Outcome of 45 dogs with laryngeal paralysis treated by unilateral arytenoid lateralization or bilateral ventriculocordectomy.
The purpose of this retrospective study was to assess risk factors and complications affecting postoperative outcome of dogs with laryngeal paralysis treated by either unilateral arytenoid lateralization (UAL) or bilateral ventriculocordectomy (VCC). Medical records of all dogs having either UAL or VCC between 2000 and 2011 were analyzed. Twenty-five dogs had VCC and 20 dogs had UAL. The overall postoperative complications rates for VCC and UAL were similar (52% and 60%, respectively; P = .0887). Dogs that had UAL were more likely to have acute postoperative respiratory distress and aspiration pneumonia (P = .0526). Dogs with VCC were more likely to have chronic postoperative respiratory distress and aspiration pneumonia (P = .0079). Revision surgery was required in 6 dogs (24%) following VCC and 2 dogs (10%) following UAL. Sex, breed, presenting complaint, type of service provided, and concurrent diseases were not significantly associated with higher risk of either death or decreased survival time postoperatively with either procedure. Overall postoperative complication rates, required revision surgeries, and episodes of aspiration pneumonia were similar in dogs undergoing UAL and VCC surgeries. Dogs that had VCC appeared to have an increased risk of lifelong complications postoperatively compared with UAL; therefore, VCC may not be the optimal choice for treatment of laryngeal paralysis.


CRLX101 (formerly IT-101)-A Novel Nanopharmaceutical of Camptothecin in Clinical Development.
CRLX101 (formerly IT-101) is a first-in-class nanopharmaceutical, currently in Phase 2a development, which has been developed by covalently conjugating camptothecin (CPT) to a linear, cyclodextrin-polyethylene glycol (CD-PEG) co-polymer that self-assembles into nanoparticles. As a nanometer-scale drug carrier system, the cyclodextrin polymeric nanoparticle technology, referred to as "CDP", has unique design features and capabilities. Specifically, CRLX101 preclinical and clinical data confirm that CDP can address not only solubility, formulation, toxicity, and pharmacokinetic challenges associated with administration of CPT, but more importantly, can impart unique biological properties that enhance CPT pharmacodynamics and efficacy.


The association between fear of cancer recurrence and quality of life among Chinese cancer survivors: main effect hypothesis and buffering hypothesis.
The aim of the present study is to examine whether fear of cancer recurrence (FCR) is related to health-related quality of life (HRQOL) among Chinese cancer survivors, an understudied population (i.e., main effect hypothesis). Also, we investigated whether the FCR-HRQOL link is moderated by two coping strategies, avoidance and positive reappraisal (i.e., buffering hypothesis). This is a cross-sectional study conducted among 238 Chinese cancer survivors in Beijing. Participants completed a set of questionnaires including FCR, coping, and HRQOL. FCR was related to lower physical, psychological, social, and spiritual well-beings, even when demographics, cancer-related factors, and coping were taken into account. There was only one moderation effect between FCR and avoidance coping. Surprisingly, the detrimental effect of FCR on spiritual well-being was lessened among those with high avoidance coping such that the negative association between FCR and spiritual well-being was only found in those with low avoidance coping and not among those with high avoidance coping. Findings largely supported the main effect hypothesis. FCR was associated with diverse domains of HRQOL among Chinese cancer survivors. The buffering hypothesis was largely not supported in this population. Rather, in some cases, the effects of FCR and coping strategies on HRQOL were independent. Thus, ways to attenuate the harmful effects of FCR on HRQOL among Chinese cancer survivors remain unresolved. It is urgent and timely that future studies focus on FCR and HRQOL in this population.


Repetitive transcranial magnetic stimulation over the left parietal cortex facilitates visual search for a letter among its mirror images.
Interference by task irrelevant information is seen in visual search paradigms using letters. Thus, it is harder to find the letter 'N' among its mirror reversals 'И' than vice versa. This observation, termed the reversed letter effect, involves both a linguistic association and an interference of task irrelevant information—the shape of 'N' or 'И' is irrelevant, the search requires merely distinguishing the tilts of oblique bars. We adapted the repetitive transcranial magnetic stimulation (rTMS) methods that we previously used, and conducted three rTMS experiments using healthy subjects. The first experiment investigated the effects of rTMS on the left and right posterior parietal cortex (PPC) on the search performance. The second experiment focused on the role of the left PPC. The third experiment explored whether another left posterior region, known to be involved in word reading (ventral occipito-temporal cortex, vOTC), plays a role. We found that rTMS on right PPC and left VOTC had no effect on the speed and accuracy of the visual search regardless of whether the target is 'N' or its mirror reversal. In contrast, rTMS on the left PPC speeded up the search on finding target 'N' among its mirror images. We suggest that left PPC is involved in letter recognition, and that rTMS on left PPC facilitated our visual search task by reducing task interference triggered by task irrelevant letter recognition.


Weight and Metabolic Outcomes 12 Years after Gastric Bypass.
Few long-term or controlled studies of bariatric surgery have been conducted to date. We report the 12-year follow-up results of an observational, prospective study of Roux-en-Y gastric bypass that was conducted in the United States. A total of 1156 patients with severe obesity comprised three groups: 418 patients who sought and underwent Roux-en-Y gastric bypass (surgery group), 417 patients who sought but did not undergo surgery (primarily for insurance reasons) (nonsurgery group 1), and 321 patients who did not seek surgery (nonsurgery group 2). We performed clinical examinations at baseline and at 2 years, 6 years, and 12 years to ascertain the presence of type 2 diabetes, hypertension, and dyslipidemia. The follow-up rate exceeded 90% at 12 years. The adjusted mean change from baseline in body weight in the surgery group was -45.0 kg (95% confidence interval [CI], -47.2 to -42.9; mean percent change, -35.0) at 2 years, -36.3 kg (95% CI, -39.0 to -33.5; mean percent change, -28.0) at 6 years, and -35.0 kg (95% CI, -38.4 to -31.7; mean percent change, -26.9) at 12 years; the mean change at 12 years in nonsurgery group 1 was -2.9 kg (95% CI, -6.9 to 1.0; mean percent change, -2.0), and the mean change at 12 years in nonsurgery group 2 was 0 kg (95% CI, -3.5 to 3.5; mean percent change, -0.9). Among the patients in the surgery group who had type 2 diabetes at baseline, type 2 diabetes remitted in 66 of 88 patients (75%) at 2 years, in 54 of 87 patients (62%) at 6 years, and in 43 of 84 patients (51%) at 12 years. The odds ratio for the incidence of type 2 diabetes at 12 years was 0.08 (95% CI, 0.03 to 0.24) for the surgery group versus nonsurgery group 1 and 0.09 (95% CI, 0.03 to 0.29) for the surgery group versus nonsurgery group 2 (P<0.001 for both comparisons). The surgery group had higher remission rates and lower incidence rates of hypertension and dyslipidemia than did nonsurgery group 1 (P<0.05 for all comparisons). This study showed long-term durability of weight loss and effective remission and prevention of type 2 diabetes, hypertension, and dyslipidemia after Roux-en-Y gastric bypass. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).


Polo-like kinase 1 regulates RhoA during cytokinesis exit in human cells.
Both RhoA (Rho1) and polo-like kinase 1 (Plk1) are implicated in the regulation of cytokinesis, a cellular process that marks the division of cytoplasm of a parent cell into daughter cells after nuclear division. Cytokinesis failure is often accompanied by the generation of cells with an unstable tetraploid content, which predisposes it to chromosomal instability and oncogenic transformation. Several studies using lower eukaryotic systems demonstrate that RhoA and Plk1 are essential for mitotic progression and cytokinesis. Physical and functional interactions between RhoA and Plk-1 were analyzed using subcellular localization of RhoA and Plk1 in HeLa cells by immunofluorescence and co-precipitation techniques, followed by Western blotting in RhoA transfected cells. Plk1 localizes to kinetochores as well as to spindle poles during prophase and metaphase; it translocates to the midbody during telophase. RhoA is also enriched at the midbody region during telophase and colocalizes with Plk1. Recombinant RhoA, expressed as a GFP fusion protein, is enriched in the nucleus of HeLa and U2OS cells. Ectopically expressed GFP-RhoA does not cause significant cell death, although there exist a group of cells that appear to exhibit a delay in mitotic exit or in impaired cytokinesis. Co-immunoprecipitation reveals that RhoA and Plk1 physically interact and that their interaction appears to be enhanced during mitosis. Given the role of RhoA and Plk1 in cytokinesis, our findings suggest that regulated activation of RhoA is important for cytokinesis and that Plk1 may alter activation of RhoA during mitotic cytokinesis.


Water retained in tall Cryptomeria japonica leaves as studied by infrared micro-spectroscopy.
Recent studies in the tallest tree species suggest that physiological and anatomical traits of tree-top leaves are adapted to water-limited conditions. In order to examine water retention mechanism of leaves in a tall tree, infrared (IR) micro-spectroscopy was conducted on mature leaf cross-sections of tall Cryptomeria japonica D. Don from four different heights (51, 43, 31 and 19 m). We measured IR transmission spectra and mainly analyzed OH (3700-3000 cm-1) and C-O (1190-845 cm-1) absorption bands, indicating water molecules and sugar groups, respectively. The changes in IR spectra of leaf sections from different heights were compared with bulk-leaf hydraulics. Both average OH band area of the leaf sections and leaf water content were larger in the upper-crown, while osmotic potential at saturation did not vary with height, suggesting higher dissolved sugar contents of upper-crown leaves. As cell-wall is the main cellular structure of leaves, we inferred that larger average C-O band area of upper-crown leaves reflected higher content of structural polysaccharides such as cellulose, hemicellulose and pectin. Infrared micro-spectroscopic imaging showed that the OH and C-O band areas are large in the vascular bundle, transfusion tissue and epidermis. Infrared spectra of individual tissue showed that much more water is retained in vascular bundle and transfusion tissue than mesophyll. These results demonstrate that IR micro-spectroscopy is a powerful tool for visualizing detailed, quantitative information on the spatial distribution of chemical substances within plant tissues, which cannot be done using conventional methods like histochemical staining. The OH band could be well reproduced by four Gaussian OH components around 3530 (free water: long H bond), 3410 (pectin-like OH species), 3310 (cellulose-like OH species) and 3210 (bound water: short H bond) cm-1, and all of these OH components were higher in the upper crown while their relative proportions did not vary with height. Based on the spectral analyses, we inferred that polysaccharides play a key role in biomolecular retention of water in leaves of tall C. japonica.


Cholelithiasis in children in a Chinese hospital: report of 52 cases.
Over a period of 22 years (1958-1980), 52 children with cholelithiasis were treated in the Hunan Medical College Hospital in Ghangsha, China. Enteric helminthiasis is a common endemic disease in China and the countries of the Far East. Common in this region also is biliary ascariasis, which can precipitate an abdominal emergency in children. Both these conditions make differentiation of primary acute cholecystitis from the acute cholecystitis that is a complication of biliary ascariasis difficult in children. But, whatever the etiology of the disease, cholelithiasis was confirmed in all 52 children, an incidence of 1:62.4 the frequency of this disease in adults, or eight times higher than that which occurs in Western countries. Table 1 shows the distribution according to sex and age in our patients.


Novel application of S-nitrosoglutathione-Sepharose to identify proteins that are potential targets for S-nitrosoglutathione-induced mixed-disulphide formation.
Site-specific S-glutathionylation is emerging as a novel mechanism by which S-nitrosoglutathione (GSNO) may modify functionally important protein thiols. Here, we show that GSNO-Sepharose mimicks site-specific S-glutathionylation of the transcription factors c-Jun and p50 by free GSNO in vitro. Both c-Jun and p50 were found to bind to immobilized GSNO through the formation of a mixed disulphide, involving a conserved cysteine residue located in the DNA-binding domains of these transcription factors. Furthermore, we show that c-Jun, p50, glycogen phosphorylase b, glyceraldehyde-3-phosphate dehydrogenase, creatine kinase, glutaredoxin and caspase-3 can be precipitated from a mixture of purified thiol-containing proteins by the formation of a mixed-disulphide bond with GSNO-Sepharose. With few exceptions, protein binding to this matrix correlated well with the susceptibility of the investigated proteins to undergo GSNO- but not diamide-induced mixed-disulphide formation in vitro. Finally, it is shown that covalent GSNO-Sepharose chromatography of HeLa cell nuclear extracts results in the enrichment of proteins which incorporate glutathione in response to GSNO treatment. As suggested by DNA-binding assays, this group of nuclear proteins include the transcription factors activator protein-1, nuclear factor-kappaB and cAMP-response-element-binding protein. In conclusion, we introduce GSNO-Sepharose as a probe for site-specific S-glutathionylation and as a novel and potentially useful tool to isolate and identify proteins which are candidate targets for GSNO-induced mixed-disulphide formation.


High-quality multiterminal suspended graphene devices.
We introduce a new scheme to realize suspended, multiterminal graphene structures that can be current annealed successfully to obtain uniform, very high quality devices. A key aspect is that the bulky metallic contacts are not connected directly to the part of graphene probed by transport measurements, but only through etched constriction, which prevents the contacts from acting invasively. The device high quality and uniformity is demonstrated by a reproducibly narrow (δn ~ 10(9) cm(-2)) resistance peak around charge neutrality, by carrier mobility values exceeding 10(6) cm(2) V(-1) s(-1), by the observation of integer quantum Hall plateaus starting at 30 mT and of symmetry broken states at about 200 mT, and by the occurrence of a negative multiterminal resistance directly proving the occurrence of ballistic transport. As these multiterminal devices enable measurements that cannot be done in a simpler two-terminal configuration, we anticipate that their use in future studies of graphene-based systems will be particularly relevant.


Comparison between dry needling plus manual therapy with manual therapy alone on pain and function in overhead athletes with scapular dyskinesia: A randomized clinical trial.
Muscles' trigger points can induce scapular dyskinesia (SD) which interferes with overhead athletes' professional training. We aimed to evaluate effects of dry needling (DN) alone and plus manual therapy (MT) on pain and function of overhead athletes with SD. 40 overhead athletes (15 male, 25 female) aged 18-45 with at least 3 points Numeric Rating Scale (NRS) pain intensity during training were recruited and randomly allocated to the treatment group: MT followed by DN on trigger points of Subscapularis, Pectoralis minor, Serratus anterior, upper and lower Trapezius muscles; or the control group: MT alone. The effect of shoulder trigger points DN plus MT with MT alone on pain, function, Pain Pressure Threshold (PPT) and SD in athletes with SD were compared. Both the examiner and the therapist were blinded to group assignment. Both groups were analyzed. Pain, disability and SD were improved in treatment group (P < .05). On the other hand, when only MT was applied, despite reduction in pain and disability (P < .001), scapular slide only improved in hands on waist position. Comparing the differences between groups showed a substantial reduction in pain (P < .001) and disability (P = .02) with significant improvement in scapular dyskinesia in treatment group (P = .02). Moreover, PPT significantly increased in the control group (P = .004). No adverse effects reported by the participants during this study. DN is an easy and applicable method that can synergistically reduce pain, disability and dyskinesia when it is combined with manual techniques to treat shoulder dysfunctions.


Reproductive effects of subchronic exposure to acetamiprid in male rats.
Acetamiprid, a selective agonist of nicotinic acetylcholine recetors, is one of the most widely used neonicotinoids. There is limited data about toxicity of acetamiprid on male reproductive system. Therefore, the study aimed to investigate the reproductive toxic potential of acetamiprid in male rats orally treated with acetamiprid with low (12.5 mg/kg) medium (25 mg/kg) or high dose (35 mg/kg) for 90 days. According to our results, sperm concentration and plasma testosterone levels decreased in dose dependent manner. Gonadotropin-releasing hormone (GnRH), follicle-stimulating hormeone (FSH), luteinizing hormone (LH) levels increased at low and medium dose groups and acetamiprid caused lipid peroxidation and glutathione (GSH) depletion in the testes. Histologic examinations revealed that acetamiprid induced apoptosis in medium and high dose groups and proliferation index dramatically decreased in high dose group. In conclusion, acetamiprid caused toxicity on male reproductive system in the high dose. The mechanism of the toxic effect may be associated with oxidative stress, hormonal disruptions and apoptosis.


Clinical and molecular genetic features of ARC syndrome.
Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (MIM 208085) is an autosomal recessive multisystem disorder that may be associated with germline VPS33B mutations. VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients. We characterised clinical and molecular features of ARC syndrome in order to identify potential genotype-phenotype correlations. The clinical phenotype of 62 ARC syndrome patients was analysed. In addition to classical features described previously, all patients had severe failure to thrive, which was not adequately explained by the degree of liver disease and 10% had structural cardiac defects. Almost half of the patients who underwent diagnostic organ biopsy (7/16) developed life-threatening haemorrhage. We found that most patients (9/11) who suffered severe haemorrhage (7 post biopsy and 4 spontaneous) had normal platelet count and morphology. Germline VPS33B mutations were detected in 28/35 families (48/62 individuals) with ARC syndrome. Several mutations were restricted to specific ethnic groups. Thus p.Arg438X mutation was common in the UK Pakistani families and haplotyping was consistent with a founder mutation with the most recent common ancestor 900-1,000 years ago. Heterozygosity was found in the VPS33B locus in some cases of ARC providing the first evidence of a possible second ARC syndrome gene. In conclusion we state that molecular diagnosis is possible for most children in whom ARC syndrome is suspected and VPS33B mutation analysis should replace organ biopsy as a first line diagnostic test for ARC syndrome.


Rapid Detection of Bacillus anthracis Bloodstream Infections by Use of a Novel Assay in the GeneXpert System.
Bacillus anthracis is a tier 1 select agent with the potential to quickly cause severe disease. Rapid identification of this pathogen may accelerate treatment and reduce mortality in the event of a bioterrorism attack. We developed a rapid and sensitive assay to detect B. anthracis bacteremia using a system that is suitable for point-of-care testing. A filter-based cartridge that included both sample processing and PCR amplification functions was loaded with all reagents needed for sample processing and multiplex nested PCR. The assay limit of detection (LOD) and dynamic range were determined by spiking B. anthracis DNA into individual PCR mixtures and B. anthracis CFU into human blood. One-milliliter blood samples were added to the filter-based detection cartridge and tested for B. anthracis on a GeneXpert instrument. Assay specificity was determined by testing blood spiked with non-anthrax bacterial isolates or by testing blood samples drawn from patients with concurrent non-B. anthracis bacteremia or nonbacteremic controls. The assay LODs were 5 genome equivalents per reaction and 10 CFU/ml blood for both the B. anthracis Sterne and V1B strains. There was a 6-log10 dynamic range. Assay specificity was 100% for tests of non-B. anthracis bacterial isolates and patient blood samples. Assay time was less than 90 min. This automated system suitable for point-of-care detection rapidly identifies B. anthracis directly from blood with high sensitivity. This assay might lead to early detection and more rapid therapy in the event of a bioterrorism attack.


Assessment of prognostic factors in stage IIIA endometrial cancer.
The objective of this study was the assessment of prognostic factors in stage IIIA endometrial cancer. Between 1984 and 1993, 51 patients with stage IIIA endometrial cancer received definitive treatment at our institution. Thirty-seven patients had positive peritoneal cytologic findings only (stage IIIA1), and 14 had adnexal or uterine serosal involvement (USI) (stage IIIA2). Median follow-up of surviving patients was 82.5 months. The 5-year disease-related survival (DRS) and recurrence-free survival (RFS) were 88 and 73%, respectively. RFS was 79% in patients with stage IIIA1 disease, compared with 57% in patients with stage IIIA2 disease (P = 0.04). However, DRS did not significantly differ between stages IIIA1 and IIIA2. In the 37 patients with stage IIIA1 tumors, histologic grade 3, nonendometrioid histologic subtype, and lymphovascular invasion (LVI) significantly predicted a poor prognosis, with extraabdominal sites of failure (P < 0.05). Of the 22 patients who had stage IIIA1 disease with endometrioid histologic subtype and without LVI, none had recurrence [17 had whole abdominal irradiation (WAR) or intraperitoneal injection of (32)P, 2 had pelvic external radiotherapy (PRT)]. By contrast, of the 15 patients with either nonendometrioid histologic subtype or LVI, 9 (60%) had recurrence and 7 (47%) died of disease (12 had WAR or (32)P). An extraabdominal component was present in 7 of the 9 recurrences observed in this subgroup. Among the 14 patients with stage IIIA2 tumors (6 had WAR, 6 had PRT), those with USI had a 5-year DRS of 83% and a rate of extraabdominal failure of 83%, compared with 100 and 12.5% in patients without USI (P < 0.05). Patients with stage IIIA endometrial cancer who have endometrioid tumors, no LVI, and positive peritoneal cytologic findings as the only sign of extrauterine disease have an excellent prognosis. Nonendometrioid histologic subtype, LVI, and USI are strong predictors of distant failures and poor prognosis. Patients with either of these histologic factors should be considered candidates for systemic adjuvant therapy.


The cardiac, oxyntic and pyloric glands in the developing opossum (Didelphis virginiana).
In the opossum the fundic area of the gastric mucosa develops first, and oxyntic glands show early division into gastric pits and glandular components which then grow simultaneously. At 40 d postnatum the oxyntic glands are longer than the gastric pits but in the pyloric glands the pits still are longer than the glands and it is not until the 73rd postnatal day, that pyloric glands are longer than their pits. Development of the cardiac glands is delayed even more and the length of the gland does not surpass that of the pit until about 95 d postnatum. Argyrophil cells are concentrated in the cardia and fundus at birth and during early postnatal life, but the population of these cells shifts to the pylorus in the adult. Argyrophil cells of the cardiac, oxyntic and pyloric glands are concentrated in glandular regions with the highest mitotic activity.


Local regulation of vasopressin and oxytocin secretion by extracellular ATP in the isolated posterior lobe of the rat hypophysis.
It is now widely accepted that ATP functions as a signalling substance in the nervous system. The presence of P2 receptors mediating the action of extracellular ATP in brain regions involved in hormonal regulation raises the possibility that a similar role for ATP might also exist in the neuroendocrine system. In this study, the release from the rat isolated neurohypophysis preparation of endogenous ATP, oxytocin and vasopressin (AVP) were measured simultaneously using luciferin-luciferase and RIA techniques. After 70 min preperfusion, electrical field stimulation caused a rapid increase in the amount of ATP in the effluent and the release of AVP and oxytocin also increased stimulation-dependently. Inhibition of voltage-dependent Na+ channels by tetrodotoxin (1 microM) reduced the stimulation-evoked release of AVP and oxytocin; however, the evoked release of ATP remained unaffected. The effect of endogenous ATP on the hormone secretion was tested by suramin (300 microM), the P2 receptor antagonist. Suramin significantly increased the release of AVP, and the release of oxytocin was also enhanced. ATP, when applied to the superfusing medium, decreased the release of AVP, but not that of oxytocin, and its effect was prevented by suramin. ATP (60 nmol), added to the tissues, was readily decomposed to ADP, AMP and adenosine measured by HPLC combined with ultraviolet light detection, and the kinetic parameters of the enzymes responsible for inactivation of ATP (ectoATPase and ecto5'-nucleotidase) were also determined (Km=264+/-2.7 and 334+/-165 microM and vmax=6.7+/-1.1 and 2.54+/-0.24 nmol/min per preparation (n=3) for ectoATPase and ecto5'-nucleotidase respectively). Taken together, our data demonstrate the stimulation-dependent release, P2 receptor-mediated action and extracellular metabolism of endogenous ATP in the posterior lobe of the hypophysis and indicate its role, as a paracrine regulator, in the local control of hormone secretion.


Persistency and clinical outcomes associated with latanoprost and beta-blocker monotherapy: evidence from a European retrospective cohort study.
To evaluate persistency (time on initial therapy) and the clinical impact of latanoprost versus beta-blocker monotherapy in treating glaucoma. This observational, multicenter, retrospective medical chart review study conducted in four European countries included patients with primary open-angle glaucoma or ocular hypertension who began their first glaucoma treatment with latanoprost or a beta-blocker between November 1996 and November 1998. Persistency and glaucoma-related clinical outcomes data were abstracted for the 2 years following treatment initiation. In all, 260 patient charts were analyzed (94 latanoprost, 166 beta-blocker). Patients in the latanoprost group stayed on therapy twice as long as those who received a beta-blocker (p < 0.0001). After adjusting for baseline characteristics, patients receiving a beta-blocker as initial therapy were 3.8 times more likely to change therapy than those initially treated with latanoprost (p < 0.0001). Patients in the latanoprost group also experienced greater mean decreases in intraocular pressure (IOP) than those receiving a beta-blocker (7.4 mmHg versus 4.6 mmHg, respectively; p < 0.0001), and fewer had worsened optic nerve head excavation (1.7% versus 14.2%, respectively; p < 0.05) by the time of their first therapy change or last study visit, whichever came first. Over a 2-year period, latanoprost was associated with significantly greater persistency and better clinical IOP outcomes compared with beta-blocker therapy.


pUL21 is a viral phosphatase adaptor that promotes herpes simplex virus replication and spread.
The herpes simplex virus (HSV)-1 protein pUL21 is essential for efficient virus replication and dissemination. While pUL21 has been shown to promote multiple steps of virus assembly and spread, the molecular basis of its function remained unclear. Here we identify that pUL21 is a virus-encoded adaptor of protein phosphatase 1 (PP1). pUL21 directs the dephosphorylation of cellular and virus proteins, including components of the viral nuclear egress complex, and we define a conserved non-canonical linear motif in pUL21 that is essential for PP1 recruitment. In vitro evolution experiments reveal that pUL21 antagonises the activity of the virus-encoded kinase pUS3, with growth and spread of pUL21 PP1-binding mutant viruses being restored in adapted strains where pUS3 activity is disrupted. This study shows that virus-directed phosphatase activity is essential for efficient herpesvirus assembly and spread, highlighting the fine balance between kinase and phosphatase activity required for optimal virus replication.


Candida species diversity and antifungal susceptibility patterns in oral samples of HIV/AIDS patients in Baja California, Mexico.
Candidiasis is the most common opportunistic fungal infection in HIV patients. The aims of this study were to identify the prevalence of carriers of Candida, Candida species diversity, and in vitro susceptibility to antifungal drugs. In 297 HIV/AIDS patients in Baja California, Mexico, Candida strains were identified by molecular methods (PCR-RFLP) from isolates of oral rinses of patients in Tijuana, Mexicali, and Ensenada. 56.3% of patients were colonized or infected with Candida. In Tijuana, there was a significantly higher percentage of carriers (75.5%). Out of the 181 strains that were isolated, 71.8% were Candida albicans and 28.2% were non-albicans species. The most common non-albicans species was Candida tropicalis (12.2%), followed by Candida glabrata (8.3%), Candida parapsilosis (2.2%), Candida krusei (1.7%), and Candida guilliermondii (1.1%). Candida dubliniensis was not isolated. Two associated species were found in 11 patients. In Mexicali and Ensenada, there was a lower proportion of Candida carriers compared to other regions in Mexico and worldwide, however, in Tijuana, a border town with many peculiarities, a higher carrier rate was found. In this population, only a high viral load was associated with oral Candida carriers. Other factors such as gender, use of antiretroviral therapy, CD4+ T-lymphocyte levels, time since diagnosis, and alcohol/ tobacco consumption, were not associated with Candida carriers.


The proportion of upper gastrointestinal symptoms in the community associated with Helicobacter pylori, lifestyle factors, and nonsteroidal anti-inflammatory drugs. Leeds HELP Study Group.
Upper gastrointestinal disorders are common in the community, yet the determinants of these symptoms are poorly characterized. The association between upper gastrointestinal symptoms and Helicobacter pylori (H. pylori), socioeconomic status, nonsteroidal antiinflammatory drug (NSAID) use, smoking, alcohol, and coffee intake was assessed in a cross-sectional survey. Subjects between the ages of 40-49 yr were randomly selected from the lists of 36 primary care centers. Participants attended their local primary care center and were interviewed by a researcher using a validated dyspepsia questionnaire. H. pylori status was determined by a nonfasting 13C-urea breath test. A total of 32,929 subjects were invited, and 8,407 (25%) attended and were eligible. Of these, 2,329 (28%) were H. pylori positive and 3,177 (38%) had dyspepsia. Also, 44% of H. pylori-infected participants reported dyspepsia compared with 36% of uninfected subjects [odds ratio = 1.39; 95% confidence interval (CI) 1.26-1.53]. H. pylori infection remained a significant risk factor for dyspepsia in a multiple logistic regression model (odds ratio = 1.21; 95% CI 1.09-1.34), suggesting that 5% of dyspepsia in the population is attributable to H. pylori. NSAIDs, low educational attainment, renting accommodation, absence of central heating, sharing a bed with siblings, and being married were also significantly associated with dyspepsia in this model. Smoking, but not drinking alcohol or coffee, was marginally associated with dyspepsia, but this finding was not robust. These factors were not associated with any dyspepsia subtype. H. pylori is significantly associated with dyspepsia and may be responsible for 5% of upper gastrointestinal symptoms in the community.


Microbial growth fluctuating in response to solar-terrestrial activity variations.
Populations of microorganisms display fluctuations in the variable physiological and biochemical properties during cultivation under constant laboratory conditions. A series of explanations were proposed for this phenomenon, and different factors were studied as possible regulators. It was found that such fluctuations possess cosmic rhythms, but no factor(s) were proposed that could sufficiently explain and predict the magnitude of changes that happened on a daily basis in the long-term experiments. In this study we investigated specific growth rate fluctuations of Saccharomyces cerevisiae yeasts that were marked daily during cultivation under constant conditions. The effects of different solar and terrestrial factors were then analysed. The significant correlation indices were found for growth rate fluctuations against solar wind speed and the number of flares M on the Sun. These two factors determined the cyclic nature of the growth rate fluctuations, and thus its general course of increase or decrease. The effects of several other factors (Flares C number, planetary A index variation, and changes in the atmospheric factors such as temperature and humidity) and their two-way interactions were significant in producing an equation to describe the magnitude of changes of the yeast's growth parameters. The R2 of the equation achieved 91% and adjusted R2 was 78%. It is obvious that temperature and humidity are the factors that cannot directly influence the yeast populations under laboratory conditions and thus we suppose that they only reflect modifications of the really important factor(s) that take place in the Earth's atmosphere. We have concluded that different solar and terrestrial factors are responsible for the fluctuations in the daily kinetic parameters of the yeast growth.


Detection of telomerase activity in oral rinses from head and neck squamous cell carcinoma patients.
Telomerase is a ribonucleoprotein that maintains telomere length and whose activity is associated with escape from cellular senescence. Telomerase activity has been found in germline, immortalized, and malignant tumor cells. Using a modified PCR-based assay for telomerase activity, 26 of 35 (80%) primary, fresh, head and neck squamous cell cancer specimens and 3 of 6 head and neck squamous dysplastic lesions possessed telomerase activity. In addition, 14 of 44 (32%) oral rinses from a separate group of head and neck squamous cell cancer patients contained detectable telomerase activity, whereas 1 of 22 (5%) oral rinses from normal control patients exhibited telomerase activity. Telomerase activity in oral rinses was compared with corresponding activity in paired primary tumor samples for 19 cases: 7 of 19 demonstrated activity in both tumor and oral rinse, 2 of 19 lacked activity in both tumor and oral rinse, 10 of 19 tumors demonstrated activity that could not be detected in corresponding oral rinses, and there were no examples of positive oral rinses with corresponding negative tumors. Although currently limited in its sensitivity, analysis of telomerase activity in oral rinses represents a novel method to detect the presence of cancer cells shed in the upper aerodigestive tract.


Renal clearance of glycation adducts: anti-glycation defence in uraemia and dialysis.
Increased plasma concentrations of free AGEs (advanced glycation end products) in uraemia are due to impaired renal clearance exacerbated by dietary load and breakdown of the elevated protein-bound AGEs. Increased protein-bound AGEs most probably reflect increased synthesis due to the increased oxidative and carbonyl stress of uraemia, which is exacerbated by the dialysis procedure. Use of biocompatible peritoneal dialysis fluids and haemodialysis membranes will be beneficial, but strategies to further reduce AGE formation are required. These should focus on the hydroimidazalone AGEs, which are quantitatively the most important, and not only on the conventionally monitored AGEs N (epsilon)-carboxymethyl-lysine and pentosidine.


Sessile polypoid gastric heterotopia of rectum: a report of 2 cases and review of the literature.
The term heterotopia, a term derived from Greek, implies "other place." It refers to the finding of normal tissues at foreign sites. Heterotopic gastric tissue rarely involves the large bowel. We report 2 cases of this rare entity. Case reports of 2 patients with sessile polypoid lesion in the rectum, with a review of the available literature, using both MEDLINE and relevant bibliographies of published articles. Biopsies of the rectal lesions in our 2 cases revealed the presence of gastric tissue. Only 27 other such cases have been reported in the English literature. Patients with rectal gastric heterotopia usually present with bleeding, but other presentations and complications are possible. Endoscopic or surgical excision is the treatment of choice, although the lesions also respond to histamine 2 receptor blockers.


Pre-harvest Nitrogen Limitation and Continuous Lighting Improve the Quality and Flavor of Lettuce (Lactuca sativa L.) under Hydroponic Conditions in Greenhouse.
Short-term nitrogen limitation and continuous lighting (red/blue = 3:1) were applied individually and in combination to butterhead and red oak leaf lettuce for 1, 2, or 3 days before harvest to assess their effects on improving the nutritional value and sweet taste and reducing nitrate content and bitterness of lettuce. The results suggested that a 3-day nitrogen limitation combined with continuous lighting reduced the lettuce content of nitrate and sesquiterpene lactones and improved the quantities of soluble sugar, soluble protein, anthocyanins, and phenolic compounds without reducing the fresh weight of lettuce. In addition, in vitro simulated digestion results suggested that the 3-day nitrogen limitation combined with continuous lighting significantly improved the sweetness and reduced the bitterness of lettuce compared to the control. In conclusion, nitrogen limitation combined with continuous lighting for 3 days before harvest effectively enhanced the quality and taste of lettuce, showing great potential for its use in hydroponic lettuce production.


Statistical phylogenetic tree analysis using differences of means.
We propose a statistical method to test whether two phylogenetic trees with given alignments are significantly incongruent. Our method compares the two distributions of phylogenetic trees given by two input alignments, instead of comparing point estimations of trees. This statistical approach can be applied to gene tree analysis for example, detecting unusual events in genome evolution such as horizontal gene transfer and reshuffling. Our method uses difference of means to compare two distributions of trees, after mapping trees into a vector space. Bootstrapping alignment columns can then be applied to obtain p-values. To compute distances between means, we employ a "kernel method" which speeds up distance calculations when trees are mapped in a high-dimensional feature space, e.g., splits or quartets feature space. In this pilot study, first we test our statistical method on data sets simulated under a coalescence model, to test whether two alignments are generated by congruent gene trees. We follow our simulation results with applications to data sets of gophers and lice, grasses and their endophytes, and different fungal genes from the same genome. A companion toolkit, Phylotree, is provided to facilitate computational experiments.


Rejection! Or is it? Correlation among molecular microscope diagnostic system, histopathology and clinical judgement following heart transplantation.
Little is known about clinical decision making among discordant findings concerning for rejection with endomyocardial biopsy (EMBx) and Molecular Microscope Diagnostic System (MMDx) in patients following heart transplantation. Two hundred and twenty-eight corresponding EMBx and MMDx specimens from 135 adult heart transplant patients were retrospectively reviewed. Rejection was classified as t-cell mediated rejection ≥2R and/or antibody mediated rejection ≥1. Clinical decision making among concordant and discordant cases of EMBx and MMDx results were reviewed. Patient characteristics were comparable between concordant and discordant patient groups (median age 60 yrs., 76% male, and 71% White). A total of 167/228 specimens (73%) were concordant for no rejection with 98% agreement in clinical decision making and 25/228 (11%) concordant for rejection with 64% agreement in clinical decision making. Among the 36/228 (16%) discordant samples, clinical decision-making agreed on treatment for rejection in five of the MMDx samples and three of the EMBx samples. MMDx can be an additional tool to diagnose rejection not detected by the traditional EMBx and influence clinical decision making in guiding appropriate treatment. Ongoing investigation into the clinical utility of MMDx is warranted to determine the significance of discordant findings among diagnostic modalities when assessing for rejection.


Annual return rates to mammography facilities by women age 50 and older.
Data were collected at multiple mammography facilities to determine the use of inreach strategies for asymptomatic women age 50 and older and the annual return rates for screening by this age group. Interviews with 26 facility managers indicated that the majority use a reminder strategy. Using chart audits in a subset (n = 10) of the facilities of 475 randomly-selected patients, the return rate in 1991 (of patients seen in 1990) averaged 41% within 18 months after the 1990 appointment. Those data suggest that mammography providers, as well as the women they serve, could benefit from interventions to encourage annual mammograms.


Autoptic and echocardiographic findings in seven foetuses with congenital heart anomalies, lung lobation defects and normal visceroatrial arrangement.
Congenital heart defects may be associated with various extracardiac and chromosomal anomalies, and complex cardiac defects may occur in the presence of heterotaxy syndromes, in which both lungs are bilobate, in left isomerism, or both trilobate, in right isomerism. Lung lobation defects are otherwise very rare. Lung lobation is recognisable only at autopsy; however, its definition is fundamental for evaluation of the visceroatrial arrangement, together with other characteristic signs. We report seven cases of congenital heart defects diagnosed prenatally at 14-31 weeks of gestation (wg), 5 females and 2 males, in which autopsy revealed lung lobation defects in the presence of normal visceroatrial arrangement, in association with other extracardiac anomalies or dysmorphism. Three foetuses had hypoplastic left heart syndrome, one had corrected transposition of great arteries, one had tricuspid atresia, one Ebstein's anomaly and one had ventricular septal defect in trisomy 21. In six cases, pregnancy had been terminated, while the foetus with Ebstein's anomaly died in utero at 32 wg for supraventricular tachycardia. Monolobate, bilobate, trilobate and quadrilobate lungs were found in these foetuses, together with other minor extracardiac anomalies or dysmorphism. Autoptic analysis in cases with prenatal diagnosis is needed to confirm echographic findings and reveal other minor anomalies, undetectable by ultrasound imaging that may complete the malformation pattern, which is useful to the couple for genetic counselling.


Skin reaction in antiviral therapy for chronic hepatitis C: a role for polyethylene glycol interferon?
In the past decade, different modalities of antiviral therapy have been adopted aimed at eradicating hepatitis C virus infection. Initially, interferon was used in monotherapy, then interferon combined with ribavirin and amantadine. Recently, interferon has been conjugated with polyethylene glycol to allow optimization of its pharmacokinetic properties and to improve its antiviral activity. This study focused on the characteristics of the skin reactions that we observed in 27 patients with naïve hepatitis C who received polyethylene glycol interferon-ribavirin-amantadine or polyethylene glycol interferon-ribavirin and in 10 previous non-responders to interferon monotherapy who were retreated with triple therapy. In 9 patients (7 on triple therapy) dermatitis-like lesions were observed, and in 5 the severity of the lesions necessitated withdrawal from therapy.


Shiga toxin-producing Escherichia coli in beef retail markets from Argentina.
Shiga toxin-producing Escherichia coli (STEC) are foodborne pathogens that cause mild or serious diseases and can lead to people death. This study reports the prevalence and characteristics of STEC O157 and non-O157 in commercial ground beef and environmental samples, including meat table, knife, meat mincing machine, and manipulator hands (n = 450) obtained from 90 retail markets over a nine-month period. The STEC isolates were serotyped and virulence genes as stx (Shiga toxin), rfb(O157)] (O157 lipopolysaccharide), fliC(H7) (H7 flagellin), eae (intimin), ehxA (enterohemolysin) and saa (STEC autoagglutinating adhesin), were determined. STEC O157 were identified in 23 (25.5%) beef samples and 16 (4.4%) environmental samples, while STEC non-O157 were present in 47 (52.2%) and 182 (50.5%), respectively. Among 54 strains isolated, 17 were STEC O157:H7 and 37 were STEC non-O157. The prevalent genotype for O157 was stx(2)/eae/ehxA/fliC(H7) (83.4%), and for STEC non-O157 the most frequent ones were stx(1)/stx(2)/saa/ehxA (29.7%); stx(2) (29.7%); and stx(2)/saa/ehxA (27%). None of the STEC non-O157 strains were eae-positive. Besides O157:H7, other 20 different serotypes were identified, being O8:H19, O178:H19, and O174:H28 the prevalent. Strains belonging to the same serotype could be isolated from different sources of the same retail market. Also, the same serotype could be detected in different stores. In conclusion, screening techniques are increasingly sensitive, but the isolation of STEC non-O157 is still a challenge. Moreover, with the results obtained from the present work, although more studies are needed, cross-contamination between meat and the environment could be suspected.


Metabolism and disposition of the anticancer agent sulofenur in mouse, rat, monkey, and human.
The elimination and metabolism of sulofenur [N-(5-indanesulfonyl)-N'-(4-chlorophenyl)urea, LY186641] was examined in mice, rats, monkeys, and humans. The compound, which is efficacious in a wide number of solid-tumor in vivo models, is currently being developed as an anticancer agent. Its diarylsulfonylurea structure is unique among such agents, and the basis of its activity is unknown but apparently novel. A major goal of these studies was to determine whether p-chloroaniline is formed in significant quantities during the course of sulofenur metabolism. p-Chloroaniline, capable of being formed by hydrolysis of this diarylsulfonylurea, is known to induce methemoglobinemia and/or hemolytic anemia. In animal studies using rats and monkeys, as well as in clinical trials of sulofenur, elevated levels of methemoglobin have been noted. The metabolism was thus compared to the known metabolism of p-chloroaniline. Sulofenur (I) is well absorbed in both monkey and human; practically all of the excreted radiolabel from an oral dose is in the urine. Metabolism is extensive; the major excretion products are the 1-hydroxyindanyl (II) and 1-ketoindanyl (III) derivatives in all species, along with significant amounts of the 3-hydroxyindanyl (IV) and 3-ketoindanyl (V) metabolites in the mouse and rat. Dihydroxyindanyl secondary metabolites also are present, but no sulofenur is observed in the urine samples. Known metabolites account for over 95% of the radiocarbon present in urine samples from a patient given [14C-p-chlorophenyl]sulofenur.(ABSTRACT TRUNCATED AT 250 WORDS)


Description of a pilot anal pap smear screening program among individuals attending a Veteran's Affairs HIV clinic.
Despite the higher risk of anal cancer among HIV-infected individuals currently there are no national or international guidelines for anal dysplasia screening. We assessed acceptance and feasibility of screening for anal intraepithelial neoplasia (AIN), the rate of abnormalities, and relationship between the presence of AIN and a history of receptive anal intercourse. Eighty-two percent of HIV-patients approached during routine clinic visit agreed to participate in the study with anal Pap smear collection; 53% had abnormal cytology results and among those undergoing high-resolution anoscopy with biopsy, 55% had high-grade AIN, including 2 cases of carcinoma in situ. Anal cytology was well accepted and it was feasible to be incorporated into HIV primary care practice. Abnormal cytology was not significantly associated with history of anal intercourse (p = 0.767). The high rate of abnormal results reinforces the need for further evaluation of the role of systematic anal Pap smear screening for HIV patients.


Genetic analysis of the psychomotor stimulant effect of ethanol.
Genetic influences on the psychomotor stimulant effect of ethanol may be a key feature of abuse liability. While earlier work has shown the activational effects of ethanol to be under the influence of a relatively uncomplicated additive genetic system, preliminary data from our laboratory suggested the possibility of nonadditive genetic variance. In the present study, a full Mendelian cross was conducted to further characterize gene action and search for quantitative trait loci (QTL) influencing the psychomotor stimulant properties of ethanol. We tested 3062 mice of the six Mendelian cross genotypes (P1, P2, F1, F2, BC1 and BC2) derived from a cross between the C57BL/6J (B6) and C3H/HeJ (C3H) inbred strains of mice. On day 1, mice were injected with saline, put in a holding cage for 5 min, then placed in an activity monitor for 5 min. On day 2, mice were injected with 1.5 g/kg ethanol, and activity again monitored for 5 min. Analysis showed the expected activation in the C3H strain and little activation in the B6 strain, with no effect of sex. Biometrical genetic analysis showed a best-fit model that included the mean (m), additive effect (a), and an epistatic parameter (i = homozygote by homozygote interaction). Analysis showed good evidence for QTL on chromosomes 1 (logarithm of odds (LOD) 3.4-7.5, 88-100 cM), 6 (LOD 9.1-10.4, 46-50 cM) and 15 (LOD 7.3-8.8, 28-32 cM). While the regions on chromosomes 1 and 6 have previously been implicated in several different ethanol-related phenotypes, this is the first report of a QTL influencing the psychomotor stimulant properties of ethanol on chromosome 15. Other studies have identified QTL in this region of chromosome 15 mediating locomotor activation caused by other psychostimulants, including cocaine, amphetamine and phencyclidine.


Use of receiver operating characteristic curves to evaluate the clinical performance of analytical systems.
The usefulness of an analytical system in patient care is ultimately judged not by its analytical performance but by its clinical performance, i.e., its ability to separate apparently similar patients into two subgroups, one of which has a particular clinically important condition and another subgroup which does not. This clinical performance can be studied with the tools of signal detectability theory, originally developed to analyze the performance of radar and data-transmission systems. Each classification made by an analytical system may be categorized as a true-positive, true-negative, false-positive, or false-negative decision. For laboratory tests the proportion of decisions in each category depends on the biological overlap between the two subgroups, the analytical performance of the system, and the decision level chosen. The clinical performance of the analytical system for all possible decision levels is represented by the receiver operating characteristic curve, which plots the true-positive rate against the false-positive rate. The use of these curves permits comparison of alternative analytical techniques at equal true-positive rates and at all possible decision levels. These comparisons show the effect of analytical improvements on clinical performance.


Long-term Patient and Graft Survival of Kidney Transplant Recipients With Hepatitis C Virus Infection in the United States.
Hepatitis C virus (HCV) infection is common among kidney transplant (KTx) recipients. However, the impact of HCV infection on long-term graft and recipient survival after KTx from large-scale data remains to be determined. We used the Organ Procurement and Transplantation Network database to identify all adults undergoing KTx in 2004 to 2006 in the United States. A propensity score was created to match each HCV-positive recipient with an HCV-negative control for unbiased comparisons. Survival analysis was conducted to evaluate recipient and death-censored graft survival. Out of 33 357 adult primary KTx recipients, 1470 (4.4%) were HCV-positive: 1364 HCV-positive and -negative pairs were selected by propensity score matching. Based on multivariable regression models, HCV is associated with a higher risk of death (hazard ratio [HR], 1.50; 95% confidence interval [95% CI], 1.28-1.75) and graft failure (HR, 1.26; 95% CI, 1.08-1.47). Infection was a more common cause of death in HCV-positive patients than in HCV-negative recipients (HR, 1.64; 95% CI, 1.12-2.42). The incidence of death due to liver failure was 0.23% per year among HCV-positive recipients, whereas no HCV-negative recipients died from liver failure. Graft failure due to recurrent disease was higher in HCV-positive than in HCV-negative recipients (HR, 2.00; 95% CI, 1.06-3.78). HCV infection is associated with decreased long-term recipient and graft survival. Future studies are needed to examine whether recently available, safe, and effective antiviral therapy improves the long-term clinical outcome in these patients.


Mycobacterium avium complex prosthetic joint infection: A systematic review of the literature and pooled analysis.
Mycobacterium avium complex (MAC) prosthetic joint infection (PJI) has been rarely reported. This study aimed to investigate the epidemiology and outcomes of MAC PJI. A systematic review of the literature regarding the MAC infection following total joint arthroplasty including hip and knee joint was performed. Multiple databases were searched for published English-written articles up to May 2023. Studies that reported cases of PJI by MAC were reviewed. A total of 17 patients were identified and analyzed from 11 published studies. All patients presented with joint symptom of pain or swelling prior to the diagnosis and MAC was confirmed by culture. The most of the patients (16/17 patients, 94.1%) were noted to have underlying medical condition(s) that might have affected immunity. Treatment consisted of anti-MAC medication therapy only in two patients and anti-MAC medication therapy plus surgery in 15 patients. Among the patients who underwent surgery, 14 patients (82.3%) had removal of the prosthesis including seven patients who had two-stage surgery to have reimplantation of the prosthesis. No relapse of MAC infection was reported despite of one case of relapse of infection caused by different pyogenic bacteria. The rate of overall mortality was 29.4%, however, identified attributable mortality due to MAC infection was low (5.9%). PJI by MAC is a rare disease. However, MAC needs to be considered in the differential diagnosis in immunocompromised patients presenting with symptoms of PJI. Two-stage exchange arthroplasty may result in successful treatment outcomes without higher risks of relapse of infection if undertaken in association with appropriate active anti-MAC antibiotic therapy.


The tools of management: keeping high touch in a high tech world.
Three of Naisbitt's Megatrends: information processing, high tech/high touch and participatory management--welded into tools of management--have particular relevance for nurses throughout the world. Their use is explored in this paper delivered at a Special Interest Session in Tel Aviv at the ICN Congress.


Historical highlights in cardiac pacing.
The benchmarks in cardiac pacing are identified, beginning with F. Steiner (1871), who rhythmically stimulated the chloroform-arrested hearts of 3 horses, 1 donkey, 10 dogs, 14 cats, and 8 rabbits. The chloroform-arrested heart in human subjects was paced by T. Greene in the following year (1872) in the UK. In 1882, H. Ziemssen in Germany applied cardiac pacing to a 42-year old woman who had a large defect in the anterior left chest wall subsequent to resection of an enchondroma. Intentional cardiac pacing did not occur until 1932, when A.A. Hyman in the US demonstrated that cardiac pacing could be clinically practical. Hyman made a batteryless pacemaker for delivery in induction shock stimuli (60-120/min) to the atria. His pacemaker was powered by a hand-wound, spring-driven generator which provided 6 min of pacemaking without rewinding. Closed-chest ventricular pacing was introduced in the US in 1952 by P.M. Zoll et al. Zoll (1956) also introduced closed-chest ventricular defibrillation. W.L. Weirich et al. (1958) demonstrated that direct-heart stimulation in closed-chest patients could be achieved with slender wire electrodes. S. Furman and J.B. Schwedel (1959) developed a monopolar catheter electrode for ventricular pacing in man. In the same year, W. Greatbatch and W.M. Chardack developed the implantable pacemaker.


Adrenocortical suppression in cats given megestrol acetate.
Megestrol acetate was given orally to 8 cats at a dose of 2.5 mg every other day for 2 weeks and to 8 cats at a dose of 5.0 mg every day for 2 weeks. Four cats were designated nontreated controls. Pre-ACTH-stimulated plasma concentrations of cortisol (hydrocortisone) and ACTH-stimulated cortisol and tolerance to large-dose glucose infusion (IV) were determined on each of the 20 cats given megestrol acetate. Cats were restrained with acepromazine maleate and ketamine hydrochloride during blood sample collection and large-dose glucose infusion. Adrenocortical function and tolerance to large-dose glucose infusion were reevaluated for 4 weeks--after 1st and 2nd weeks of megestrol acetate treatment of the treated groups, and after 1st and 2nd weeks when treatment was stopped (ie, experiment weeks 3 and 4). Each week a cat from the control group and 2 cats from the 2 treated groups were selected to determine the changes occurring during the experiment for that week; after collection of plasma samples, each week's 5 selected cats were euthanatized and necropsied. Significant impairment of adrenocortical function and alteration of adrenocortical morphology occurred with both treated groups. The most severe adrenocortical alterations occurred in the cats 1 week after megestrol acetate was no longer given (ie, experiment week 3). Megestrol acetate-induced adrenocortical suppression contributed to the death of 1 cat. It was concluded that if stress occurs to cats on treatment or soon after treatment with megestrol acetate, glucocorticoids should be supplemented. The effects of megestrol acetate on glucose tolerance were overshadowed by the unforeseen intolerance caused by chemical restraint with acepromazine maleate and ketamine hydrochloride.


Primary carcinomas of the urethra.
Urethral carcinomas are rare, and information reported in the literature is relatively limited. In this review, the authors present separate discussions on the pathology of carcinomas occurring in men and women with emphasis on the diverse histological subtypes. Because tumor type and prognosis correspond to anatomic location, normal anatomy and histology have been given due consideration. Of particular note in the recent literature is an expanded experience with clear cell carcinoma, a distinctive tumor primarily of the female urethra that has generated considerable interest with respect to its prognosis and relationship to urethral diverticulum. The authors use this review to illustrate several features of the pathology of these neoplasms synthesize the literature, and place into perspective the clinical, pathological, and prognostic features.


Associations Between Multiple Leisure Activities, Mental Health and Substance Use Among Adolescents in Denmark: A Nationwide Cross-Sectional Study.
Background: Previous research has suggested that leisure activity may benefit mental health and protect against substance use among adolescents, but more research is needed to asses associations with a wide range of outcomes. The aim of this study was to assess associations between multiple leisure activities and (1) mental health outcomes and (2) substance use outcomes in a sample of Danish adolescents. Methods: Using data from the Danish part of the European School Survey Project on Alcohol and Other Drugs (ESPAD) collected in 2019, nation-wide cross-sectional data from 2,488 participants aged 15 or 16 in Denmark were analyzed to assess associations between number of leisure activity types and outcomes pertaining to mental health and substance use. Results: Our results show that engaging in multiple activity types at least once a week-as compared to one single type of activity-is associated with increased odds for high mental well-being, and reduced odds for mental health problems. Engaging in multiple activity types is also associated with reduced odds for overall substance use and for using substances as a coping method. Among those using substances, engaging in multiple activity types is associated with reduced odds of above average substance use. Conclusion: Increasing opportunities for adolescents to engage in leisure activities is suggested to be useful in enhancing mental health and preventing substance use and promoting mental health. Promoting and increasing access to leisure activities among adolescents could be a promising avenue for policy and practice.


Distant metastases in head-and-neck squamous cell carcinoma treated with intensity-modulated radiotherapy.
To determine the pattern and risk factors for distant metastases in head-and-neck squamous cell carcinoma (HNSCC) after curative treatment with intensity-modulated radiotherapy (IMRT). This was a retrospective study of 284 HNSCC patients treated in a single institution with IMRT. Sites included were oropharynx (125), oral cavity (70), larynx (55), hypopharynx (17), and unknown primary (17). American Joint Committee on Cancer stage distribution includes I (3), II (19), III (42), and IV (203). There were 224 males and 60 females with a median age of 57. One hundred eighty-six patients were treated with definitive IMRT and 98 postoperative IMRT. One hundred forty-nine patients also received concurrent cisplatin-based chemotherapy. The median follow-up for all patients was 22.8 months (range, 0.07-77.3 months) and 29.5 months (4.23-77.3 months) for living patients. The 3-year local recurrence-free survival, regional recurrence-free survival, locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 94.6%, 96.4%, 92.5%, 84.1%, and 68.95%, respectively. There were 45 patients with distant metastasis. In multivariate analysis, distant metastasis was strongly associated with N stage (p = 0.046), T stage (p < 0.0001), and pretreatment maximum standardized uptake value of the lymph node (p = 0.006), but not associated with age, gender, disease sites, pretreatment standardized uptake value of the primary tumor, or locoregional control. The freedom from distant metastasis at 3 years was 98.1% for no factors, 88.6% for one factor, 68.3% for two factors, and 41.7% for three factors (p < 0.0001 by log-rank test). With advanced radiation techniques and concurrent chemotherapy, the failure pattern has changed with more patients failing distantly. The majority of patients with distant metastases had no local or regional failures, indicating that these patients might have microscopic distant disease before treatment. The clinical factors identified here should be incorporated in future clinical trials.


Ureaplasma gallorale, an isolate from chickens, is most closely related to the human isolate, U. urealyticum.
Ureaplasma gallorale is a urease-containing mycoplasma (a member of the Mollicutes) which is pathogenic for chickens, from which it was originally isolated. We amplified the 16S rRNA gene of this bacterium and then cloned and sequenced the amplicon. A phylogenetic analysis based on an alignment of the 16S rRNA sequences of U. gallorale and several other Ureaplasma species revealed that U. gallorale is more closely related to Ureaplasma urealyticum than to other Ureaplasma species.


Renal function and heart failure risk in older black and white individuals: the Health, Aging, and Body Composition Study.
Chronic kidney disease is a risk factor for heart failure, an association that may be particularly important in blacks who are disproportionately affected by both processes. Our objective was to determine whether the association of chronic kidney disease with incident heart failure differs between blacks and whites. The study population comprised participants in the Health, Aging, and Body Composition Study without a diagnosis of heart failure (1124 black and 1676 white community-dwelling older persons). The main predictors were quintiles of cystatin C and creatinine concentrations and estimated glomerular filtration rate. The main outcome measure was incident heart failure. Over a mean 5.7 years, 200 participants developed heart failure. High concentrations of cystatin C and low estimated glomerular filtration rate were each associated with heart failure, but the magnitude was greater for blacks than for whites (cystatin C concentration: adjusted hazard ratio for quintile 5 [> or =1.18 mg/dL] vs quintile 1 [<0.84 mg/dL] was 3.0 [95% confidence interval 1.4-6.5] in blacks and 1.4 [95% confidence interval, 0.8-2.5] in whites; estimated glomerular filtration rate: adjusted hazard ratio for quintile 5 (<59.2 mL/min) vs quintile 1 (>86.7 mL/min) was 2.7 [95% confidence interval, 1.4-4.9] in blacks and 1.8 [95% confidence interval, 0.9-3.6] in whites). For cystatin C, this association was observed at more modest decrements in kidney function among blacks as well. The population attributable risk of heart failure was 47% for blacks with moderate or high concentrations of cystatin C (> or =0.94 mg/dL) (56% prevalence) but only 5% among whites (64% prevalence). The association of kidney dysfunction with heart failure appears stronger in blacks than for whites, particularly when cystatin C is used to measure kidney function.


[A woman with skin abnormalities and muscle weakness].
A 54-year-old woman presented to the emergency department with progressive proximal muscle weakness and a symmetric skin rash. Physical examination demonstrated a heliotrope rash, Gottron lesions, mechanic's hands and symmetrical erythema of the face, neck and upper legs. The diagnosis 'dermatomyositis' was established. Subsequently, the patient was successfully treated with prednisolone 1 mg/kg.


Spine and spinal cord war injuries during the war in Croatia.
The present report summarizes the experience of an evacuation hospital in southern Croatia in treating 96 patients with spine and spinal cord war injuries. A retrospective review was done for 96 wounded persons (86 soldiers, 10 civilians) with spinal cord injuries from August 1991 through December 1995. The ages ranged from 15 to 59 years (mean, 28.3 years for soldiers, 38.5 years for civilians). Diagnostic procedures were plain radiography, computed tomography, and computed tomographic myelography. However, in most cases a more conservative surgical approach was used. The highest rates of admittance were recorded in 1992 (N = 38) and 1993 (N = 47). The lumbar spine was injured in 55% of the patients, the cervical and thoracic spines in 17.7%. All injuries were caused by projectiles from automatic rifles and sniper fire (51%) and from fragments of explosive devices (49%). Blast injury of the spinal cord was found in 10 patients. The most frequent complications caused by the fragments were wound infection, urinary tract infection, decubitus, and pneumonia. Four patients (4.2%) died in the hospital, and 43.0% of patients survived but were severely handicapped. Careful clinical examination combined with modern diagnostic imaging and use of broad-spectrum antibiotics reduced the need for surgical intervention in patients with spinal cord injuries.


Differences by gender, ethnicity, and acculturation in the efficacy of the keepin' it REAL model prevention program.
This study examined whether the efficacy of keepin' it REAL, a model program for substance use prevention in schools, was moderated by gender, ethnicity, and acculturation. Gender differences in program efficacy may arise through boys' higher risk of drug use, inadequate attention to girls' developmental issues, or cultural factors like polarized gender expectations. Data came from a randomized trial in 35 Phoenix, Arizona, middle schools involving 4,622 mostly Latino 7th graders. Using multi-level mixed models and multiple imputation missing techniques, results for the total sample showed no gender differences in program effects on recent substance use, but the program was more effective in fostering boys' than girls' anti-drug norms. Subgroup analyses demonstrated several more beneficial program effects for boys than girls (less alcohol and cigarette use and stronger anti-drug norms), but only among less acculturated Latinos. There were no gender differences in program effects among more acculturated Latinos, nor among non-Latino whites.


Group Size Effect on Cooperation in One-Shot Social Dilemmas II: Curvilinear Effect.
In a world in which many pressing global issues require large scale cooperation, understanding the group size effect on cooperative behavior is a topic of central importance. Yet, the nature of this effect remains largely unknown, with lab experiments insisting that it is either positive or negative or null, and field experiments suggesting that it is instead curvilinear. Here we shed light on this apparent contradiction by considering a novel class of public goods games inspired to the realistic scenario in which the natural output limits of the public good imply that the benefit of cooperation increases fast for early contributions and then decelerates. We report on a large lab experiment providing evidence that, in this case, group size has a curvilinear effect on cooperation, according to which intermediate-size groups cooperate more than smaller groups and more than larger groups. In doing so, our findings help fill the gap between lab experiments and field experiments and suggest concrete ways to promote large scale cooperation among people.


Contrast-Enhanced 3-T Perfusion MRI With Quantitative Analysis for the Characterization of Musculoskeletal Tumors: Is It Worth the Trouble?
The purpose of this study was to evaluate the diagnostic performance of quantitative perfusion parameters in 3-T MRI for benign-malignant differentiation in musculoskeletal tumors. Ninety-five patients with histologically proven musculoskeletal tumors were prospectively included in this study. All patients underwent 3-T contrast-enhanced perfusion MRI with T1 mapping. The extended Tofts pharmacokinetic model was used to obtain four semiquantitative and four quantitative perfusion parameters for each tumor. Two radiologists evaluated all images and manually placed the ROIs in consensus. The 95 patients had 57 (59%) benign and 38 (41%) malignant tumors. Thirty-seven (39%) were bone and 58 (61%) were soft-tissue tumors. No significant differences were found in the perfusion parameters of benign and malignant tumors (p = 0.105-0.609). The best performance for benign-malignant differentiation was found for fractional volume of the extravascular extracellular space, which yielded 79% and 38% sensitivity and specificity. When soft-tissue tumors were considered, the transfer constant from plasma to the extravascular extracellular space exhibited a significant difference (p = 0.028) and had 79% and 27% sensitivity and specificity. Quantitative perfusion MRI had fair sensitivity and poor specificity for benign-malignant differentiation, which was similar to that obtained with semiquantitative parameters.


Pilot study of an exercise intervention suitable for older heart failure patients with left ventricular systolic dysfunction.
Most studies of exercise training for heart failure have been conducted on relatively young patients with little comorbidity. Such programmes are unsuitable for the majority of older frail heart failure patients. To test the acceptability and tolerability of an outpatient exercise programme in older heart failure patients with comorbid disease. 17 patients aged 70 years and over with left ventricular systolic dysfunction attended twice weekly group exercise classes for 12 weeks, focussing on endurance exercise and everyday functional tasks. Outcome measures were proportion of sessions attended; adverse events and reasons for non-attendance; six-minute walk, accelerometry, hospital depression and anxiety score, Guyatt quality of life scale, carer strain and satisfaction scores. 83% of sessions were attended; 80% of subjects attended at least 80% of allocated sessions. One adverse incident occurred in 324 person-sessions. Encouraging improvements were seen in six minute walk test (+19 m, p=0.14) and in Functional Limitation Profile score (-82 points, p=0.02). 50% of informal carers attended at least one session. No increase in carer strain was noted. Twice-weekly group exercise focussing on aerobic endurance and everyday functional tasks was acceptable and well-tolerated in this patient group.


Effects of gomisin A on liver functions in hepatotoxic chemicals-treated rats.
The effects of gomisin A, which is a lignan component of schizandra fruits, on liver functions in various experimental liver injuries and on bile secretion in CCl4-induced liver injury were studied. Gomisin A weakly accelerated the disappearance of plasma ICG by itself at a high dose (100 mg/kg, i.p.). All of the hepatotoxic chemicals used in this study inhibited the excretion of ICG from plasma. Gomisin A showed a tendency to prevent the delays of the disappearance of plasma ICG induced by CCl4, d-galactosamine and orotic acid, but not that by ANIT. Bile flow and biliary outputs of total bile acids and electrolytes (Na+, K+, Cl- and HCO3-) were decreased in CCl4-treated rats. Gomisin A maintained bile flow and biliary output of each electrolyte nearly to the level of the vehicle-treated group, but did not affect biliary output of total bile acids. These findings suggest that gomisin A possesses a liver function-facilitating property in normal and liver injured rats and that its preventive action on CCl4-induced cholestasis is due to maintaining the function of the bile acids-independent fraction.


Primary B-cell lymphoblastic lymphoma of the testis.
We present a rare case of primary lymphoblastic B-cell lymphoma of the testis focusing on ultrasonographic and pathological features and clinical implications. Pathological examination revealed primary testicular lymphoblastic B-cell lymphoma which was treated with adjuvant chemotherapy, including rachicentesis with administration of chemotherapy and with radiotherapy of contralateral testis. Primary testicular lymphoblastic B cell lymphoma is an aggressive disease and it is necessary a multimodal therapy (surgery, chemotherapy and radiotherapy) to prevent metastasis.


Upregulation of TRPC1 contributes to contractile function in isoproterenol-induced hypertrophic myocardium of rat.
The transient receptor potential canonical channel 1 (TRPC1) is a crucial component of the stretch-activated ion channels (SACs). The objective of this research was to demonstrate the contribution of TRPC1 in maintaining cardiac contractile function in the hypertrophic myocardium. Hypertrophic rat hearts were induced by injecting isoproterenol intraperitoneally, and the expressions of TRPC1/3/6 and Na(+)/Ca(2+) exchanger 1 (NCX1) proteins were analyzed by Western blot. The intracellular calcium images, the action potential of myocardium, the length-dependent contractile force of ventricle muscle and the cardiac output of isolated heart were investigated. The expression of TRPC1 was increased in the hypertrophic myocardium. After being stretched, the ascendant amplitude of the increase in the intracellular calcium ion concentration ([Ca(2+)]i) in the hypertrophic myocardium was higher than that in the normal myocardium. The increase of the APD50 and the amplitude of the membrane potential depolarization were more significant in the hypertrophic myocardium after the activation of SACs. When the heart preparations were perfused with Tyrode's solution, there was no difference in the cardiac systolic function between the cardiac hypertrophy group and the control group. Gadolinium, a SACs blocker, reduced the length-dependent contractile force and suppressed the ascending limb of the Frank-Starling curves in the hypertrophic heart. The upregulation of TRPC1 contributes to the contractile function in the hypertrophic myocardium by increasing [Ca(2+)]i through the SACs.


Low-dose effects of bisphenol A on mammary gland development in rats.
Bisphenol A (BPA) is widely used in food contact materials, toys, and other products. Several studies have indicated that effects observed at doses near human exposure levels may not be observed at higher doses. Many studies have shown effects on mammary glands at low doses of BPA, however, because of small number of animals or few doses investigated these data have not been used by EFSA as point of departure for the newly assessed tolerable daily intake (TDI). We performed a study with perinatal exposure to BPA (0, 0.025, 0.25, 5, and 50 mg/kg bw/day) in rats (n = 22 mated/group). One of the aims was to perform a study robust enough to contribute to the risk assessment of BPA and to elucidate possible biphasic dose-response relationships. We investigated mammary gland effects in the offspring at 22, 100, and 400 days of age. Male offspring showed increased mammary outgrowth on pup day (PD) 22 at 0.025 mg/kg BPA, indicating an increased mammary development at this low dose only. Increased prevalence of intraductal hyperplasia was observed in BPA females exposed to 0.25 mg/kg at PD 400, but not at PD 100, and not at higher or lower doses. The present findings support data from the published literature showing that perinatal exposure to BPA can induce increased mammary growth and proliferative lesions in rodents. Our results indicate that low-dose exposure to BPA can affect mammary gland development in male and female rats, although higher doses show a different pattern of effects. The observed intraductal hyperplasia in female rats could be associated with an increased risk for developing hyperplastic lesions, which are parallels to early signs of breast neoplasia in women. Collectively, current knowledge on effects of BPA on mammary gland at low doses indicates that highly exposed humans may not be sufficiently protected.


Creatine and guanidinoacetate reference values in a French population.
Creatine and guanidinoacetate are biomarkers of creatine metabolism. Their assays in body fluids may be used for detecting patients with primary creatine deficiency disorders (PCDD), a class of inherited diseases. Their laboratory values in blood and urine may vary with age, requiring that reference normal values are given within the age range. Despite the long known role of creatine for muscle physiology, muscle signs are not necessarily the major complaint expressed by PCDD patients. These disorders drastically affect brain function inducing, in patients, intellectual disability, autistic behavior and other neurological signs (delays in speech and language, epilepsy, ataxia, dystonia and choreoathetosis), being a common feature the drop in brain creatine content. For this reason, screening of PCDD patients has been repeatedly carried out in populations with neurological signs. This report is aimed at providing reference laboratory values and related age ranges found for a large scale population of patients with neurological signs (more than 6 thousand patients) previously serving as a background population for screening French patients with PCDD. These reference laboratory values and age ranges compare rather favorably with literature values for healthy populations. Some differences are also observed, and female participants are discriminated from male participants as regards to urine but not blood values including creatine on creatinine ratio and guanidinoacetate on creatinine ratio values. Such gender differences were previously observed in healthy populations; they might be explained by literature differential effects of testosterone and estrogen in adolescents and adults, and by estrogen effects in prepubertal age on SLC6A8 function. Finally, though they were acquired on a population with neurological signs, the present data might reasonably serve as reference laboratory values in any future medical study exploring abnormalities of creatine metabolism and transport.


Catecholamine Contents of Different Region of Adult Rat Brain Are Altered Following Short and Long-term Exposures to Pb(+2.).
Catecholamine is a group of neurotransmitters that is believed to be responsible for the normal function of animal brain. Physiological and behavioral changes of human body have been reported due to the damage of the brain function following lead exposure. Due to the assumption of lead disposal in brain tissue with two year for its half-life, which results in alteration of brain function, we investigated the ability of lead to change the brain catecholamines during short and long-term studies. Rats were exposed daily with varying amounts of lead and catecholamine contents of cerebellum, mid-brain and brain cortex were determined. Acute peritoneal administration of single dose of lead as lead acetate (260 μmol/Kg) after 2 h reduced (p < 0.05) the catecholamine levels of cerebellum, mid-brain and cortex part by 34.9%, 35.44% and 23.8%, respectively. The extension of experiment time to 5 h, significant (p < 0.05) reductions in catecholamine levels of mentioned regions of brain by 32.35%, 12.35% and 19.3% were seen respectively. Daily intraperitoneal administration of 10 μmol/Kg lead for 30 and 60 days reduced catecholamines levels of cerebellum (22.22% and 30.44%), midbrain (12.48% and 26.27%) and brain cortex (11.58% and 26.7%) respectively. It might be concluded that brain dysfunction in lead intoxicated rat occurred through the reduction in the catecholamine levels of different parts of brain. Lead might be therefore considered as a probable factor in causing neurological disease in lead exposed man.


Identification of the major allergens in wheat flour responsible for baker's asthma.
Baker's asthma, a typical occupational allergic disease, is a serious problem in the food industries. In this study, purification and identification of major allergens recognized by IgEs in sera of allergic patients were performed. Major immunoreactive proteins were purified from the albumin fraction by gel filtration on a Toyopearl HW-50 column followed by reverse-phase HPLC. The N-terminal amino acid sequences and molecular masses measured by MS indicated that the major immunoreactive proteins are members of the alpha-amylase inhibitor family, 0.19 and 0.28. Significant leukotriene release by each purified protein was observed in cell-associated stimulation tests, suggesting in vivo activity of these antigens. Carbohydrate analyses of major allergens indicated that they are monoglycosylated but not N-glycosylated in spite of the presence of a potential N-glycosylation site. Recombinant 0.19 expressed in Escherichia coli showed the same reactivity with IgE as native wheat 0.19 in Western blotting and ELISA using methyl vinyl ether maleic anhydride co-polymer as an immobilizing reagent, suggesting that the allergenic epitopes are located in the peptide portions.


Controversial treatment of spasticity: exploring alternative therapies for motor function in children with cerebral palsy.
The treatment and management of children with cerebral palsy is an ever-evolving story. In the past 20 years, a number of exciting innovations in treatment have expanded the opportunities to help children. At the same time, the field has experienced a remarkable proliferation of "alternative" therapies-approaches based on ideas about the biologic basis of neurodevelopmental disabilities and their management that differ considerably from conventional thinking in Western medicine. Professionals working with children with cerebral palsy and their families are frequently asked for an opinion about or even endorsement of these new and "promising" approaches to therapy. These can be very difficult to provide when the evidence is limited, peer-reviewed reports are scarce, and the primary source of information is the World Wide Web. The purposes of this article are to discuss briefly why it can be difficult to ascertain whether any treatment--conventional or alternative--does more harm than good, and to consider what rules of evidence can be applied to make a sound judgment about a new treatment. The article then discusses several current controversial alternative therapies, reviewing the available literature and offering a critical appraisal of each. Topics addressed include hyperbaric oxygen therapy, conductive education, the Adeli suit, and therapeutic (subthreshold) electrical stimulation because these approaches have been applied to children with cerebral palsy.


No change in health-related quality of life for at-risk U.S. women and men starting HIV pre-exposure prophylaxis (PrEP): Findings from HPTN 069/ACTG A5305.
Tenofovir (TDF)-containing PrEP is effective for HIV prevention, but its effect on health-related quality of life (QOL) is unknown. Using data from HPTN 069/ACTG A5305, a randomized study of potential PrEP regimens comparing maraviroc alone, or together with TDF or emtricitabine (FTC), to TDF + FTC (control), we evaluated the impact of these regimens on QOL in at-risk HIV-uninfected U.S. women and men. QOL was measured at baseline (before starting medications) and every 8 weeks through week 48 using the EQ-5D-3L. Responses were converted to a scale from 0.0 (death) to 1.0 (perfect health), using published valuation weights. Mean scores were compared between groups at each time point using nonparametric testing. Multivariable linear regression was used to adjust for potential confounders. We analyzed 186 women (median age 35 years, 65% black, 17% Hispanic) and 405 men (median age 30 years, 28% black, 22% Hispanic), including 9 transgender participants analyzed based on sex-at-birth. Mean baseline QOL was 0.91 for women and 0.95 for men. There were minimal changes in mean QOL over time for any regimen (women: p = 0.29; men: p = 0.14). There were no significant differences between participants who continued the regimen compared to participants who discontinued early (women: p = 0.61; men: p = 0.1). Mean QOL did not differ significantly by regimen at any time point, both unadjusted and after adjustment for age, race/ethnicity, adherence, and use of alcohol, marijuana, opiates, and other substances. QOL in at-risk individuals starting candidate PrEP regimens in a clinical trial is similar to the general population and maintained over time. This finding did not vary among regimens or when adjusted for demographics, adherence, and substance use. Our findings are the first to show that starting a candidate PrEP regimen in at-risk HIV-uninfected U.S. women and men was not associated with significant changes in QOL. Clinicaltrials.gov NCT01505114.


Single-cell resolution landscape of equine peripheral blood mononuclear cells reveals diverse cell types including T-bet+ B cells.
Traditional laboratory model organisms represent a small fraction of the diversity of multicellular life, and findings in any given experimental model often do not translate to other species. Immunology research in non-traditional model organisms can be advantageous or even necessary, such as when studying host-pathogen interactions. However, such research presents multiple challenges, many stemming from an incomplete understanding of potentially species-specific immune cell types, frequencies, and phenotypes. Identifying and characterizing immune cells in such organisms is frequently limited by the availability of species-reactive immunophenotyping reagents for flow cytometry, and insufficient prior knowledge of cell type-defining markers. Here, we demonstrate the utility of single-cell RNA sequencing (scRNA-Seq) to characterize immune cells for which traditional experimental tools are limited. Specifically, we used scRNA-Seq to comprehensively define the cellular diversity of equine peripheral blood mononuclear cells (PBMC) from healthy horses across different breeds, ages, and sexes. We identified 30 cell type clusters partitioned into five major populations: monocytes/dendritic cells, B cells, CD3+PRF1+ lymphocytes, CD3+PRF1- lymphocytes, and basophils. Comparative analyses revealed many cell populations analogous to human PBMC, including transcriptionally heterogeneous monocytes and distinct dendritic cell subsets (cDC1, cDC2, plasmacytoid DC). Remarkably, we found that a majority of the equine peripheral B cell compartment is comprised of T-bet+ B cells, an immune cell subpopulation typically associated with chronic infection and inflammation in human and mouse. Taken together, our results demonstrate the potential of scRNA-Seq for cellular analyses in non-traditional model organisms and form the basis for an immune cell atlas of horse peripheral blood.


Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease.
Some patients with inflammatory bowel disease have anemia that is refractory to treatment with iron and vitamins. We examined whether administering iron and recombinant erythropoietin could raise hemoglobin levels in such patients. Thirty-four patients with inflammatory bowel disease (15 with ulcerative colitis and 19 with Crohn's disease) and anemia refractory to iron therapy (hemoglobin concentrations below 10.0 g per deciliter [6.2 mmol per liter]) were randomly assigned in a prospective, double-blind, 12-week trial to receive either oral iron (100 mg per day) and subcutaneous erythropoietin (150 U per kilogram of body weight twice per week) (n=17) or oral iron and placebo (n=17). The primary measure of efficacy was an increase in hemoglobin levels of more than 1.0 g per deciliter (0.62 mmol per liter). Additional analyses were performed with other patients with inflammatory bowel disease. The severity of anemia was related to clinical disease activity as well as to in vitro monocyte secretion of interleukin-1 beta, a proinflammatory cytokine. Serum erythropoietin concentrations were increased in 52 randomly selected outpatients with inflammatory bowel disease and anemia, but the concentrations were inadequate in relation to the degree of anemia. Twelve weeks of therapy with recombinant erythropoietin and oral iron increased mean (+/-SE) hemoglobin concentrations from 8.81+/-0.27 g per deciliter (5.47+/-0.17 micromol per liter) to 10.52+/-0.41 g per deciliter (6.5+/-0.25 micromol per liter), whereas hemoglobin concentrations in the placebo group decreased from 8.69+/-0.11 g per deciliter (5.4+/-0.068 micromol per liter) to 7.84+/- 0.33 g per deciliter (4.9+/-0.2 mmol per liter) (P<0.001). After 12 weeks, hemoglobin levels had increased by more than 1.0 g per deciliter in 82 percent of the patients in the erythropoietin group, as compared with 24 percent of those in the placebo group (P=0.002). There were five treatment failures in the placebo group and two in the erythropoietin group (P=0.18); treatment failure was defined as a decrease in hemoglobin levels of more than 2.0 g per deciliter (1.24 micromol per liter) to a value below 8.0 g per deciliter (4.96 micromol per liter) or any decrease to less than 6.5 g per deciliter (4.03 micromol per liter). In patients with inflammatory bowel disease and anemia refractory to treatment with iron and vitamins, treatment with oral iron and recombinant erythropoietin can raise hemoglobin levels.


Anti-tumor effects of human peripheral gammadelta T cells in a mouse tumor model.
Peripheral gammadelta T cells derived from healthy donors were found to exhibit cytotoxicity against a variety of tumor cell lines in vitro, including CNE2, which was established from nasopharyngeal carcinoma (NPC). The anti-tumor effects were further studied in a mouse model. Control nude mice inoculated s.c. with 5 x 10(6) CNE2 cells regularly developed hypodermal tumors, which progressively increased in size, and animals had a mean survival of 35 +/- 3.4 days. Tumor growth was arrested and tumor size was reduced after animals were infused with 5 x 10(7) gammadelta T cells derived from a healthy donor. The anti-tumor effects were temporary, however, and tumor growth was resumed after about 1 week in a group of the animals that had been given a single dose of gammadelta T cells. In another group of animals given 2 doses of gammadelta cells 1 week apart, resumption of tumor growth was delayed for a further week. Mean survival of the 2 groups was increased to 61 +/- 15.7 and 74 +/- 12.9 days, respectively. Immunohistology revealed an accumulation of infused cells in tumors attended by focal tumor necrosis in specimens taken 2 days after infusion. Infiltrative cells virtually disappeared from tumor tissues 6 days after infusion, accompanied by increased mitotic indices of tumor cells. These temporal relationships suggested that the accumulation of infused gammadelta T cells in hypodermal tumors was responsible for the observed anti-tumor effects.


Management of gallstone pancreatitis: cholecystectomy or ERCP and endoscopic sphincterotomy.
Currently, cholecystectomy is recommended for patients with gallstone-induced pancreatitis. ERCP with endoscopic sphincterotomy (ES) within 24 to 48 hours is also suggested for the treatment of acute gallstone pancreatitis. The aim of this study was to determine outcome after cholecystectomy versus ES alone in patients with gallstone pancreatitis. One hundred seventeen patients with gallstone pancreatitis were included in this prospective observational study. Inclusion criteria were typical abdominal pain; serum amylase level 3 times or greater than normal; and gallbladder stones and a dilated bile duct, with or without stones, by US, CT, or ERCP. Eighty-three patients (Group A) underwent cholecystectomy after initial evaluation including ERCP in 43 (53%) and ERCP with ES in 38 (47%). The remaining 34 (Group B) underwent successful ERCP with ES alone. Mean follow-up was 33 months for Group A and 34 months for Group B. Recurrent gallstone pancreatitis was noted in 2 patients (2.4%) in Group A (bile duct stone in 2, sludge and papillary stenosis in 1), and in 1 patient (2.9%) in Group B. Ten patients in Group B had follow-up US of the gallbladder that showed disappearance of stones in 3. During follow-up, there was no significant difference in the rates of biliary complications (Group A, 3.6% vs. Group B, 11.6%; p = 0.19) or serious complications (pancreatitis, cholecystitis, cholangitis) (Group A, 3.6% vs. Group B, 5.8%). Also, there was no significant difference in procedure-related complications. Recurrence of pancreatitis after ERCP with ES alone for gallstone pancreatitis is rare. In patients who have undergone ES alone, cholecystectomy should be considered only if there are overt manifestations of gallbladder disease (e.g., biliary pain, cholecystitis, cystic duct obstruction) and not for prevention of recurrent gallstone pancreatitis. Because treatment by ES alone may be associated with a higher risk of biliary complications during follow-up compared with cholecystectomy, these patients may require close surveillance.


Prevalence of burnout syndrome among military physicians at a public hospital in Rio de Janeiro, Brazil.
Burnout syndrome is a sociopsychological disorder which develops in response to emotional tension and occupational stress, and is triggered by continuous stressors to which workers are exposed.It comprises three domains: emotional exhaustion, depersonalization and reduced personal accomplishment. To establish the prevalence of physical and emotional stress (burnout) among military physicians at Marcilio Dias Naval Hospital, Rio de Janeiro, Brazil. Cross-sectional, exploratory and descriptive study with quantitative approach.Data collection was performed from March through June 2016.Assessment instruments used were Maslach Burnout Inventory and a sociodemographic questionnaire. Burnout was more prevalent among women (57.1%), the participants who lived with a partner (64.3%), with age under 50 years old (100.0%), income up to 15 times the equivalent of the minimum wage (78.6%), who practiced physical activity (57.1%) and no leisure activities (78.6%).Alcohol consumption and smoking behaved as significant risk factors.Prevalence was higher for the depersonalization domain (44.8%), followed by personal accomplishment (28.4%) and emotional exhaustion (6.6%). The professionals at the analyzed military hospital exhibited considerable levels of burnout, especially in regard to domain depersonalization.We call the attention to the need to develop preventive programs against burnout, particularly targeting workers exposed to emotional exhaustion, to avoid the occurrence of illness.