The ultrastructure of metastatic adenocarcinoma in serous fluids. An aid in identification of the primary site of the neoplasm.
Identification of the primary sites of metastatic adenocarcinomas is a diagnostic problem, particularly in cases of occult primary neoplasms. We studied the ultrastructural morphology of 16 metastatic adenocarcinomas that presented as effusions to establish organ-specific features that would characterize adenocarcinomas from various sites. The nine cases in which the site of the primary carcinoma was known included seven derived from the breast, one from the ovary and one from the colon. The primary site was unknown in seven cases at the time of presentation. After investigations, the primary site became known in five cases (lung, colon and appendix, one case each, and the ovary in two cases). Ultrastructurally diagnostic features could be detected in gastrointestinal, ovarian, bronchioloalveolar-cell and breast carcinomas. In gastrointestinal carcinomas, the presence of short microvilli with long rootlets was specific for the group. The lamellar inclusions of type II pneumocytes were diagnostic of bronchioloalveolar-cell carcinoma. The microvilli in ovarian carcinomas were long, slender and bushy, as in mesotheliomas; however, the cells lacked the perinuclear condensation of tonofilaments seen in the latter. Breast carcinomas were associated with numerous intracytoplasmic lumina, electron-dense granules and aggregates of small vesicular bodies. We conclude that ultrastructural examination of adenocarcinomas in serious fluids can help to identify the primary site of certain neoplasms or at least shorten the list of possibilities. This may reduce costs and minimize the discomfort patients have to undergo by curtailing extensive invasive investigations in search of unknown primary neoplasms.


Periventricular intraparenchymal echodensities in the premature newborn: critical determinant of neurologic outcome.
Controversy exists concerning the degree of importance of periventricular intraparenchymal echodensities (IPE) observed on neonatal ultrasound scans in the determination of subsequent neurologic disability in premature infants. In this report, IPE was studied in 75 infants weighing less than 2,000 g at birth to determine the basic characteristics of the lesion, the likely pathogenesis, the outcome, and the aspects of the ultrasonographic appearance in the acute period of neonatal illness that are important for prediction of outcome. IPE was defined as any periventricular echodensity greater than 1 cm in at least one dimension. IPE was strikingly associated with large areas of intraventricular hemorrhage (IVH) (81% of cases). IPE was distinctly asymmetric. Thus, the lesion was either exclusively unilateral (67%) or bilateral with marked predominance on one side. The associated IVH was asymmetric in approximately 80% of cases, and in all 50 cases of large asymmetric IVH, IPE occurred on the same side as the larger amount of intraventricular blood. Moreover, more than 50% of such cases of IPE associated with large asymmetric IVH were progressive. Neuropathologic correlation showed that IPE represented hemorrhagic necrosis of periventricular tissue. Concerning pathogenesis, these data raise the possibility that large asymmetric IVH is related etiologically to IPE. Outcome varied with the severity of the IPE. Thus, the mortality rate among the 38 infants with extensive IPE was 79%. Of the survivors with extensive IPE, all had subsequent major motor deficits and all but one exhibited cognitive function less than 80% of normal. Among the 37 infants with localized IPE, the mortality rate was 38%. Of the survivors, although 79% had major motor deficits, 43% had cognitive function greater than 80% of normal. Thus, the findings demonstrate that with extensive IPE there is little or no chance for survival with normal neurologic and cognitive outcome, but with localized IPE, although major motor deficits are common, an appreciable proportion of infants have cognitive function in the normal range. Careful, quantitative assessment of the ultrasonographic features of IPE in the acute period of illness in the premature infant is of major value in estimating outcome.


Next-Generation Sequencing Identifies Gene Mutations That Are Predictive of Malignancy in Residual Needle Rinses Collected From Fine-Needle Aspirations of Thyroid Nodules.
- Thyroid nodules have a prevalence of approximately 70% in adults. Fine-needle aspiration (FNA) is a minimally invasive, cost-effective, standard method to collect tissue from thyroid nodules for cytologic examination. However, approximately 15% of thyroid FNA specimens cannot be unambiguously diagnosed as benign or malignant. - To investigate whether clinically actionable data can be obtained using next-generation sequencing of residual needle rinse material. - A total of 24 residual needle rinse specimens with malignant (n = 6), indeterminate (n = 9), or benign (n = 9) thyroid FNA diagnoses were analyzed in our clinical molecular diagnostics laboratory using next-generation sequencing assays designed to detect gene mutations and translocations that commonly occur in thyroid cancer. Results were correlated with surgical diagnoses and clinical outcomes. - Interpretable data were generated from 23 of 24 residual needle rinse specimens. Consistent with its well-known role in thyroid malignancy, BRAF V600E mutations were detected in 4 malignant cases. An NRAS mutation was detected in 1 benign case. No mutations were detected from specimens with indeterminate diagnoses. - Our data demonstrate that residual thyroid FNA needle rinses are an adequate source of material for molecular diagnostic testing. Importantly, detection of a mutation implicated in thyroid malignancy was predictive of the final surgical diagnosis and clinical outcome. Our strategy to triage thyroid nodules with indeterminate cytology with molecular testing eliminates the need to perform additional FNA passes into dedicated media or to schedule additional invasive procedures. Further investigation with a larger sample size to confirm the clinical utility of our proposed strategy is underway.


Investigation of the vasorelaxant effects of 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1) and diethylamine/nitric oxide (DEA/NO) on the human radial artery used as coronary bypass graft.
The radial artery (RA) is used as a spastic coronary bypass graft. This study was designed to investigate the mechanism of vasorelaxant effects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase (sGC) activator, and DEA/NO (diethylamine/nitric oxide), a NO-nucleophile adduct, on the human RA. RA segments (n = 25) were obtained from coronary artery bypass grafting patients and were divided into 3-4 mm vascular rings. Using the isolated tissue bath technique, the endothelium-independent vasodilatation function was tested in vitro by the addition of cumulative concentrations of YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) following vasocontraction by phenylephrine in the presence or absence of 10-5 mol/L ODQ (1H-(1,2,4)oxadiazole(4,3-a)quinoxalin-1-one), the selective sGC inhibitor, 10-7 mol/L iberiotoxin, a blocker of Ca2+-activated K+ channels, or 10-5 mol/L ODQ plus 10-7 mol/L iberiotoxin. We also evaluated the effect of YC-1 and DEA/NO on the cGMP levels in vascular rings obtained from human radial artery (n = 6 for each drug). YC-1 (10-10 to 3 x 10-7 mol/L) and DEA/NO (10-8 to 3 x 10-5 mol/L) caused the concentration-dependent vasorelaxation in RA rings precontracted with phenylephrine (10-5 mol/L) (n = 20 for each drug). Pre-incubation of RA rings with ODQ, iberiotoxin, or ODQ plus iberiotoxin significantly inhibited the vasorelaxant effect of YC-1, but the inhibitor effect of ODQ plus iberiotoxin was significantly more than that of ODQ and iberiotoxin alone (p < 0.05). The vasorelaxant effect of DEA/NO almost completely abolished in the presence of ODQ and iberiotoxin plus ODQ, but did not significantly change in the presence of iberiotoxin alone (p > 0.05). The pEC50 value of DEA/NO was significantly lower than those for YC-1 (p < 0.01), with no change Emax values in RA rings. In addition, YC-1-stimulated RA rings showed more elevation in cGMP than that of DEA/NO (p < 0.05). These findings indicate that YC-1 is a more potent relaxant than DEA/NO in the human RA. The relaxant effects of YC-1 could be due to the stimulation of the sGC and Ca2+-sensitive K+channels, whereas the relaxant effects of DEA/NO could be completely due to the stimulation of the sGC. YC-1 and DEA/NO may be effective as vasodilator for the short-term treatment of perioperative spasm of coronary bypass grafts.


Treatment of a maxillary fibrosarcoma in an adult alpaca.
An approximately 5-year-old sexually intact male alpaca was evaluated because of a right-sided maxillary mass that had recurred after previous surgical debulking. Clinical, radiographic, and CT examination revealed an approximately 1.5-cm-diameter soft tissue mass associated with expansile osteolysis of the maxillary alveolar bone, beginning at the level of the right maxillary third premolar tooth extending caudally to the level of the rostral roots of the second molar tooth. Right partial maxillectomy was performed, and histologic examination revealed an incompletely excised fibrosarcoma with osseous metaplasia. External beam radiation therapy to the tumor bed was initiated 1 month after surgery. Computerized planning was performed, and a total radiation dose of 48 Gy was prescribed in eleven 4.4-Gy fractions. Follow-up CT evaluations 6 and 58 weeks after radiation therapy was completed revealed no evidence of tumor recurrence. No clinical evidence of tumor recurrence was detected through 110 weeks after radiation therapy. The oral fibrosarcoma in the alpaca described here was successfully treated with surgical excision and adjuvant radiation therapy, resulting in excellent quality of life of the treated animal.


Melatonin anticancer effects: review.
Melatonin (N-acetyl-5-methoxytryptamine, MLT), the main hormone produced by the pineal gland, not only regulates circadian rhythm, but also has antioxidant, anti-ageing and immunomodulatory properties. MLT plays an important role in blood composition, medullary dynamics, platelet genesis, vessel endothelia, and in platelet aggregation, leukocyte formula regulation and hemoglobin synthesis. Its significant atoxic, apoptotic, oncostatic, angiogenetic, differentiating and antiproliferative properties against all solid and liquid tumors have also been documented. Thanks, in fact, to its considerable functional versatility, MLT can exert both direct and indirect anticancer effects in factorial synergy with other differentiating, antiproliferative, immunomodulating and trophic molecules that form part of the anticancer treatment formulated by Luigi Di Bella (Di Bella Method, DBM: somatostatin, retinoids, ascorbic acid, vitamin D3, prolactin inhibitors, chondroitin-sulfate). The interaction between MLT and the DBM molecules counters the multiple processes that characterize the neoplastic phenotype (induction, promotion, progression and/or dissemination, tumoral mutation). All these particular characteristics suggest the use of MLT in oncological diseases.


Bacillus subtilis phosphorylated PhoP: direct activation of the E(sigma)A- and repression of the E(sigma)E-responsive phoB-PS+V promoters during pho response.
The phoB gene of Bacillus subtilis encodes an alkaline phosphatase (PhoB, formerly alkaline phosphatase III) that is expressed from separate promoters during phosphate deprivation in a PhoP-PhoR-dependent manner and at stage two of sporulation under phosphate-sufficient conditions independent of PhoP-PhoR. Isogenic strains containing either the complete phoB promoter or individual phoB promoter fusions were used to assess expression from each promoter under both induction conditions. The phoB promoter responsible for expression during sporulation, phoB-P(S), was expressed in a wild-type strain during phosphate deprivation, but induction occurred >3 h later than induction of Pho regulon genes and the levels were approximately 50-fold lower than that observed for the PhoPR-dependent promoter, phoB-P(V). E(sigma)E was necessary and sufficient for P(S) expression in vitro. P(S) expression in a phoPR mutant strain was delayed 2 to 3 h compared to the expression in a wild-type strain, suggesting that expression or activation of sigma(E) is delayed in a phoPR mutant under phosphate-deficient conditions, an observation consistent with a role for PhoPR in spore development under these conditions. Phosphorylated PhoP (PhoP approximately P) repressed P(S) in vitro via direct binding to the promoter, the first example of an E(sigma)E-responsive promoter that is repressed by PhoP approximately P. Whereas either PhoP or PhoP approximately P in the presence of E(sigma)A was sufficient to stimulate transcription from the phoB-P(V) promoter in vitro, roughly 10- and 17-fold-higher concentrations of PhoP than of PhoP approximately P were required for P(V) promoter activation and maximal promoter activity, respectively. The promoter for a second gene in the Pho regulon, ykoL, was also activated by elevated concentrations of unphosphorylated PhoP in vitro. However, because no Pho regulon gene expression was observed in vivo during P(i)-replete growth and PhoP concentrations increased only threefold in vivo during phoPR autoinduction, a role for unphosphorylated PhoP in Pho regulon activation in vivo is not likely.


The Chlamydia trachomatis parasitophorous vacuolar membrane is not passively permeable to low-molecular-weight compounds.
Chlamydia trachomatis is an obligately intracellular bacterial parasite of eucaryotic cells that undergoes a biphasic life cycle within a parasitophorous vacuole (PV) called an inclusion. The parasitophorous vacuolar membrane (PVM) constitutes a barrier between the replicating bacteria and the nutrient-rich environment of the host cytoplasm. To determine whether the chlamydial PVM contains pores that allow passive diffusion of metabolites between the host cytoplasm and the PV, fluorescent tracer molecules were introduced directly into the cytoplasm of infected cells by transfection or microinjection. Fluorescence microscopy and laser scanning confocal microscopy were subsequently employed to determine whether equilibration of the fluorescent tracers between the cytoplasm and the PV occurred. No movement of tracer molecules as small as 520 Da from the cytoplasm to the PV was observed. These data suggest that the chlamydial PV is not passively permeable to small molecules through open channels in the PVM.


Liver Bacterial Dysbiosis With Non-Tuberculosis Mycobacteria Occurs in SIV-Infected Macaques and Persists During Antiretroviral Therapy.
Liver disease is a significant contributor to morbidity and mortality in HIV-infected individuals, even during successful viral suppression with combination antiretroviral therapy (cART). Similar to HIV infection, SIV infection of rhesus macaques is associated with gut microbiome dysbiosis and microbial translocation that can be detected systemically in the blood. As microbes leaving the intestines must first pass through the liver via the portal vein, we evaluated the livers of both SIV-infected (SIV+) and SIV-infected cART treated (SIV+cART) rhesus macaques for evidence of microbial changes compared to uninfected macaques. Dysbiosis was observed in both the SIV+ and SIV+cART macaques, encompassing changes in the relative abundance of several genera, including a reduction in the levels of Lactobacillus and Staphylococcus. Most strikingly, we found an increase in the relative abundance and absolute quantity of bacteria within the Mycobacterium genus in both SIV+ and SIV+cART macaques. Multi-gene sequencing identified a species of atypical mycobacteria similar to the opportunistic pathogen M. smegmatis. Phosphatidyl inositol lipoarabinomannan (PILAM) (a glycolipid cell wall component found in atypical mycobacteria) stimulation in primary human hepatocytes resulted in an upregulation of inflammatory transcriptional responses, including an increase in the chemokines associated with neutrophil recruitment (CXCL1, CXCL5, and CXCL6). These studies provide key insights into SIV associated changes in hepatic microbial composition and indicate a link between microbial components and immune cell recruitment in SIV+ and SIV+cART treated macaques.


IGF-II mRNA expression in breast cancer: predictive value and relationship to other prognostic factors.
Insulin-like growth factor-II (IGF-II) is an important regulator of tumor growth in breast cancer. In this study we have examined the prognostic value of IGF-II mRNA expression in breast cancer and its relationship to other predictive parameters. Sixty-eight women with infiltrating ductal carcinoma were given the same treatments including mastectomy and antitumoral therapies and followed up for 5 years. The overall 5-year survival rate was 73.5% (55/68). IGF-II mRNA was expressed in 33/64 patients (51.6%) and had no significant impact on survival. The expression of estrogen receptor (ER) and progesterone receptor (PgR) did not significantly affect the 5-year survival, but in the presence of an IGF-II mRNA signal, the survival of ER- and PgR-negative patients (n=9) was lower than that of ER- and PgR-positive patients (n=15), although the difference was not significant. The 5-year survival was not significantly different between Ki-67-positive and negative patients, but in the IGF-II positive group Ki-67-positive patients (n=7) had a significantly poorer prognosis than Ki-67-negative patients (n=26). The expression of p53 protein was associated with a poorer prognosis: 6/11 (54.5%) p53-positive patients died in the first 26 months of follow-up and 5 of these 6 patients (83.3%) also had positive IGF-II mRNA expression. IGF-II mRNA expression per se is not an independent predictive factor in breast cancer but may be a marker of poor prognosis when associated with other prognostic factors such as Ki-67 index and p53 expression.


Delivery of liposome content into plant protoplasts.
The interaction of various types of liposomes with protoplasts of Nicotiana tabacum and Capsicum annuum was studied by means of fluorescence microscopy and autoradiography. The liposomes with a positive charge displayed the strongest affinity to the protoplast membrane, whereas the maximum intracellular delivery of encapsulated protein and DNA molecules into protoplasts was exhibited by the negatively charged liposomes. The results showed that the negatively charged unilamellar liposomes prepared by the reverse-phase evaporation method represent a very promising universal vehicle system for introducing genetic information into plants.


Dementia as a determinant of social and health service use in the last two years of life 1996-2003.
Dementia is one of the most common causes of death among old people in Finland and other countries with high life expectancies. Dementing illnesses are the most important disease group behind the need for long-term care and therefore place a considerable burden on the health and social care system. The aim of this study was to assess the effects of dementia and year of death (1998-2003) on health and social service use in the last two years of life among old people. The data were derived from multiple national registers in Finland and comprise all those who died in 1998, 2002 or 2003 and 40% of those who died in 1999-2001 at the age of 70 or over (n = 145 944). We studied the use of hospitals, long-term care and home care in the last two years of life. Statistics were performed using binary logistic regression analyses and negative binomial regression analyses, adjusting for age, gender and comorbidity. The proportion of study participants with a dementia diagnosis was 23.5%. People with dementia diagnosis used long-term care more often (OR 9.30, 95% CI 8.60, 10.06) but hospital (OR 0.33, 95% CI 0.31, 0.35) and home care (OR 0.50, 95% CI 0.46, 0.54) less often than people without dementia. The likelihood of using university hospital and long-term care increased during the eight-year study period, while the number of days spent in university and general hospital among the users decreased. Differences in service use between people with and without dementia decreased during the study period. Old people with dementia used long-term care to a much greater extent and hospital and home care to a lesser extent than those without dementia. This difference persisted even when controlling for age, gender and comorbidity. It is important that greater attention is paid to ensuring that old people with dementia have equitable access to care.


Bless me reader for I have sinned: physicians and confessional writing.
From the poetry of William Carlos Williams, the novels of Walker Percy, and the short stories of Anton Chekov to the contemporary essays of Atul Gawande, physicians' contributions to literary genres have been significant. This article explores the specific form of confessional writing offered by physicians during the past half century, writing that often exposes medical error or negative feelings towards patients. A history of confessional practices as a legal tool, as religious practice, and as literary genre is offered, followed by analyses of selected confessional writings by physicians, many of them found in clinical journals such as Journal of the American Medical Association, Annals of Internal Medicine, and the Lancet. The authors of the narratives described here are engaged in several or all elements of the confessional sequence, which may offer them some resolution through the exposure and acknowledgment of their shared humanity with their patients and their expression of regret for any harm done.


Cell therapy for spinal cord injuries: what is really going on?
During the last two decades, many experiments have examined the ability of cell transplants to ameliorate the loss of function after spinal cord injuries, with the hope of developing interventions to benefit patients. Although many reports suggest positive effects, there is growing concern over the quality of the available preclinical data. It is therefore important to ask whether this worldwide investigative process is close to defining a cell transplant protocol that could be translated into human patients with a realistic chance of success. This review systematically examines the strength of the preclinical evidence and outlines mechanisms by which transplanted cells may mediate their effects in spinal cord injuries. First, we examined changes in voluntary movements in the forelimb associated with cell transplants after partial cervical lesions. Second, we examined the efficacy of transplanted cells to restore electrophysiological conduction across a complete thoracic lesion. We postulated that cell therapies found to be successful in both models could reasonably have potential to treat human patients. We conclude that although there are data to support a beneficial effect of cell transplantation, most reports provide only weak evidence because of deficits in experimental design. The mechanisms by which transplanted cells mediate their functional effects remain unclear.


Prolonged perturbations of tumour necrosis factor-alpha and interferon-gamma in mice inoculated with Clostridium piliforme.
Clostridium piliforme is an obligate intracellular bacterium that causes enterohepatic disease in many animal species. C. piliforme infections are commonly subclinical in laboratory rats and mice, and little is known about host regulation of disease or of the effects of C. piliforme infections on investigations that use subclinically infected animals. To assess host regulation of subclinical C. piliforme infections and the effects of those infections on laboratory mice, the expression of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) was evaluated at 0, 1, 3, 7, 14 and 28 days after inoculation with C. piliforme. Subclinical infection was induced in weanling C. piliforme-susceptible DBA/2 or -resistant C57BL/6 mice with either a toxic or a non-toxic C. piliforme strain. Hepatic lesions and bacteria were demonstrated histologically in both mouse strains for 14 days after inoculation with the toxigenic bacterial strain, but were never demonstrated histologically following inoculation with the non-toxigenic strain. Hepatic TNF-alpha and IFN-gamma mRNA and serum protein levels were similarly elevated in both mouse strains 1 day after inoculation with both C. piliforme strains, as evaluated by reverse transcription PCR and enzyme-linked immunosorbent assays, respectively. Elevation of IFN-gamma persisted for 14 days after inoculation; TNF-alpha remained elevated at 28 days after inoculation.


Pathogenesis and subsequent cross-protection of influenza virus infection in pigs sustained by an H1N2 strain.
The H1N1, H3N2 and, more recently, H1N2 subtypes of influenza A virus are presently co-circulating in swine herds in several countries. The objectives of this study were to investigate the pathogenesis of Sw/Italy/1521/98 (H1N2) influenza virus, isolated from respiratory tissues of pigs from herds in Northern Italy, and to evaluate its potential cross-protection against the Sw/Fin/2899/82 (H1N1) strain. In the pathogenesis test, eight pigs were intranasally infected with H1N2 virus; at pre-determined intervals, these animals were killed and necropsied, along with eight uninfected animals. In the cross-protection test, sixteen pigs were infected by intranasal (i.n.) and intratracheal (i.t.) routes with either H1N2 or H1N1 virus. Twenty days later, all pigs were challenged (by the same route), with either the homologous H1N2 or heterologous H1N1 virus strains. Control group was inoculated with culture medium alone. On post-challenge days (PCD) 1 and 3, two pigs from each infected group, along with one control pig, were killed. Clinical, virological, serological and histopathological investigations were performed in both the pathogenicity and cross-protection tests. In the pathogenicity test, mild clinical signs were observed in two pigs during 3 and 4 days, respectively. Virus was isolated from two pigs over 6 days and from lung samples of pigs killed on post-infection days 2 and 4. Seroconversion was detected in the two infected animals killed 15 days after infection. In the cross-protection study, mild clinical respiratory signs were detected in all pigs infected with either the H1N2 or H1N1 virus. The virus was isolated from nasal swabs of almost all pigs till 6 days. After the challenge infection, the pigs remained clinically healthy and virus isolation from the nasal secretions or lung samples was sporadic. Antibody titres in H1N1 or H1N2 infected groups were similar, whereas the H1N2 sub-type induced less protection against re-infection by homologous and heterologous virus than H1N1 sub-type. The controls had no signs of the disease. In the H1N2 infected pigs, a reduced number of goblet cells in nasal and tracheal mucosa and small foci of lymphomononuclear cell infiltrates in the submucosa were detected. Furthermore, the goblet cell reduction was related to the time of infection. Diffuse mild interstitial pneumonia was also recorded in pigs infected with the H1N2 virus and challenged with either H1N1or H1N2 pigs. These studies showed the moderate virulence of the H1N2 virus and a partial cross-protection against heterologous infection.


Helical tomotherapy for head and neck squamous cell carcinoma: dosimetric comparison with linear accelerator-based step-and-shoot IMRT.
Linear Accelerator-based Intensity Modulated Radiation Therapy (IMRT), either as step-and shoot (SS) or in dynamic mode, is now considered routine in the definitive management of head and neck squamous cell carcinoma (HNSCC). Helical TomoTherapy (HT) is a new platform to deliver IMRT. This study aims to compare step-and-shoot Intensity Modulated Radiation Therapy (SS IMRT) with dynamic Helical TomoTherapy (HT) dosimetrically in patients with head and neck squamous cell carcinoma (HNSCC). Twelve patients with HNSCC, previously treated with SS IMRT, were re-planned on HT using the same CT dataset. Plans were compared for target coverage and organs-at-risk (OARs) sparing. Sparing of parotids was assessed after stratifying for side (contralateral vs. ipsilateral) and site of disease (laryngopharynx vs. oropharynx). Normal tissue complication probabilities (NTCP) were also compared for the parotid glands. All HT plans showed improvement in target coverage and homogeneity, and reduction in OAR doses as compared to SS IMRT plans. For PTV 66, the mean V 99 improved by 14.65% ( P = 0.02). Dose Homogeneity (D 10-90 ) was significantly better in the HT plans (mean 2.07Gy as compared to 4.5Gy in the SS IMRT plans, P = 0.02). HT resulted in an average reduction of mean parotid dose of 12.66Gy and 18.28Gy for the contralateral and ipsilateral glands ( P = 0.003) respectively. This translated into a 24.09% and 35.22% reduction in Normal Tissue Complication Probability (NTCP) for the contralateral and ipsilateral parotids respectively ( P < 0.01). Site of disease (laryngopharynx vs. oropharynx) did not have any significant impact on parotid sparing between SS IMRT and HT. The maximum dose to the spinal cord showed a mean reduction of 12.07Gy in HT plans ( P = 0.02). Helical Tomotherapy achieved better target coverage with improved OAR sparing as compared to SS IMRT. The significant reduction in mean parotid doses translated into meaningful reduction in NTCP, with potential clinical implications in terms of reduction in Xerostomia and improved quality of life in patients with HNSCC.


Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction.
Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA) preferentially decreased by 44% in MI by a Southern blot analysis, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure.


Development of CAR-T Cell Persistence in Adoptive Immunotherapy of Solid Tumors.
Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.


Absence of sex differences in systolic blood pressure and heart rate responses to exercise in healthy young adults.
The influence of sex on systolic blood pressure (SBP) and heart rate (HR) responses associated with cardiovascular morbidity, in healthy young adults was determined in ninety healthy young adults (47 females and 43 males) exercised using Bruce protocol. SBP and HR were measured pre- and post-exercise, and during recovery. SBPresponse (peak minus pre-exercise SBP), %SBPresponse [(peak minus pre-exercise SBP)÷pre-exercise SBP]x100, SBP3 (SBP 3 minutes into recovery), SBP4 (SBP 4 minutes into recovery), SBP3:peak (SBP3÷peak SBP), %SBPd3 [(peak SBP minus SBP 3 minutes into recovery)x peak SBP]x100, %SBPd4 [(peak SBP minus SBP 4 minutes into recovery)x peak SBP]X100, HRresponse (Peak HR minus pre-exercise HR), %HRresponse [(peak HR minus pre-exercise HR)÷pre-exercise HR]x 100, HR3 (HR 3 minutes into recovery), HR4 (HR 4 minutes into recovery), %HRd3 [(peak HR minus HR 3 minutes into recovery)÷peak HR]x100, %HRd4 [(peak HR minus HR 4 minutes into recovery)÷peak HR]X100, and HR50-70 (HR between 50th and 70th seconds into recovery) were derived from SBP and HR measurements. SBPpeak, HRresponse and %HRresponse were higher in males than in females whereas, SBPresponse, %SBPresponse and HRpeak were not different. There were no significant differences in the post-exercise SBP and HR responses of males and females except for SBP3, SBP4, HR3 and HR4. After adjusting for exercise duration, body mass index (BMI), and resting SBP and HR, these variables became similar. Sex differences in some SBP and HR responses to exercise, become nonexistent after adjusting for BMI, exercise duration, and resting SBP and HR.


Prediction and interpretation of cancer survival using graph convolution neural networks.
The survival rate of cancer has increased significantly during the past two decades for breast, prostate, testicular, and colon cancer, while the brain and pancreatic cancers have a much lower median survival rate that has not improved much over the last forty years. This has imposed the challenge of finding gene markers for early cancer detection and treatment strategies. Different methods including regression-based Cox-PH, artificial neural networks, and recently deep learning algorithms have been proposed to predict the survival rate for cancers. We established in this work a novel graph convolution neural network (GCNN) approach called Surv_GCNN to predict the survival rate for 13 different cancer types using the TCGA dataset. For each cancer type, 6 Surv_GCNN models with graphs generated by correlation analysis, GeneMania database, and correlation + GeneMania were trained with and without clinical data to predict the risk score (RS). The performance of the 6 Surv_GCNN models was compared with two other existing models, Cox-PH and Cox-nnet. The results showed that Cox-PH has the worst performance among 8 tested models across the 13 cancer types while Surv_GCNN models with clinical data reported the best overall performance, outperforming other competing models in 7 out of 13 cancer types including BLCA, BRCA, COAD, LUSC, SARC, STAD, and UCEC. A novel network-based interpretation of Surv_GCNN was also proposed to identify potential gene markers for breast cancer. The signatures learned by the nodes in the hidden layer of Surv_GCNN were identified and were linked to potential gene markers by network modularization. The identified gene markers for breast cancer have been compared to a total of 213 gene markers from three widely cited lists for breast cancer survival analysis. About 57% of gene markers obtained by Surv_GCNN with correlation + GeneMania graph either overlap or directly interact with the 213 genes, confirming the effectiveness of the identified markers by Surv_GCNN.


Behavioral characterization of prediction and internal models in adolescents with autistic spectrum disorders.
Autism has been considered as a deficit in prediction of the upcoming event or of the sensory consequences of our own movements. To test this hypothesis, we recorded eye movements from high-functioning autistic adolescents and from age-matched controls during a blanking paradigm. In this paradigm, adolescents were instructed to follow a moving target with their eyes even during its transient disappearance. Given the absence of visual information during the blanking period, eye movements during this period are solely controlled on the basis of the prediction of the ongoing target motion. Typical markers of predictive eye movements such as the number and accuracy of predictive saccades and the predictive reacceleration before target reappearance were identical in the two populations. In addition, the synergy of predictive saccades and smooth pursuit observed during the blanking periods, which is a marker for the quality of internal models about target/eye motions, was comparable between these two populations. These results suggest that, in our large population of high-functioning autistic adolescent, both predictive abilities and internal models are left intact in Autism, at least for low-level sensorimotor transformations.


Looking at the bigger picture: effect of performance-based contracting of district health services on equity of access to maternal health services in Zambia.
Zambia has been using output-based approaches for over two decades to finance whole or part of the public health system. Between 1996 and 2006, performance-based contracting (PBC) was implemented countrywide with the Central Board of Health (CBoH) as the provider of health services. This study reviews the association between PBC and equity of access to maternal health services in Zambia between 1996 and 2006. A comprehensive document review was undertaken to evaluate the implementation process, followed by a trend analysis of health expenditure at district level, and a segmented regression analysis of data on antenatal care (ANC) and deliveries at health facilities that was obtained from five demographic and health survey datasets (1992, 1996, 2002, 2007 and 2014). The results show that PBC was anchored by high-level political support, an overarching policy and legal framework, and collective planning and implementation with all key stakeholders. Decentralization of health service provision was also an enabling factor. ANC coverage increased in both the lower and upper wealth quintiles during the PBC era, followed by a declining trend after the PBC era in both quintiles. Further, the percentage of women delivering at health facilities increased during the PBC era, particularly in rural areas and among the poor. The positive trend continued after the PBC era with similar patterns in both lower and upper wealth quintiles. Despite these gains, per capita health expenditure at district level declined during the PBC era, with the situation worsening after the PBC era. The study concludes that a nationwide PBC approach can contribute to improved equity of access to maternal health services and that PBC is a cost-efficient and sustainable policy reform. The study calls for policymakers to comprehensively evaluate the impact of health system reforms before terminating them.


Regulation of period 1 expression in cultured rat pineal.
The aim of the present study was to investigate the in vitro expression of Period 1 (Per1), Period 2 (Per2) and arylalkylamine N-acetyltransferase (AA-NAT) genes in the rat pineal gland to understand the mechanism(s) regulating the expression of these genes in this organ. Pineals, when maintained in vitro for 5 days, did not show circadian rhythmicity in the expression of any of the three genes monitored. Norepinephrine (NE) induced AA-NAT and Per1, whereas its effect on Per2 was negligible. Contrary to what was observed in other systems, NE stimulation did not induce circadian expression of Per1. The effect of NE on Per1 level was dose- and receptor subtype-dependent, and both cAMP and cGMP induced Per1. Per1 was not induced by repeated NE - or forskolin - stimulation. Protein synthesis was not necessary for NE-induced Per1, but it was for reduction of Per1 following NE stimulation. Per1 transcription in pinealocytes was activated by BMAL1/CLOCK. Our results indicate that important differences are present in the regulation of these genes in the mammalian pineal.


Lumpy skin disease: Insights into current status and geographical expansion of a transboundary viral disease.
Lumpy skin disease (LSD) is an emerging transboundary viral disease of livestock animals which was first reported in 1929 in Zambia. Although LSD is a neglected disease of economic importance, it extends a direct impact on the international trade and economy in livestock-dependent countries. Lumpy skin disease virus (LSDV) has been endemic in African countries, where several outbreaks have been reported previously. However, the virus has spread rapidly across the Middle East in the past two decades, reaching Russia and, recently, the Asian subcontinent. With unprecedented cluster outbreaks being reported across Asian countries like India, China, Nepal, Bangladesh, and Pakistan, LSDV is certainly undergoing an epidemiological shift and expanding its geographical footprint worldwide. Due to high mortality among livestock animals, the recent LSD outbreaks have gained attention from global regulatory authorities and raised serious concerns among epidemiologists and veterinary researchers. Despite networked global surveillance of the disease, recurrent LSD cases pose a threat to the livestock industry. Hence, this review provides recent insights into the LSDV biology by augmenting the latest literature associated with its pathogenesis, transmission, current intervention strategies, and economic implications. The review critically examines the changing epidemiological footprint of LSDV globally, especially in relation to developing countries of the Asian subcontinent. We also speculate the possible reasons contributing to the ongoing LSD outbreaks, including illegal animal trade, climate change, genetic recombination events between wild-type and vaccine strains, reversion of vaccine strains to virulent phenotype, and deficiencies in active monitoring during the COVID-19 pandemic.


Immunopathology of toxic epidermal necrolysis. Keratinocytes, HLA-DR expression, Langerhans cells, and mononuclear cells: an immunopathologic study of five cases.
Toxic epidermal necrolysis is a potentially severe mucocutaneous affliction whose cause is usually drug related. To further characterize the nature of the dermal mononuclear infiltrate as well as the epidermal alterations observed by standard microscopy, we studied five cases of toxic epidermal necrolysis using labeled monoclonal antibodies. On clinically involved areas of skin, the following occurs: (1) the dermal infiltrate is composed mainly of activated T lymphocytes, with a predominant helper phenotype; (2) the number of Langerhans cells is decreased; and (3) keratinocytes express HLA-DR molecules, normally absent on their surface. These findings, although not specific, are consistent with an immune cellular reaction, but they could also be linked to an inflammatory reaction initiated by epidermal damages whatever its primary mechanism.


Visible-Light-Induced Photocatalytic and Antibacterial Activity of TiO2 Codoped with Nitrogen and Bismuth: New Perspectives to Control Implant-Biofilm-Related Diseases.
Biofilm-associated diseases are one of the main causes of implant failure. Currently, the development of implant surface treatment goes beyond the osseointegration process and focuses on the creation of surfaces with antimicrobial action and with the possibility to be re-activated (i.e., light source activation). Titanium dioxide (TiO2), an excellent photocatalyst used for photocatalytic antibacterial applications, could be a great alternative, but its efficiency is limited to the ultraviolet (UV) range of the electromagnetic spectrum. Since UV radiation has carcinogenic potential, we created a functional TiO2 coating codoped with nitrogen and bismuth via the plasma electrolytic oxidation (PEO) of titanium to achieve an antibacterial effect under visible light with re-activation potential. A complex surface topography was demonstrated by scanning electron microscopy and three-dimensional confocal laser scanning microscopy. Additionally, PEO-treated surfaces showed greater hydrophilicity and albumin adsorption compared to control, untreated titanium. Bismuth incorporation shifted the band gap of TiO2 to the visible region and facilitated higher degradation of methyl orange (MO) in the dark, with a greater reduction in the concentration of MO after visible-light irradiation even after 72 h of aging. These results were consistent with the in vitro antibacterial effect, where samples with nitrogen and bismuth in their composition showed the greatest bacterial reduction after 24 h of dual-species biofilm formation ( Streptococcus sanguinis and Actinomyces naeslundii) in darkness with a superior effect at 30 min of visible-light irradiation. In addition, such a coating presents reusable photocatalytic potential and good biocompatibility by presenting a noncytotoxicity effect on human gingival fibroblast cells. Therefore, nitrogen and bismuth incorporation into TiO2 via PEO can be considered a promising alternative for dental implant application with antibacterial properties in darkness, with a stronger effect after visible-light application.


Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the UCSF experience with 149 patients.
The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease. This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis. A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm. Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.


Assessment of performance indicators of a radiotherapy department using an electronic medical record system.
To retrospectively assess the performance indicators of our radiotherapy department and their temporal trends, using a commercially available electronic-medical-record (EMR) system. A recent trend in healthcare quality is to define and evaluate performance indicators of the service provided. Patient and external-beam-radiotherapy-treatments data were retrieved using the Mosaiq EMR system from 1-January-2012 till 31-December-2015. Annual performance indicators were evaluated as: productivity (number of new cases/year and diagnosis distribution); complexity (ratio of Volumetric-Modulated-Arc-Therapy (VMAT) courses, average number of imaging procedures/patient); and quality (average, median and 90th percentile waiting times from admission to first treatment). The temporal trends of all performance indicators were assessed by linear regression. Productivity: the number of new cases/year increased with an average rate of 4%. Diagnosis distribution showed that breast is the main pathology treated, followed by gastro-intestinal and head-and-neck. Complexity: the ratio of VMAT courses increased from 13% to 35%, with an average rate of 7% per year. The average number of imaging procedures/patient increased from 8 to 11. Quality: the waiting times from admission to treatment remained stable over time (R2 ≤ 0.1), with average, median and 90th percentile values around 20, 15, and 31 days, respectively. An EMR system can be used to: monitor the performance indicators of a radiotherapy department, identify workflow processes needing attention and improvement, estimate future demands of resources. Temporal analysis of our data showed an increasing trend in productivity and complexity paired with constant waiting times.


Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene.
1,3-Butadiene (BD) is a common environmental contaminant classified as "carcinogenic to humans." Formation of BD-induced DNA adducts plays a major role in its carcinogenicity. BD is also an epigenotoxic agent (i.e., it affects DNA and histone methylation in the liver). We used a panel of genetically diverse inbred mice (NOD/LtJ, CAST/EiJ, A/J, WSB/EiJ, PWK/PhJ, C57BL/6J, and 129S1/SvImJ) to assess whether BD-induced genotoxic and epigenotoxic events may be subject to interstrain differences. Mice (male, 7 weeks) were exposed via inhalation to 0 or 625 ppm BD for 6 h/day and 5 days/week for 2 weeks and liver BD-DNA adducts, epigenetic alterations, and liver toxicity were assessed. N-7-(2,3,4-trihydroxybut-1-yl)-guanine adducts were detected in all strains after exposure, yet BD-induced DNA damage in CAST/EiJ mice was two to three times lower. Epigenetic effects of BD were most prominent in C57BL/6J mice where loss of global DNA methylation and loss of trimethylation of histone H3 lysine 9, histone H3 lysine 27, and histone H4 lysine 20, accompanied by dysregulation of liver gene expression indicative of hepatotoxicity, were found. Interestingly, we observed an increase in histone methylation in the absence of changes in gene expression and DNA methylation in CAST/EiJ strain. We hypothesized that mitigated genotoxicity of BD in CAST/EiJ mice may be due to chromatin condensation. Indeed, we show that in response to BD exposure, chromatin condensation occurs in CAST/EiJ, whereas the opposite effect is observed in C57BL/6J mice. These findings demonstrate that interstrain susceptibility to genotoxicity by a well-known environmental carcinogen may be due to strain-specific epigenetic events in response to the exposure.


Developmental changes in the response of trigeminal neurons to neurotrophins: influence of birthdate and the ganglion environment.
Previous studies have shown that most neurons in cultures established during the early stages of neurogenesis in the embryonic mouse trigeminal ganglion are supported by BDNF whereas most neurons cultured from older ganglia survive with NGF. To ascertain to what extent these developmental changes in neurotrophin responsiveness result from separate phases of generation of BDNF- and NGF-responsive neurons or from a developmental switch in the response of neurons from BDNF to NGF, we administered BrdU to pregnant mice at different stages of gestation to identify neurons born at different times and studied the survival of labelled neurons in dissociated cultures established shortly after BrdU administration. Most early-generated neurons responded to BDNF, neurons generated at intermediate times responded to both factors and late-generated neurons responded to NGF, indicating that there are overlapping phases in the generation of BDNF- and NGF-responsive neurons and that late-generated neurons do not switch responsiveness from BDNF to NGF. To ascertain if early-generated neurons do switch their response to neurotrophins during development, we used repeated BrdU injection to label all neurons generated after an early stage in neurogenesis and studied the neurotrophin responsiveness of the unlabelled neurons in cultures established after neurogenesis had ceased. The response of these early-generated neurons had decreased to BDNF and increased to NGF, indicating that at least a proportion of early-generated neurons switch responsiveness to neurotrophins in vivo. Because early-generated neurons do not switch responsiveness from BDNF to NGF in long-term dissociated cultures, we cultured early trigeminal ganglion explants with and without their targets for 24 hours before establishing dissociated cultures. This period of explant culture was sufficient to enable many early-generated neurons to switch their response from BDNF to NGF and this switch occurred irrespective of presence of target tissue. Our findings conclusively demonstrate for the first time that individual neurons switch their neurotrophin requirements during development and that this switch depends on cell interactions within the ganglion. In addition, we show that there are overlapping phases in the generation of BDNF- and NGF-responsive neurons in the trigeminal ganglion.


The association between plasminogen activator inhibitor type-1 and clinical outcome in paediatric sepsis.
: Acute phase protein plasminogen activator inhibitor type-1 (PAI-1) is a key element in fibrinolysis inhibition in sepsis-induced disseminated intravascular coagulation (DIC). Elevated PAI-1 level is related to worse outcome in sepsis. The aim of this study was to investigate the relationship between plasma PAI-1 level and clinical outcome in children with sepsis. A total of 35 children with sepsis were enrolled into this prospective study. Plasma PAI-1 was measured on day-1 and day-4. Systemic coagulation profile was measured on day-4. Individuals were followed up until 28 days. The mean PAI-1 from day-1 to day-4 in overt DIC children was not statistically significant. Contrarily, among nonovert DIC individuals, there was a significant difference (P ≤ 0.001) in PAI-1 levels on day-1 compared with day-4 were 95.25 ± 46.57 vs. 60.36 ± 37.31 ng/ml, respectively. Among survivors, mean PAI-1 level on day-1 was statistically higher than PAI-1 level on day-4 (82.47 ± 44.43 vs. 58.39 ± 32.98 ng/ml), P = 0.021. There was no significant difference between PAI-1 levels on day-1 compared with day-4 in nonsurvivors. PAI-1 was correlated to DIC score with r = 0.606 (P ≤ 0.001). PAI-1 levels significantly decreased on day-4 compared with day-1 among nonovert DIC individuals, and not in overt DIC individuals. Changes in PAI-1 levels in nonsurvivors did not differ. PAI-1 level was positively correlated with DIC score.


Instability of Doppler cerebral blood flow in monochorionic twins.
The purpose of this study was to evaluate Doppler flow velocity changes in cerebral vessels of monochorionic twins with twin-twin transfusion syndrome (TTTS). Repeated Doppler umbilical and cerebral blood flow studies were performed in 7 twin pairs with TTTS. Eight monochorionic twin pairs and 11 dichorionic twin pairs served as control groups. The following Doppler parameters were assessed: umbilical artery pulsatility index (PI), middle cerebral artery (MCA) PI, cerebroplacental ratio, delta PI between the umbilical artery and MCA, and peak systolic velocity (PSV) in the MCA. Significant variations in PSV in the MCA and cerebral indices were found in the study group of monochorionic twins with TTTS. Periods of high PSV with low PI in the MCA were followed by lower PSV in the same fetus. Repeated measurements in the comparison groups were stable without significant variations. The delta cerebroplacental ratio was significantly higher in the study group (0.38 versus 0.09 and 0.19 in the comparison groups; P < .02). Significant changes in Doppler flow velocity and indices suggest instability of cerebral blood flow with episodes of "hyperperfusion" in monochorionic twins with TTTS. Further studies are needed to elucidate the relationship of these transient changes to neurologic sequelae in the neonate.


A randomized, controlled trial of acupuncture for chronic low-back pain.
Chronic low-back pain (cLBP) is a common condition throughout the world, and acupuncture is widely sought for treatment. As clinical evidence for the benefits of acupuncture grows, acupuncture for cLBP is receiving increased recognition and acceptance by both patients and professionals. Time method acupuncture has been previously researched with respect to chronic gastritis. For individuals with cLBP in the current study, the research team examined the efficacy of adding confluent acupoints, related to the daytime period in time method acupuncture, to regular acupuncture and also evaluated the persistence of the benefits of such acupuncture in comparison with regular acupuncture. The study was a randomized, controlled trial (RCT). The setting was an outpatient clinic of the Dongzhimen Hospital in Beijing, China. Participants were Chinese men and women with cLBP. Sixty participants were randomly divided into 2 groups to receive acupuncture. The control group received a treatment that followed a routine acupuncture (RA) protocol, while the intervention group received a treatment that followed an RA protocol plus acupuncture in confluent points related to time (TA). The research team measured the change in participants' scores using the visual analogue scale (VAS), the number of therapy sessions needed, the number of days that participants were absent from work during the treatment period and at 12 wk posttreatment, and the number of pain relapses between the end of treatment and the 4- and 12-wk follow-ups. VAS scores decreased from 69.6 ± 7.9 to 11.8 ± 4.9 in the intervention group compared with a decrease from 69.2 ± 8.0 to 15.7 ± 10.0 in the control group (P = .001). The intervention group received fewer therapy sessions (8.1 ± 2.0) than did the control group (10.1 ± 2.0, P < .001). Compared with the controls, the intervention group showed fewer days absent from work (0.5 vs 1.4; P = .03) and fewer pain relapses (4.0 vs 7.0; P = .04) at the 12-wk follow-up. In the 2 groups combined, VAS decreased from 69.4 ± 7.9 before the first session of acupuncture to 13.8 ± 8.0 after the last session (P < .001), and the number of therapy sessions needed for pain relief was 9.1 ± 2.2. Accompanying routine acupuncture with time method acupuncture can enhance the efficacy of treatment and the persistence of its benefits in individuals with cLBP.


In-silico genomic characterization of Staphylococcus haemolyticus on a global scale: lineages, resistome, and virulome.
Staphylococcus haemolyticus belongs to the Coagulase-Negative Staphylococci (CoNS), exhibiting the highest levels of antibiotic resistance within this group of bacteria. This species has been increasingly implicated in nosocomial and animal infections worldwide, with a prevalence of methicillin-resistant Staphylococcus haemolyticus (MRSH). Most information about this organism comes from regional analyzes or with the absence of typing data, thus not revealing the real role of S. haemolyticus strains in world public health. Here, we performed an enhanced global epidemiological analysis considering all available S. haemolyticus genomes from all continents, including genomes of nosocomial, environmental, and animal origin (n = 310). Furthermore, we added original genomic information from a clinical MRSH from the Brazilian Amazon region. The resistome and virulome of the genomes were associated with their mobilome, being inferred based on the presence of specific genes and databases such as CARD, VFDB, and PlasmidFinder, respectively. Phylogenetic analysis revealed three main groups, the main one covering most of the clinical clonal complex 3 (CC3) genomes in the world. The virulome of some genomes in this cluster showed the complete capsule operon (capA-capM). Importantly, this virulome trait could be associated with the mobilome, since the capsule operon, as well as a whole set of genes of the type VII secretion system, were observed in plasmids. In addition, the resistome of the main cluster (CC3) was larger, characterized mainly by the presence of the mecA gene, in addition to a set of other genes (aad, aac-aph, aph, erm), contrasting with the poor resistome of the other two clusters. Several insertion sequences were identified, some of them linked to specific clusters, and resistance genes, such as the rare cfrA (IS257). Therefore, successful lineages of CC3 S. haemolyticus causing human infections are widespread worldwide, raising concern about the impact of this scenario on public health.


T-cell intracellular antigen (TIA)-proteins deficiency in murine embryonic fibroblasts alters cell cycle progression and induces autophagy.
Mice lacking either T-cell intracellular antigen 1 (TIA1) or TIA1 related/like protein (TIAR/TIAL1) show high rates of embryonic lethality, suggesting a relevant role for these proteins during embryonic development. However, intrinsic molecular and cellular consequences of either TIA1 or TIAR deficiency remain poorly defined. By using genome-wide expression profiling approach, we demonstrate that either TIA1 or TIAR inactivation broadly alter normal development-associated signalling pathways in murine embryonic fibroblasts (MEF). Indeed, these analyses highlighted alterations of cytokine-cytokine and ECM-receptor interactions and Wnt, MAPK, TGF-beta dependent signalling pathways. Consistent with these results, TIA1 and TIAR knockout (KO) MEF show reduced rates of cell proliferation, cell cycle progression delay and increased cell size. Furthermore, TIA-proteins deficiency also caused metabolic deficiencies, increased ROS levels and DNA damage, promoting a gentle rise of cell death. Concomitantly, high rates of autophagy were detected in both TIA1 and TIAR KO MEF with induction of the formation of autophagosomes, as evidenced by the up-regulation of the LC3B protein, and autolysosomes, measured by colocalization of LC3B and LAMP1, as a survival mechanism attempt. Taken together, these observations support that TIA proteins orchestrate a transcriptome programme to activate specific developmental decisions. This program is likely to contribute to mouse physiology starting at early stages of the embryonic development. TIA1/TIAR might function as cell sensors to maintain homeostasis and promote adaptation/survival responses to developmental stress.


Emergence of multiple fluconazole-resistant Candida parapsilosis sensu stricto clones with persistence and transmission in China.
We explored the epidemiological and molecular characteristics of Candida parapsilosis sensu stricto isolates in China, and their mechanisms of azole resistance. Azole susceptibilities of 2318 non-duplicate isolates were determined using CLSI broth microdilution. Isolates were genotyped by a microsatellite typing method. Molecular resistance mechanisms were also studied and functionally validated by CRISPR/Cas9-based genetic alterations. Fluconazole resistance occurred in 2.4% (n = 56) of isolates, and these isolates showed a higher frequency of distribution in ICU inpatients compared with susceptible isolates (48.2%, n = 27/56 versus 27.8%, 613/2208; P = 0.019). Microsatellite-genotyping analysis yielded 29 genotypes among 56 fluconazole-resistant isolates, of which 10 genotypes, including 37 isolates, belonged to clusters, persisting and transmitting in Chinese hospitals for 1-29 months. Clusters harbouring Erg11Y132F (5/10; 50%) were predominant in China. Among these, the second most dominant cluster MT07, including seven isolates, characteristically harbouring Erg11Y132F and Mrr1Q625K, lent its carriage to being one of the strongest associations with cross-resistance and high MICs of fluconazole (>256 mg/L) and voriconazole (2-8 mg/L), causing transmission across two hospitals. Among mutations tested, Mrr1Q625K led to the highest-level increase of fluconazole MIC (32-fold), while mutations located within or near the predicted transcription factor domain of Tac1 (D440Y, T492M and L518F) conferred cross-resistance to azoles. This study is the first Chinese report of persistence and transmissions of multiple fluconazole-resistant C. parapsilosis sensu stricto clones harbouring Erg11Y132F, and the first demonstration of the mutations Erg11G307A, Mrr1Q625K, Tac1L263S, Tac1D440Y and Tac1T492M as conferring resistance to azoles.


Resolving occlusive lesions of the basilar artery.
Progression of severe basilar artery stenosis to occlusion is a well-recognized phenomenon, but regression of a severe basilar artery atherothrombotic lesion has not been described previously. In this report, two patients with a symptomatic severe basilar artery occlusive lesion showed substantial angiographic improvement after 3 months of anticoagulation in one case and 4 months after superficial temporal artery to superior cerebellar artery bypass in the other case. The findings in these cases indicate that clinical improvement in similar cases may reflect recanalization of a basilar artery occlusive lesion. The uncertain natural history and potential for regression of symptomatic basilar artery atherothrombosis make us hesitant to recommend posterior circulation revascularization immediately after such lesions are first demonstrated angiographically.


The Effect of Oligomerization on A Solid-Binding Peptide Binding to Silica-Based Materials.
The bifunctional linker-protein G (LPG) fusion protein comprises a peptide (linker) sequence and a truncated form of Streptococcus strain G148 protein G (protein G). The linker represents a multimeric solid-binding peptide (SBP) comprising 4 × 21-amino acid sequence repeats that display high binding affinity towards silica-based materials. In this study, several truncated derivatives were investigated to determine the effect of the SBP oligomerization on the silica binding function of LPG (for the sake of clarity, LPG will be referred from here on as 4 × LPG). Various biophysical characterization techniques were used to quantify and compare the truncated derivatives against 4 × LPG and protein G without linker (PG). The derivative containing two sequence repeats (2 × LPG) showed minimal binding to silica, while the truncated derivative with only a single sequence (1 × LPG) displayed no binding. The derivative containing three sequence repeats (3 × LPG) was able to bind to silica with a binding affinity of KD = 53.23 ± 4.5 nM, which is 1.5 times lower than that obtained for 4 × LPG under similar experimental conditions. Circular dichroism (CD) spectroscopy and fluorescence spectroscopy studies indicated that the SBP degree of oligomerization has only a small effect on the secondary structure (the linker unravels the beginning of the protein G sequence) and chemical stability of the parent protein G. However, based on quartz crystal microbalance with dissipation monitoring (QCM-D), oligomerization is an important parameter for a strong and stable binding to silica. The replacement of three sequence repeats by a (GGGGS)12 glycine-rich spacer indicated that the overall length rather than the SBP oligomerization mediated the effective binding to silica.


Continuous engagement of a self-specific activation receptor induces NK cell tolerance.
Natural killer (NK) cell tolerance mechanisms are incompletely understood. One possibility is that they possess self-specific activation receptors that result in hyporesponsiveness unless modulated by self-major histocompatability complex (MHC)-specific inhibitory receptors. As putative self-specific activation receptors have not been well characterized, we studied a transgenic C57BL/6 mouse that ubiquitously expresses m157 (m157-Tg), which is the murine cytomegalovirus (MCMV)-encoded ligand for the Ly49H NK cell activation receptor. The transgenic mice were more susceptible to MCMV infection and were unable to reject m157-Tg bone marrow, suggesting defects in Ly49H(+) NK cells. There was a reversible hyporesponsiveness of Ly49H(+) NK cells that extended to Ly49H-independent stimuli. Continuous Ly49H-m157 interaction was necessary for the functional defects. Interestingly, functional defects occurred when mature wild-type NK cells were adoptively transferred to m157-Tg mice, suggesting that mature NK cells may acquire hyporesponsiveness. Importantly, NK cell tolerance caused by Ly49H-m157 interaction was similar in NK cells regardless of expression of Ly49C, an inhibitory receptor specific for a self-MHC allele in C57BL/6 mice. Thus, engagement of self-specific activation receptors in vivo induces an NK cell tolerance effect that is not affected by self-MHC-specific inhibitory receptors.


Klebsiella pneumoniae nitrogenase. The pre-steady-state kinetics of MoFe-protein reduction and hydrogen evolution under conditions of limiting electron flux show that the rates of association with the Fe-protein and electron transfer are independent of the oxidation level of the MoFe-protein.
The pre-steady-state kinetics of H2 evolution from Klebsiella pneumoniae nitrogenase functioning at 23 degrees C, pH 7.4, under conditions of extremely low electron flux through the MoFe-protein exhibited a lag phase of several minutes duration. The approach to a steady-state rate of H2 evolution was accompanied by a 50% decrease in the amplitude of the MoFe-protein e.p.r. signal. These kinetics have been simulated using our published kinetic model for nitrogenase [Lowe & Thorneley (1984) Biochem. J. 224, 877-886], which was developed using data obtained with nitrogenase functioning at high electron fluxes. The e.p.r. data showed that the rate of complex-formation between reduced Fe-protein and the MoFe-protein (k+1 = 5 x 10(7) M-1.s-1) is the same for the resting (E0) and one-electron-reduced (E1H) states of the MoFe-protein. Stopped-flow spectrophotometry also showed that electron transfer from the Fe-protein to the MoFe-protein in states E0 and E1H occurs at the same rate (kobs. = 140 s-1). These data support our previous assumption that the rate constants that define the 'Fe-protein cycle' are independent of the level of reduction of the MoFe-protein.


Impact of isolated acetabular and lower extremity fractures on long-term outcome.
The long-term clinical status of surviving patients with multiple injuries has not been well described. The aim of this study was to evaluate the long-term outcome of acetabular and lower limb injuries. Patients treated at a Level I trauma center at least 10 years before participation in this study were invited for a follow-up physical examination. Six hundred thirty-seven patients were examined. Inclusion criteria are as follows: Injury Severity Score ≥16 Points;treatment in a Level I trauma center; and injuries of the lower limb: fractures of the acetabulum, proximal femur, femoral shaft,knee joint, and tibial shaft. Exclusion criteria are as follows: incomplete follow-up examination, amputations, ankle and foot fractures, and patients older than 60 years and younger than 3 years. The follow-up examination included the following parameters:range of motion, pain, limping, successful rehabilitation, and outcome scores. Of 525 patients with fractures of the acetabulum and lower limb, 229 patients fulfilled the inclusion criteria. Mean age: 24.9 (range,3–60) years; Injury Severity Score: 19.66 (range, 16–43). The most frequent rates of ongoing local pain were stated by patients with fractures of the acetabulum (50%) and the proximal femur (45%). Moreover, the incidence of abnormal gait was significantly lower in patients with femoral shaft fractures when compared with the patients with fractures of the acetabulum (3.7% vs. 35%;p 0.0001), proximal femur (3.7% vs. 20%; p≤ 0.006), and tibial shaft (3.7% vs. 14.7%; p = 0.023). Our results demonstrate a better long-term outcome in patients with femur shaft fractures, whereas patients with articular fractures and proximal femur fractures were associated with poorer outcomes. Fracture location is determining factor for long-term outcome


Prevalence of silent myocardial ischaemia during exercise stress testing. Its relation to effort tolerance and myocardial perfusion abnormalities.
The number of underperfused myocardial segments, the extent of coronary artery disease and the severity of impairment of coronary flow reserve were compared in 147 consecutive patients exhibiting painful or painless ischaemic ST segment depression on exercise testing. Of 147 patients, only 61 (41%) experienced angina (group 1) whilst 86 (59%) did not (group 2). In the two groups coronary disease was comparable for both extent and distribution, and neither the location of transient perfusion defects nor their relation to areas of old myocardial necrosis appeared to influence the presence or absence of chest pain. However, exercise duration, exercise time and rate-pressure product at the beginning of ischaemia were lower in group 1. Furthermore, a greater proportion of asymptomatic patients had only one ischaemic segment on 99mTc-MIBI perfusion scintigraphy. We conclude that: (1) in patients with effort angina and coronary disease, the incidence of electrocardiographic silent ischaemic events induced by exercise is similar to that observed in studies based on continuous ECG monitoring. (2) Exertional angina is more frequently associated with greater ischaemic areas and with more severe degrees of impairment of residual coronary flow reserve. (3) The presence of an old myocardial infarction does not appear to influence the incidence of ischaemic cardiac pain.


How I treat von Willebrand disease.
The deficiency or abnormal activity of von Willebrand factor, a multi-adhesive protein which binds platelets to exposed subendothelium and carries factor VIII in circulation, is responsible for von Willebrand disease, the most frequent inherited bleeding disorder. Clinical symptoms are characterized by mucous membrane and soft tissue bleeding, bleeding after surgery and rarely joint and gastrointestinal bleeding. Intriguingly, also factor VIII, the protein deficient in hemophilia A, may be variably reduced because VWF stabilizes it into circulation. Treatment strategies are well designed for patients with levels of VWF activity <30 U/dL, while the diagnosis and the magnitude of risk may be difficult to be assessed accurately for subjects with levels between 30 and 50 U/dL. Three types of the disorder have been identified according to partial (type 1) or severe VWF quantitative deficiency (type 3) while patients who present variable abnormality of VWF structure are categorized as type 2. The aim of treatment is to correct either the abnormal/reduced von Willebrand factor and the associated deficiency of factor VIII, when present. Desmopressin is able to transiently correct the deficiency of FVIII and VWF for up to 8-12 h in a significant proportion of patients with type 1 von Willebrand disease and factor VIII and von Willebrand factor levels ≥10 U/dL. When desmopressin is not usual (mainly in patients with type 2 and 3 VWD) or correction is required cannot be used for an extended time (e.g., major surgery), von Willebrand factor-containing concentrates, with or without FVIII, must be used.


Ventilation during extracorporeal gas exchange in acute respiratory distress syndrome.
Accumulating evidence ascribes the benefit of extracorporeal gas exchange, at least in most severe cases, to the provision of a lung healing environment through the mitigation of ventilator-induced lung injury (VILI) risk. In spite of pretty homogeneous criteria for extracorporeal gas exchange application (according to the degree of hypoxemia/hypercapnia), ventilatory management during extracorporeal membrane oxygenation (ECMO)/carbon dioxide removal (ECCO2R) varies across centers. Here we summarize the recent evidence regarding the management of mechanical ventilation during extracorporeal gas exchange for respiratory support. At present, the most common approach to protect the native lung against VILI following ECMO initiation involves lowering tidal volume and driving pressure, making modest reductions in respiratory rate, while typically maintaining positive end-expiratory pressure levels unchanged.Regarding ECCO2R treatment, higher efficiency devices are required in order to reduce significantly respiratory rate and/or tidal volume. The best compromise between reduction of native lung ventilatory load, extracorporeal gas exchange efficiency, and strategies to preserve lung aeration deserves further investigation.


Extraction from prawn shells of substances cryoprotective for Vibrio cholerae.
Substances cryoprotective for Vibrio cholerae were detected from prawn shells immersed in phosphate-buffered saline. This cryoprotective activity was heat resistant and sensitive to treatment with trypsin. For the exhibition of its full activity, the presence of Mg ion was indispensable. The cryoprotective activity of this substance was more active than that of other known cryoprotectants, like glycerol or serum.


[Retrospective evaluation of angina pectoris in patients with primary and recurrent myocardial infarct].
Retrospective analysis of information on 283 patients with myocardial infarction (186 males and 97 females) showed that 64.7% of persons who had suffered from the disease for the first time and 88.6% of those with recurrent myocardial infarction had a history of anginose pain. Exacerbation of angina pectoris had occurred in 56.0% of patients with no previous myocardial infarction and in 71,4% of those with recurrent infarction. A preinfarction state was encountered in primary and recurrent myocardial infarction with equal frequency (in 73.0 and 74.7% of cases, respectively). Nitroglycerin efficacy diminishes in the month preceding myocardial infarction. During exacerbation of angina pectoris, 39.8% of patients who had no previous myocardial infarction and 73.8% of those with a history of the disease applied for medical advice.


A qualitative exploration of a health trainer programme in two UK primary care trusts.
World Health Organization data illustrate a worldwide re-emergence of interest in the scope of lay health workers for extending services to 'hard-to-reach' community groups. In the UK, the health trainer model of service delivery represents one such innovative way of working, first described in the White Paper Choosing Health: Making Healthier Choices Easier and more recently in the Kings Fund report. The scheme was introduced into selected primary care settings in England from 2005 and rolled out nationally from 2007. The aim of this study was to examine the perceived value of the health trainer scheme. This paper describes qualitative data from two studies undertaken in 2007-2009, comprising in-depth consultations with key primary care stakeholders, health trainers and their clients in two primary care trusts in northern and central England. Data was collected via 12 semi-structured interviews with key stakeholders and service users and from 8 focus groups with a total of 33 trainee and qualified health trainers. The UK health trainer approach was regarded as effective in contributing to the support of a broad spectrum of health and welfare issues across widely diverse communities in the two primary care trusts evaluated. Study data also indicated a wide-ranging impact of the health trainer service, extending not only to the lay health workers themselves, but also to their families, friends and colleagues. The health trainer service appears to be not only 'fit for purpose', but also to bring with it certain 'added value', which was not predicted by the two primary care service providers at the outset. A critical factor in this success appears to be the unique combination of time, the 'person next door' and a 'one-to-one' approach, which facilitated an innovative and highly productive connection between the health trainer and client. However, participants in this evaluation perceived that the current format and constituents of service performance data were significantly failing to credit the health trainer scheme with the full extent of this impact.


Scheduling jobs and a variable maintenance on a single machine with common due-date assignment.
We investigate a common due-date assignment scheduling problem with a variable maintenance on a single machine. The goal is to minimize the total earliness, tardiness, and due-date cost. We derive some properties on an optimal solution for our problem. For a special case with identical jobs we propose an optimal polynomial time algorithm followed by a numerical example.


Generation of achromatic Bessel beams using a compensated spatial light modulator.
We report the creation of white-light, achromatic Bessel beams using a spatial light modulator and a prism to compensate for the dispersion. Unlike the Bessel beam created by a refractive axicon, this achromatic beam has a radial wavevector and hence an intensity cross-section which is independent of wavelength. The technique also lends itself to the generation of higher order Bessel beams with an on-axis optical vortex and associated orbital angular momentum.


1,135 ionomes reveal the global pattern of leaf and seed mineral nutrient and trace element diversity in Arabidopsis thaliana.
Soil is a heterogeneous reservoir of essential elements needed for plant growth and development. Plants have evolved mechanisms to balance their nutritional needs based on availability of nutrients. This has led to genetically based variation in the elemental composition, the 'ionome', of plants, both within and between species. We explore this natural variation using a panel of wild-collected, geographically widespread Arabidopsis thaliana accessions from the 1001 Genomes Project including over 1,135 accessions, and the 19 parental accessions of the Multi-parent Advanced Generation Inter-Cross (MAGIC) panel, all with full-genome sequences available. We present an experimental design pipeline for high-throughput ionomic screenings and analyses with improved normalisation procedures to account for errors and variability in conditions often encountered in large-scale, high-throughput data collection. We report quantification of the complete leaf and seed ionome of the entire collection using this pipeline and a digital tool, Ion Explorer, to interact with the dataset. We describe the pattern of natural ionomic variation across the A. thaliana species and identify several accessions with extreme ionomic profiles. It forms a valuable resource for exploratory genetic mapping studies to identify genes underlying natural variation in leaf and seed ionome and genetic adaptation of plants to soil conditions.


Development of adaptive immune effector therapies in solid tumors.
State-of-the-art treatment strategies have drastically ameliorated the outcome of patients affected by cancer. However, resistant and recurrent solid tumors are generally nonresponsive to conventional therapies. A central factor in the sequence of events that lead to cancer is an alteration in antitumor immune surveillance, which results in failure to recognize and eliminate the transformed tumor cell. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancer provides the basis for improved therapies. Targeted strategies, such as T-cell therapy, not only generally spare normal tissues, but also use alternative antineoplastic mechanisms that synergize with other therapeutics. Despite encouraging success in hematologic malignancies, adaptive cellular therapies for solid tumors face unique challenges because of the immunosuppressive tumor microenvironment, and the hurdle of T-cell trafficking within scarcely accessible tumor sites. This review provides a brief overview of current cellular therapeutic strategies for solid tumors, research carried out to increase efficacy and safety, and results from ongoing clinical trials.


Lambert-Eaton myasthenic syndrome immunoglobulins react with multiple types of calcium channels in small-cell lung carcinoma.
Barium currents through voltage-gated calcium (Ca2+) channels were studied in the small-cell lung carcinoma cell line NCI-H345 using patch clamp techniques. Pharmacological dissection of whole-cell barium currents revealed that 23% of the current was sensitive to nitrendipine, 35% to omega-conotoxin GVIA, and between 10 and 39% to omega-Aga-IVA. This implies that these cells express L-, N-, and P-type calcium channels. Only large cells expressed current that was sensitive to omega-Aga-IVA. The size dependency of this P-type channel expression may reflect the cell cycle stage. Cell-attached recordings revealed three unitary conductances: 5 to 6 pS, 10 to 12 pS, and 20 to 23 pS. The largest conductance channel (20-23 pS) was sensitive to Bay K 8644 and is presumed to represent L-type calcium channels. The frequency of observing the medium conductance channel (10-12 pS) was reduced by exposure to omega-conotoxin GVIA and may represent N-type channels. Incubation of cells with Lambert-Eaton myasthenic syndrome IgG for 24 to 48 hours removed up to 71% of the whole-cell current. Incubation with control human IgG (normal or myasthenia gravis) had no effect. Lambert-Eaton myasthenic syndrome IgG did not selectively target one "presynaptic" type of calcium channel, but rather appeared to target many of the calcium channel types that are expressed on small-cell lung carcinoma cells.


An appraisal of oral retinoids in the treatment of pachyonychia congenita.
Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16, or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Available studies assessing oral retinoid treatment for PC are limited to a few case reports. We sought to assess overall effectiveness, adverse effects, and patient perspective in patients with PC receiving oral retinoids. In a questionnaire-based retrospective cross-sectional survey of 30 patient with PC assessing oral retinoids (10-50 mg/d for 1-240 months), we determined the clinical score, satisfaction score, visual analog pain scale, and adverse effects. In 50% of patients there was thinning of hyperkeratoses (average improvement 1.6 on a scale from -3 to +3) (95% confidence interval 1.2-1.9, P < .001). In all, 14% observed amelioration of their pachyonychia; 79% did not experience any nail change. The self-reported overall satisfaction score with oral retinoid treatment was 2 or greater in 50% of the patients (mean 4.5 on a scale of 1-10). Although 33% reported decreased and 27% increased plantar pain with treatment, 40% did not notice any pain change. All patients experienced adverse effects, and 83% reported to have discontinued medication. Risk/benefit analysis favored lower retinoid doses (≤25 mg/d) over a longer time period (>5 months), compared with higher doses (>25 mg/d) for a shorter time (≤5 months). The retrospective, cross-sectional study design is prone to a recall bias. Oral retinoids are effective in some patients with PC. However, many patients discontinued medication because adverse effects outweighed the benefits. Careful dose titration is warranted in patients informed about potential adverse effects.


[The development of the American carcass rendering industry (author's transl)].
The American rendering organization is different from that in Europe, it has historycally developed as an industry separate from slaughter houses, it has grown and waxed very profitable on a world wide basis, and finally it is now under technological attack which may eventually fundamentally change it and make it more like the organization of rendering that you have in much of Europe after all.


Development of a comprehensive software application for calculations in nuclear medicine and radiopharmacy.
In the daily practice of in-hospital or centralized radiopharmacies, there is a need to perform reliable numeric calculations. Furthermore, several nuclear medicine diagnostic tests also involve carrying out calculations. In both cases, these calculations are sometimes complex or tedious and prone to error. We report the development of a computer software program that performs a comprehensive range of calculations required in radiopharmacy and nuclear medicine diagnostic tests. This software was developed and compiled in the Visual Basic programming language using algorithms and methods reflected in the scientific literature. We developed 2 versions of the software program, which we call Nucleolab. It automatically performs calculations relating to radiopharmacy practice as well as 9 diagnostic nuclear medicine tests. The 0.1 version performs all these calculations, and the 1.2 version also has a database that enables the user to save and recover diagnostic test results and issue custom reports. The software can be downloaded at www.radiofarmacia.org/nucleolab-english. To our knowledge, ours is the first attempt to develop a comprehensive software application that facilitates calculations in nuclear medicine and radiopharmacy, reducing errors and improving efficiency and accuracy.


The prevalence of acute respiratory symptoms and role of protective measures among Malaysian hajj pilgrims.
Respiratory symptoms including cough, runny nose, sore throat, and fever are the most common clinical manifestations faced by hajj pilgrims in Mecca. The aim of the study was to determine the prevalence of respiratory symptoms among Malaysian hajj pilgrims and the effect of a few protective measures taken by hajj pilgrims to reduce respiratory symptoms. A cross-sectional study was conducted by distributing survey forms to Malaysian hajj pilgrims at transit center before flying back to Malaysia. The recruitment of respondents to the survey was on a voluntary basis. A total of 387 survey forms were available for analysis. The mean age was 50.4 +/- 11.0 years. The common respiratory symptoms among Malaysian hajj pilgrims were: cough 91.5%, runny nose 79.3%, fever 59.2%, and sore throat 57.1%. The prevalence of hajj pilgrims with triad of cough, subjective fever, and sore throat were 40.1%. The symptoms lasted less than 2 weeks in the majority of cases. Only 3.6% did not suffer from any of these symptoms. Seventy-two percent of hajj pilgrims received influenza vaccination before departure and 72.9% wore facemasks. Influenza vaccination was not associated with any of respiratory symptoms but it was significantly associated with longer duration of sore throat. Wearing masks was significantly associated with sore throat and longer duration of sore throat and fever. The prevalence of respiratory symptoms was high among Malaysian hajj pilgrims and the current protective measures seemed inadequate to reduce it. Beside standardization of the term used in hajj studies, more collaborative effort should be taken to reduce respiratory symptoms. The hajj authority should prepare for the challenge of pandemic influenza by providing more healthcare facilities and implementation of more strict measures to reduce the transmission of pandemic influenza strain among hajj pilgrims.


Correlations of acute myocardial infarction complicated by cerebral infarction with insulin resistance, adiponectin and HMGB1.
To investigate the correlations of acute myocardial infarction (AMI) complicated by cerebral infarction with insulin resistance, adiponectin and high-mobility group box 1 (HMGB1). A total of 326 AMI patients receiving percutaneous coronary intervention (PCI) were selected as the research objects. They were divided into cerebral infarction group (n=24) and non-cerebral infarction group (n=302) based on their complication of cerebral infarction. In addition, 165 healthy people were enrolled as control group. Changes in the levels of HMGB1, adiponectin, fasting insulin (FINS), insulin sensitive index (ISI), insulin resistance, N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein (CRP), interleukin-6 (IL-6), myocardial infarction markers and coagulation function indexes were compared among the three groups. Correlations among those indexes were analyzed. AMI patients had higher levels of HMGB1, FINS, homeostasis model assessment of insulin resistance (HOMA-IR), ISI, creatine kinase isoenzyme (CK-MB), cardiac troponin I (cTnI), prothrombin time (PT), CRP and IL-6 than those in healthy participates, especially in those complicated with cerebral infarction. Conversely, levels of adiponectin, myoglobin (Mb), activated partial thromboplastin time (APTT), antithrombin III (AT-III), activated coagulation time (ACT) and NT-proBNP were the lowest in cerebral infarction group, and highest in control group (p<0.05). AMI complicated with cerebral infarction was negatively correlated with the levels of AT-III and adiponectin, but positively associated with the levels of NT-proBNP, HOMA-IR and HMGB1 (p<0.05). AMI complicated with cerebral infarction has negative correlations with the levels of AT-III and adiponectin, but positively associated with the levels of NT-proBNP, HOMA-IR and HMGB1, possessing certain clinical significance in AMI treatment.


Femtosecond laser-assisted mushroom configuration deep anterior lamellar keratoplasty.
To review patient outcomes after femtosecond laser-assisted mushroom configuration deep anterior lamellar keratoplasty. Seven eyes of seven patients with a mean age of 30 years underwent femtosecond laser-assisted mushroom configuration deep anterior lamellar keratoplasty from April 2008 to September 2008. Patients had keratoconus, corneal ectasia or scarring. Set for 100 mum of residual cornea, the femtosecond laser was used to create a mushroom-shaped recipient bed and donor button (having a larger anterior than posterior diameter). The posterior central lamella was manually dissected using Melles technique. Mean follow up was 4 months (range, 3-6.5 months). Preoperative mean best-corrected visual acuity was 20/95 (range, 20/40-20/400). Intraoperative complications included two cases (28.6%) of small Descemet membrane perforation. Postoperatively, there was one case of stromal rejection that resolved with topical steroids and two cases of steroid-related intraocular pressure rise that were treated with a prostaglandin analog. At 3 months, mean best-corrected visual acuity was 20/40 (range, 20/25-20/60), mean spherical equivalent refraction was -3.21 D (range, -6.75 D to plano), mean cylindrical refractive error was 3.57 D (range, 1.5-7 D), and mean keratometric cylinder measured 5.56 D (range, 3.79-7.00 D). Selective suture removal occurred in six patients (86%) at a mean of 3.8 months (range, 2-6 months) postoperatively. This preliminary series demonstrates that the use of the femtosecond laser to perform corneal cuts in a mushroom configuration for deep anterior lamellar keratoplasty is feasible. The mechanical stability and wound healing advantages for stepped corneal wounds should be considered in lamellar surgery.


A review of design and reporting issues in self-reported prevalence studies of leg ulceration.
The aim of this review was to examine design and reporting issues that affect prevalence estimates of leg ulceration obtained using self-report and outline strategies to strengthen the validity and reliability of research in this area. We identified leg ulcer prevalence studies and evaluated them against the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) statement. The authors draw upon the wider literature and their own empirical work in discussing strategies to overcome design and reporting issues. Common deficiencies in the design and reporting of studies include wide variations in diagnostic criteria and age parameters for participant selection, a lack of description of efforts to address bias/study size rationale, and low participation rates in clinical examination stages. These factors and differences in statistical methods of analysis affect the validity and reliability of findings and hinder interpretation, making comparisons across populations difficult. Opportunities for subgroup analyses are frequently missed. Self-report is a valuable means of capturing leg ulcer prevalence, but the future design and reporting of studies need to be strengthened, including addressing weaknesses in validation strategies. Capture-recapture analysis or a multiple-methods approach has the potential to yield the most valid and reliable prevalence estimates.