivery. Pre- and postassessments include a parental questionnaire about child's health behaviors, and weight and height measurements of children. Over 3 cycles, 116 and 107 families registered for virtual and in-person delivery, respectively, with 70 (60.3%) and 84 (78.5%) attending ≥1 session (p = 0.003). More families in virtual delivery spoke Spanish (41.4% vs. 22.6%, p = 0.01), but children did not differ in age, gender, and severe obesity status, and baseline behavior scores and graduation rates were similar. Improvement from baseline in BMIp95 was -3.71 [standard deviation (SD) 5.26] for virtual delivery and -1.95 (3.69) (p = 0.06) for in-person. Behavior questionnaire improvement [+15.9 (12.9) vs. +14.2 (12.0), p = 0.51] did not differ. The virtual implementation demonstrated good effect and may be useful in nonpandemic environments.


Elucidating the interaction of clofazimine with bovine liver catalase; a comprehensive spectroscopic and molecular docking approach.
Nowadays, understanding of interface between protein and drugs has become an active research area of interest. These types of interactions provide structural guidelines in drug design with greater clinical efficacy. Thus, structural changes in catalase induced by clofazimine were monitored by various biophysical techniques including UV-visible spectrometer, fluorescence spectroscopy, circular dichroism, and dynamic light scattering techniques. Increase in absorption spectra (UV-visible spectrum) confers the complex formation between drug and protein. Fluorescence quenching with a binding constants of 2.47 × 104 M-1 revealed that clofazimine binds with protein. Using fluorescence resonance energy transfer, the distance (r) between the protein (donor) and drug (acceptor) was found to be 2.89 nm. Negative Gibbs free energy change (ΔG°) revealed that binding process is spontaneous. In addition, an increase in α-helicity was observed by far-UV circular dichroism spectra by adding clofazimine to protein. Dynamic light scattering results indicate that topology of bovine liver catalase was slightly altered in the presence of clofazimine. Hydrophobic interactions are the main forces between clofazimine and catalase interaction as depicted by molecular docking studies. Apart from hydrophobic interactions, some hydrogen bonding was also observed during docking method. The results obtained from the present study may establish abundant in optimizing the properties of ligand-protein mixtures relevant for numerous formulations.


Heparin binding induces a conformational change in pigment epithelium-derived factor.
Pigment epithelium-derived factor (PEDF) is a noninhibitory serpin found in plasma and in the extracellular space. The protein is involved in different biological processes including cell differentiation and survival. In addition, it is a potent inhibitor of angiogenesis. The function is likely associated with binding to cell surface receptors in a heparin-dependent way (Alberdi, E. M., Weldon, J. E., and Becerra, S. P. (2003) BMC Biochem. 4, 1). We have investigated the structural basis for this observation and show that heparin induces a conformational change in the vicinity of Lys(178). This structural change was evident both when binding to intact heparin and specific heparin-derived oligosaccharides at physiological conditions or simply when exposing PEDF to low ionic strength. Binding to other glycosaminoglycans, heparin-derived oligosaccharides smaller than hexadecasaccharides (dp16), or type I collagen did not affect the structure of PEDF. The conformational change is likely to expose the epitope involved in binding to the receptor and thus regulates the interactions with cell surface receptors.


An UPLC-MS detection method for the quantification of five antibiotics in human plasma.
An UPLC-MS detection method for the quantification of amikacin, flucloxacillin, meropenem, penicillin G and vancomycin was developed and validated. The calibration curves were found to be linear from 0.47 to 50 mg/l for amikacin, 1.28 to 135 mg/l for flucloxacillin, 0.75 to 80 mg/l for meropenem, 0.38 to 80 mg/l for penicillin G and 0.73 to 80 mg/l for vancomycin. Between- and within-run accuracy was ranged between 85 and 115%. Between and within imprecision expressed as CV was within 15%. The validated method was successfully applied to a PK study in very preterm and small for gestational age infants treated for nosocomial sepsis and/or meningitis.


SNAP-tagging live cells via chelation-assisted copper-catalyzed azide-alkyne cycloaddition.
SNAP-tag is a single-turnover enzyme that has become a powerful tool, hence a popular choice, of targeted cellular protein labeling. Three SNAP-tag substrates that carry the copper-chelating 2-picolyl azide moiety are prepared, one of which has an unconventional 5-pyridylmethyl-substituted guanine structure, rather than the usual benzylguanine that is optimized to be accepted by SNAP-tag. All three substrates are effective in transferring a 2-picolyl azide moiety to SNAP-tag in live cells under conventional labeling conditions (30-minute incubation of cells with labeling reagents at 37 °C under 5% CO2). Live cells that are decorated with chelating azido groups on the extracellular side of membranes undergo copper-catalyzed azide-alkyne cycloaddition (CuAAC) with an ethynyl-functionalized fluorophore to accomplish membrane protein labeling by a fluorescent dye. The chelation-assisted CuAAC labeling step is rapid (<1 minute) with a relatively low dose of the copper catalyst (20 μM), and consequently exerts no ill effect on the labeled cells. A SNAP-tag substrate that carries a non-chelating azide moiety, on the other hand, fails to produce satisfactory labeling under the same constraints. The rapid, live cell-compatible SNAP-tag/chelation-assisted CuAAC two-step method expands the utility of SNAP-tag in protein labeling applications.


Internal structure changes of eyelash induced by eye makeup.
To investigate how eye makeup affects eyelash structure, internal structure of eyelashes were observed with a scanning X-ray microscopic tomography system using synchrotron radiation light source. Eyelash samples were obtained from 36 Japanese women aged 20-70 years and whose use of eye makeup differed. Reconstructed cross-sectional images showed that the structure of the eyelash closely resembled that of scalp hair. The eyelash structure is changed by use of eye makeup. There was a positive correlation between the frequency of mascara use and the degree of cracking in cuticle. The positive correlation was also found between the frequency of mascara use and the porosity of the cortex. By contrast, the use of eyelash curler did not affect the eyelash structure with statistical significance.


Synthetic High-Density Lipoprotein-Based Nanomedicine to Silence SOCS1 in Tumor Microenvironment and Trigger Antitumor Immunity against Glioma.
Immunotherapies have shed light on the treatment of many cancers, but have not improved the outcomes of glioma (GBM). Here, we demonstrated that suppressor of cytokine signaling 1 (SOCS1) was associated with the GBM-associated immunosuppression and developed a multifunctional nanomedicine, which silenced SOCS1 in the tumor microenvironment (TME) of GBM and triggered strong antitumor immunity against GBM. Synthetic high-density lipoprotein (sHDL) was selected as the nanocarrier and a peptide was used to facilitate the blood-brain-barrier (BBB) penetration. The nanocarrier was loaded with a small interfering RNA (siRNA), a peptide, and an adjuvant to trigger antitumor immunity. The nanomedicine concentrated on the TME in vivo, further promoting dendritic cell maturation and T cell proliferation, triggering strong cytotoxic T lymphocyte responses, and inhibiting tumor growth. Our work provides an alternative strategy to simultaneously target and modulate the TME in GBM patients and points to an avenue for enhancing the efficacy of immunotherapeutics.


A prototypicality validation of the Comprehensive Assessment of Psychopathic Personality model (CAPP).
Cooke and colleagues recently developed the lexically based model of psychopathy named the Comprehensive Assessment of Psychopathic Personality (CAPP, Cooke, Hart, Logan, & Michie, 2004). The current study was the first to evaluate aspects of the validity of a translated version of the CAPP model, which comprises 33 symptoms from six domains of personality functioning. Prototypicality ratings from 796 Norwegian community residents, forensic mental health professionals, and corrections professionals were obtained. Most CAPP symptoms were evaluated as highly prototypical of psychopathy by all three groups. Symptoms from the Self, Dominance, and Attachment domains were perceived as more prototypical than those from the Behavioral domain. Confirmatory Factor Analysis (CFA) indicated that two CAPP domains were unidimensional whereas evidence of unidimensionality was somewhat weaker for the other domains, but improved substantially after removal of problematic symptoms. Overall, the findings support the content validity of the CAPP model. This may have relevance to the current considerations regarding reformulation of the criteria for Antisocial Personality Disorder in DSM-V.


[Stable isotopes of zooplankton and their applications in the research of aquatic ecosystems].
Zooplankton plays a mediating role in the food web of aquatic ecosystems, the stable carbon and nitrogen isotopes (δ13C and δ15N) of which have been widely used to study the utilization of food resources, material cycling pathways, and trophic relationships. The δ13C and δ15N values of zooplankton have been used to predict primary productivity, sources and sinks of pollutants and environmental changes. To better use δ13C and δ15N of zooplankton as ecological and environmental indicators, it is particularly important to understand their temporal and spatial variations and the influencing factors. Based on related literature, we synthesized spatial and temporal variations in δ13C and δ15N of zooplankton in different aquatic ecosystems and taxa groups, and the use of δ13C and δ15N indicators for ecological processes and environmental changes. The δ13C and δ15N of zooplankton are largely affected by its food sources, and its stable isotope compositions are in turn affected by primary productivity and nitrogen sources. We proposed that the combination of δ13C and δ15N in zooplankton with transportation and transformation of emerging pollutants would form a multi-means, multi-disciplinary and multi-scale research direction in the fields of earth science and biology.


Squamous Cell Lung Cancer Associated With Systemic Sclerosis.
We here describe a 50-year-old woman diagnosed with squamous cell lung cancer (SqLC) with underlying interstitial lung disease (ILD) 14 years after a diagnosis of systemic sclerosis (SSc). We reviewed the literature and collected 21 well-documented cases with SqLC associated with SSc including the present case. Several characteristics of SqLC associated with SSc have been found. First, the average age at diagnosis of SqLC is 57 years, which is much younger than that reported for patients without SSc. Second, SqLC could occur even in never or light smokers, although SqLC usually has a strong association with smoking history. Third, two-thirds of the available cases have ILD. In addition, SqLC developed in the area of ILD in most cases with ILD. Fourth, SqLC generally occurs after a long period from the diagnosis of SSc; the average of this interval reaches 12 years. It would be helpful to know these features so that physicians follow up and treat SSc patients adequately.


Large scale production of phage antibody libraries using a bioreactor.
One of the limitations of the use of phage antibody libraries in high throughput selections is the production of sufficient phage antibody library at the appropriate quality. Here, we successfully adapt a bioreactor-based protocol for the production of phage peptide libraries to the production of phage antibody libraries. The titers obtained in the stirred-tank bioreactor are 4 to 5 times higher than in a standard shake flask procedure, and the quality of the phage antibody library produced is indistinguishable to that produced using standard procedures as assessed by Western blotting and functional selections. Availability of this protocol will facilitate the use of phage antibody libraries in high-throughput scale selections.


Dengue outbreak in Hadramout, Yemen, 2010: an epidemiological perspective.
We analyzed surveillance data of a dengue outbreak (2010) reported to the Hadramout Health Office (Yemen) and retrospectively analyzed dengue-related epidemiological and entomological events reported in Hadramout from 2005 to 2009. A total of 630 immunoglobulin M (IgM) -confirmed dengue cases of 982 febrile cases was reported during the period from February to June of 2010; 12 cases died, giving case fatality a rate of 1.9%. Among febrile cases, the highest proportion of dengue cases (37.3%) was reported in the 15- to 24-year-old age group. The overall attack rate was 0.89/1,000. The average number of cases reported by month over the preceding 5-year period compared with the 2010 data is consistent with endemicity of dengue in the region and supports epidemic designation for the dengue activity in 2010. Recognition of endemic dengue transmission and potential for substantial dengue epidemics highlight the need for consistent laboratory-based surveillance that can support prevention and control activities accordingly.


Associates of Engagement in Adult-Oriented Follow-Up Care for Childhood Cancer Survivors.
Understanding how to predict appropriate uptake of adult-oriented medical care is important for adult patients with pediatric-onset chronic health conditions with continued health vulnerability. We examined associates of engagement in adult survivors of childhood cancer following transfer to adult-oriented care. Adult survivors of childhood cancer (N = 80), within 1-5 years post transfer from pediatric to adult-oriented follow-up care, completed assessments of engagement with recommended adult-oriented follow-up care and psychosocial and transition readiness measures. Measures were validated with adolescent and young adults and/or intended to measure readiness to transition to adult care. Earlier age at diagnosis, parental involvement in health care decision-making, higher motivation, and increased comfort speaking to providers about health concerns were significantly associated with attendance at adult-oriented follow-up care visits. Associates of engagement in adult care are complex, representing social-ecological variables. Current measures of transition readiness or adolescent and young adult health-related measures may not adequately capture the associates of engagement in care or identify targets of intervention to promote successful transfer of care. Identifying patients at risk for loss to follow-up will be useful to design interventions for young adult survivors of childhood cancer and other young adults with pediatric-onset chronic conditions who require ongoing adult-oriented care.


Alzheimer's disease and the pivotal role of the hypothalamus and the intrinsic opioid system.
Although the "cholinergic hypothesis" of the pathophysiology of Alzheimer's disease has received great attention during the past years, it has recently come under increasing criticism specifically owing to failure of therapeutic endeavors based on this premise. As the potential broad role of the intrinsic opioids in the neurochemical modulation of diverse brain functions emerges, the realization that these data may be reconciled to a unifying hypothesis underlying the nature of some chronic dementing diseases (including Alzheimer's disease, Korsakoff disease and Parkinson's disease) occurs. Certain specific characteristics of the known pathologic changes and neurotransmitter deficits of Alzheimer's disease may be explained based on an early vulnerability of the hypothalamus combined with derangements of endorphinergic functions which follow. The latter may be implicated in the subsequent degeneration of structures receiving projections from the arcuate nucleus of the hypothalamus. This is based on the known role of endorphins in the modulation of central neurotransmitters and specifically acetylcholine activity. In addition, the reciprocal neuroendocrine and neuroimmunologic interactions mediated through the hypothalamus, may be of further importance in the evolution of Alzheimer's disease.


Synthesis of novel spiro[2.3]hexane carbocyclic nucleosides via enzymatic resolution.
[reaction: see text] Novel R- and S-spiro[2.3]hexane nucleosides have been synthesized. The key step involved the Pseudomonas cepacia lipase catalyzed resolution of racemic compound 2, synthesized in seven steps starting from diethoxyketene and diethyl fumarate, to give (+)-acetate 3 and (-)-alcohol 13. (+)-Acetate 3 and (-)-acetate 14 were converted to R- and S-9-(6-hydroxymethylspiro[2.3]hexane)-4-adenine, respectively.


Endorectal color and duplex imaging of the normal rectal wall and rectal masses.
This study investigates the ability of endorectal ultrasonography aided by color flow and pulse wave Doppler techniques to identify submucosal arterial plexuses of the normal rectal wall and to detect vessels supplying rectal wall masses. Color flow and pulsed wave Doppler analysis of 62 normal submucosal arterial plexuses and vessels feeding rectal wall masses (one rectal endometriosis and seven rectal cancers) was performed. The color signals from normal submucosal arterial plexuses and the one case of rectal endometriosis were judged to be sparse or decreased in comparison to color signals from rectal cancers. The median and mean P1 values for normal submucosal arterial plexuses were significantly greater than those for the central feeding vessels or small peripheral vessels within rectal masses. Our experience with color and duplex endorectal ultrasonography suggests that different vascular structures exist in normal persons compared to those in rectal wall masses. Pathologically, rectal cancers possess vessels with and without a smooth muscle layer, which may produce the high and low resistance signals identified by pulse Doppler.


Self-perceived social status and health in older Hong Kong Chinese women compared with men.
Economic and social factors are determinants of health, as are psychosocial factors. The present study compared self-perceived social status and its relation to health, health related quality of life and lifestyle in older women with men, adjusting for age, education level and maximum lifetime income. A cross-sectional study was conducted of 4,000 men and women aged 65 years and over in a community in the North Eastern part of Hong Kong, a Special Administrative Region in China. Participants were asked to rate their community status, education, income and occupation, on two ladders, each with ten rungs. The distributions of the two ladder scores differed, showing that although participants may not have been ranked highly in terms of money, education and job respectability, they may have ranked their community standing highly. Women and older participants tended to rank their community standing highly in spite of lower ratings in the objective measures. A social gradient in self-perceived social status, independent of objective socioeconomic measures, was noted for physical performance and health-related quality of life, rather than related to presence of specific chronic diseases or lifestyle. However, the different ratings of the two ladders suggested that mechanisms by which the gradient operates may differ between women and men. Further studies are needed to explore the health and psychosocial consequences of the gender difference in self-rated social status.


Effects of lipoprotein nanoparticles' composition and size on their internalization in plant and mammalian cells.
The internalization of engineered high-density lipoprotein nanoparticles (engineered lipoproteins [eLPs]) with different lipid and protein compositions, zeta potentials, and/or sizes were analyzed in representative plant and mammalian cells. The impact of the addition of a cell-penetrating peptide to eLPs on the internalization was very small in Bright Yellow (BY)-2 protoplasts compared with HeLa cells. When eLPs were prepared with one of the abundant lipids in BY-2 cells, digalactosyldiacylglycerol (DGDG) (eLP4), its internalization was dramatically increased only in HeLa cells. Such an increase in HeLa cells was also obtained for liposomes containing DGDG in a DGDG content-dependent manner. Increasing the size and zeta potential of eLPs improved their internalization in both HeLa cells and in BY-2 protoplasts but to quite varying degrees. Although eLPs tended to stay at the plasma membrane (PM) in BY-2 protoplasts with much less internalization, the PM-bound eLPs somehow promoted the internalization of coexisting nanobeads in cell culture media. These results provide fundamental insight into the future design of lipid nanoparticles for drug delivery in mammalian and plant cells.