bluuebunny/crossref_metadata_2025 huggingface dataset:
A longitudinal study of chiropractic use among older adults in the United States
Authors: Weigel Paula , Hockenberry Jason M , Bentler Suzanne E , Obrizan Maksym , Kaskie Brian , Jones Michael P , Ohsfeldt Robert L , Rosenthal Gary E , Wallace Robert B , Wolinsky Fredric D
Published: January 2011

Background

Longitudinal patterns of chiropractic use in the United States, particularly among Medicare beneficiaries, are not well documented. Using a nationally representative sample of older Medicare beneficiaries we describe the use of chiropractic over fifteen years, and classify chiropractic users by annual visit volume. We assess the characteristics that are associated with chiropractic use versus nonuse, as well as between different levels of use.

Methods

We analyzed data from two linked sources: the baseline (1993-1994) interview responses of 5,510 self-respondents in the Survey on Assets and Health Dynamics Among the Oldest Old (AHEAD), and their Medicare claims from 1993 to 2007. Binomial logistic regression was used to identify factors associated with chiropractic use versus nonuse, and conditional upon use, to identify factors associated with high volume relative to lower volume use.

Results

There were 806 users of chiropractic in the AHEAD sample yielding a full period prevalence for 1993-2007 of 14.6%. Average annual prevalence between 1993 and 2007 was 4.8% with a range from 4.1% to 5.4%. Approximately 42% of the users consumed chiropractic services only in a single calendar year while 38% used chiropractic in three or more calendar years. Chiropractic users were more likely to be women, white, overweight, have pain, have multiple comorbid conditions, better self-rated health, access to transportation, higher physician utilization levels, live in the Midwest, and live in an area with fewer physicians per capita. Among chiropractic users, 16% had at least one year in which they exceeded Medicare's "soft cap" of 12 visits per calendar year. These over-the-cap users were more likely to have arthritis and mobility limitations, but were less likely to have a high school education. Additionally, these over-the-cap individuals accounted for 58% of total chiropractic claim volume. High volume users saw chiropractors the most among all types of providers, even more than family practice and internal medicine combined.

Conclusion

There is substantial heterogeneity in the patterns of use of chiropractic services among older adults. In spite of the variability of use patterns, however, there are not many characteristics that distinguish high volume users from lower volume users. While high volume users accounted for a significant portion of claims, the enforcement of a hard cap on annual visits by Medicare would not significantly decrease overall claim volume. Further research to understand the factors causing high volume chiropractic utilization among older Americans is warranted to discern between patterns of "need" and patterns of "health maintenance".
Dysphagia in head and neck cancer patients following intensity modulated radiotherapy (IMRT)
Authors: Peponi Evangelia , Glanzmann Christoph , Willi Bettina , Huber Gerhard , Studer Gabriela
Published: January 2011

Background

To evaluate the objective and subjective long term swallowing function, and to relate dysphagia to the radiation dose delivered to the critical anatomical structures in head and neck cancer patients treated with intensity modulated radiation therapy (IMRT, +/- chemotherapy), using a midline protection contour (below hyoid, ~level of vertebra 2/3).

Methods

82 patients with stage III/IV squamous cell carcinoma of the larynx, oropharynx, or hypopharynx, who underwent successful definitive (n = 63, mean dose 68.9Gy) or postoperative (n = 19, mean dose 64.2Gy) simultaneous integrated boost (SIB) -IMRT either alone or in combination with chemotherapy (85%) with curative intent between January 2002 and November 2005, were evaluated retrospectively. 13/63 definitively irradiated patients (21%) presented with a total gross tumor volume (tGTV) >70cc (82-173cc; mean 106cc). In all patients, a laryngo-pharyngeal midline sparing contour outside of the PTV was drawn. Dysphagia was graded according subjective patient-reported and objective observer-assessed instruments. All patients were re-assessed 12 months later. Dose distribution to the swallowing structures was calculated.

Results

At the re-assessment, 32-month mean post treatment follow-up (range 16-60), grade 3/4 objective toxicity was assessed in 10%. At the 32-month evaluation as well as at the last follow up assessment mean 50 months (16-85) post-treatment, persisting swallowing dysfunction grade 3 was subjectively and objectively observed in 1 patient (1%). The 5-year local control rate of the cohort was 75%; no medial marginal failures were observed.

Conclusions

Our results show that sparing the swallowing structures by IMRT seems effective and relatively safe in terms of avoidance of persistent grade 3/4 late dysphagia and local disease control.
Guidelines in the management of obstructing cancer of the left colon: consensus conference of the world society of emergency surgery (WSES) and peritoneum and surgery (PnS) society
Authors: Ansaloni Luca , Andersson Roland E , Bazzoli Franco , Catena Fausto , Cennamo Vincenzo , Di Saverio Salomone , Fuccio Lorenzo , Jeekel Hans , Leppäniemi Ari , Moore Ernest , Pinna Antonio D , Pisano Michele , Repici Alessandro , Sugarbaker Paul H , Tuech Jean-Jaques
Published: January 2011

Background

Obstructive left colon carcinoma (OLCC) is a challenging matter in terms of obstruction release as well of oncological issues. Several options are available and no guidelines are established. The paper aims to generate evidenced based recommendations on management of OLCC.

Methods

The PubMed and Cochrane Library databases were queried for publications focusing on OLCC published prior to April 2010. A extensive retrieval, analyses, and grading of the literature was undertaken. The findings of the research were presented and largely discussed among panellist and audience at the Consensus Conference of the World Society of Emergency Surgery (WSES) and Peritoneum and Surgery (PnS) Society held in Bologna July 2010. Comparisons of techniques are presented and final committee recommendation are enounced.

Results

Hartmann's procedure should be preferred to loop colostomy (Grade 2B). Hartmann's procedure offers no survival benefit compared to segmental colonic resection with primary anastomosis (Grade 2C+); Hartmann's procedure should be considered in patients with high surgical risk (Grade 2C). Total colectomy and segmental colectomy with intraoperative colonic irrigation are associated with same mortality/morbidity, however total colectomy is associated with higher rates impaired bowel function (Grade 1A). Segmental resection and primary anastomosis either with manual decompression or intraoperative colonic irrigation are associated with same mortality/morbidity rate (Grade 1A). In palliation stent placement is associated with similar mortality/morbidity rates and shorter hospital stay (Grade 2B). Stents as a bridge to surgery seems associated with lower mortality rate, shorter hospital stay, and a lower colostomy formation rate (Grade 1B).

Conclusions

Loop colostomy and staged procedure should be adopted in case of dramatic scenario, when neoadjuvant therapy could be expected. Hartmann's procedure should be performed in case of high risk of anastomotic dehiscence. Subtotal and total colectomy should be attempted when cecal perforation or in case of synchronous colonic neoplasm. Primary resection and anastomosis with manual decompression seems the procedure of choice. Colonic stents represent the best option when skills are available. The literature power is relatively poor and the existing RCT are often not sufficiently robust in design thus, among 6 possible treatment modalities, only 2 reached the Grade A.
Two novel human NUMB isoforms provide a potential link between development and cancer
Authors: Karaczyn Aldona , Bani-Yaghoub Mahmud , Tremblay Roger , Kubu Chris , Cowling Rebecca , Adams Tamara L , Prudovsky Igor , Spicer Douglas , Friesel Robert , Vary Calvin , Verdi Joseph M
Published: January 2011

We previously identified four functionally distinct human NUMB isoforms. Here, we report the identification of two additional isoforms and propose a link between the expression of these isoforms and cancer. These novel isoforms, NUMB5 and NUMB6, lack exon 10 and are expressed in cells known for polarity and migratory behavior, such as human amniotic fluid cells, glioblastoma and metastatic tumor cells. RT-PCR and luciferase assays demonstrate that NUMB5 and NUMB6 are less antagonistic to NOTCH signaling than other NUMB isoforms. Immunocytochemistry analyses show that NUMB5 and NUMB6 interact and complex with CDC42, vimentin and the CDC42 regulator IQGAP1 (IQ (motif) GTPase activating protein 1). Furthermore, the ectopic expression of NUMB5 and NUMB6 induces the formation of lamellipodia (NUMB5) and filopodia (NUMB6) in a CDC42- and RAC1-dependent manner. These results are complemented by in vitro and in vivo studies, demonstrating that NUMB5 and NUMB6 alter the migratory behavior of cells. Together, these novel isoforms may play a role in further understanding the NUMB function in development and cancer.
DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease
Authors: Chen Jianmin , Cohen Mark L , Lerner Alan J , Yang Yan , Herrup Karl
Published: January 2011

Background

Although the cerebellum is considered to be predominantly involved in fine motor control, emerging evidence documents its participation in language, impulsive behavior and higher cognitive functions. While the specific connections of the cerebellar deep nuclei (CDN) that are responsible for these functions are still being worked out, their deficiency has been termed "cerebellar cognitive affective syndrome" - a syndrome that bears a striking similarity to many of the symptoms of Alzheimer's disease (AD). Using ectopic cell cycle events and DNA damage markers as indexes of cellular distress, we have explored the neuropathological involvement of the CDN in human AD.

Results

We examined the human cerebellar dentate nucleus in 22 AD cases and 19 controls for the presence of neuronal cell cycle events and DNA damage using immunohistochemistry and fluorescence in situ hybridization. Both techniques revealed several instances of highly significant correlations. By contrast, neither amyloid plaque nor neurofibrillary tangle pathology was detected in this region, consistent with previous reports of human cerebellar pathology. Five cases of early stage AD were examined and while cell cycle and DNA damage markers were well advanced in the hippocampus of all five, few indicators of either cell cycle events (1 case) or a DNA damage response (1 case) were found in CDN. This implies that CDN neurons are most likely affected later in the course of AD. Clinical-pathological correlations revealed that cases with moderate to high levels of cell cycle activity in their CDN are highly likely to show deficits in unorthodox cerebellar functions including speech, language and motor planning.

Conclusion

Our results reveal that the CDN neurons are under cellular stress in AD and suggest that some of the non-motor symptoms found in patients with AD may be partly cerebellar in origin.
Regulation patterns in signaling networks of cancer
Authors: Schramm Gunnar , Kannabiran Nandakumar , König Rainer
Published: January 2011

Background

Formation of cellular malignancy results from the disruption of fine tuned signaling homeostasis for proliferation, accompanied by mal-functional signals for differentiation, cell cycle and apoptosis. We wanted to observe central signaling characteristics on a global view of malignant cells which have evolved to selfishness and independence in comparison to their non-malignant counterparts that fulfill well defined tasks in their sample.

Results

We investigated the regulation of signaling networks with twenty microarray datasets from eleven different tumor types and their corresponding non-malignant tissue samples. Proteins were represented by their coding genes and regulatory distances were defined by correlating the gene-regulation between neighboring proteins in the network (high correlation = small distance). In cancer cells we observed shorter pathways, larger extension of the networks, a lower signaling frequency of central proteins and links and a higher information content of the network. Proteins of high signaling frequency were enriched with cancer mutations. These proteins showed motifs of regulatory integration in normal cells which was disrupted in tumor cells.

Conclusion

Our global analysis revealed a distinct formation of signaling-regulation in cancer cells when compared to cells of normal samples. From these cancer-specific regulation patterns novel signaling motifs are proposed.
Understanding protein evolutionary rate by integrating gene co-expression with protein interactions
Authors: Pang Kaifang , Cheng Chao , Xuan Zhenyu , Sheng Huanye , Ma Xiaotu
Published: January 2011

Background

Among the many factors determining protein evolutionary rate, protein-protein interaction degree (PPID) has been intensively investigated in recent years, but its precise effect on protein evolutionary rate is still heavily debated.

Results

We first confirmed that the correlation between protein evolutionary rate and PPID varies considerably across different protein interaction datasets. Specifically, because of the maximal inconsistency between yeast two-hybrid and other datasets, we reasoned that the difference in experimental methods contributes to our inability to clearly define how PPID affects protein evolutionary rate. To address this, we integrated protein interaction and gene co-expression data to derive a co-expressed protein-protein interaction degree (ePPID) measure, which reflects the number of partners with which a protein can permanently interact. Thus, irrespective of the experimental method employed, we found that (1) ePPID is a better predictor of protein evolutionary rate than PPID, (2) ePPID is a more robust predictor of protein evolutionary rate than PPID, and (3) the contribution of ePPID to protein evolutionary rate is statistically independent of expression level. Analysis of hub proteins in the Structural Interaction Network further supported ePPID as a better predictor of protein evolutionary rate than the number of distinct binding interfaces and clarified the slower evolution of co-expressed multi-interface hub proteins over that of other hub proteins.

Conclusions

Our study firmly established ePPID as a robust predictor of protein evolutionary rate, irrespective of experimental method, and underscored the importance of permanent interactions in shaping the evolutionary outcome.
Antithrombotic therapy and outcomes of cervical arterial dissection in the trauma patient: a case series
Authors: Hinson Holly E , Stallmeyer M JB , Furuno Jon P , Yarbrough Karen L , Cole John W
Published: January 2011

Background

The use of antithrombotic therapy (anticoagulants and/or antiplatelets) in the setting of traumatic cervical arterial dissection (CAD) for the prevention of stroke remains controversial. This issue is further complicated by the frequent co-existence of intracranial hemorrhage (ICH) and other intracranial injuries, and also the wide variability in treatment due to a lack of evidence-based guidance. To address these controversies, a registry in a major Level I trauma center was created. The purpose of this investigation was to compare the safety of antithrombotic therapy in post-traumatic CAD. Analysis from the first year is presented.

Methods

All cervical dissections from the year 2005 were identified in patients at least 18 years of age by diagnosis code from radiology and trauma databases. Presence of arterial injury and grade, and other intracranial disease or injury such as stroke was diagnosed by a trauma radiologist and adjudicated by a neuroradiologist.

Results

Fifty-five patients with cervical artery dissection were identified. Fourteen patients presented with a total of 20 acute, post-traumatic intracranial hemorrhages (ICH). Seven of the 14 patients with ICH were treated with antithrombotic therapy, and none extended their intracranial hemorrhages. Of the 41 patients without pre-existing ICH, 28 were treated with antithrombotic therapy and only one developed an interval hematoma. Among all 55 cases, two patients developed an acute ischemic stroke in the territory of the dissected artery after admission; both patients were in the untreated group.

Conclusion

In so far as antithrombotic therapy may offer benefit in preventing early ischemic stroke following cervical artery dissection, these data suggest withholding antiplatelet or other antithrombotics following trauma may not be warranted, even in the setting of intracranial hemorrhage. From a safety perspective, this registry-based case series indicates antithrombotic management of arterial injury did not contribute to development or progression of ICH, even in patients with pre-existing ICH. This data suggest that instituting early antithrombotic therapy presents a low risk of ICH or hemorrhage extension among traumatic cervical dissection patients.
Birt-Hogg-Dubé renal tumors are genetically distinct from other renal neoplasias and are associated with up-regulation of mitochondrial gene expression
Authors: Klomp Jeff A , Petillo David , Niemi Natalie M , Dykema Karl J , Chen Jindong , Yang Ximing J , Sääf Annika , Zickert Peter , Aly Markus , Bergerheim Ulf , Nordenskjöld Magnus , Gad Sophie , Giraud Sophie , Denoux Yves , Yonneau Laurent , Méjean Arnaud , Vasiliu Viorel , Richard Stéphane , MacKeigan Jeffrey P , Teh Bin T , Furge Kyle A
Published: January 2011

Background

Germline mutations in the folliculin (FLCN) gene are associated with the development of Birt-Hogg-Dubé syndrome (BHDS), a disease characterized by papular skin lesions, a high occurrence of spontaneous pneumothorax, and the development of renal neoplasias. The majority of renal tumors that arise in BHDS-affected individuals are histologically similar to sporadic chromophobe renal cell carcinoma (RCC) and sporadic renal oncocytoma. However, most sporadic tumors lack FLCN mutations and the extent to which the BHDS-derived renal tumors share genetic defects associated with the sporadic tumors has not been well studied.

Methods

BHDS individuals were identified symptomatically and FLCN mutations were confirmed by DNA sequencing. Comparative gene expression profiling analyses were carried out on renal tumors isolated from individuals afflicted with BHDS and a panel of sporadic renal tumors of different subtypes using discriminate and clustering approaches. qRT-PCR was used to confirm selected results of the gene expression analyses. We further analyzed differentially expressed genes using gene set enrichment analysis and pathway analysis approaches. Pathway analysis results were confirmed by generation of independent pathway signatures and application to additional datasets.

Results

Renal tumors isolated from individuals with BHDS showed distinct gene expression and cytogenetic characteristics from sporadic renal oncocytoma and chromophobe RCC. The most prominent molecular feature of BHDS-derived kidney tumors was high expression of mitochondria-and oxidative phosphorylation (OXPHOS)-associated genes. This mitochondria expression phenotype was associated with deregulation of the PGC-1α-TFAM signaling axis. Loss of FLCN expression across various tumor types is also associated with increased nuclear mitochondrial gene expression.

Conclusions

Our results support a genetic distinction between BHDS-associated tumors and other renal neoplasias. In addition, deregulation of the PGC-1α-TFAM signaling axis is most pronounced in renal tumors that harbor FLCN mutations and in tumors from other organs that have relatively low expression of FLCN. These results are consistent with the recently discovered interaction between FLCN and AMPK and support a model in which FLCN is a regulator of mitochondrial function.
Glycogen synthase kinase-3β inhibition induces nuclear factor-κB-mediated apoptosis in pediatric acute lymphocyte leukemia cells
Authors: Hu Yanni , Gu Xiaoyan , Li Ruiyan , Luo Qing , Xu Youhua
Published: January 2011

Background

Molecular therapies that target genetic abnormalities in leukemic cells and their affected signaling pathways have been emerging in pediatric acute lymphoblastic leukemia (ALL). Glycogen synthase kinase-3β (GSK-3β) has recently been found to positively regulate the activity of nuclear factor-κB (NF-κB). Here, we investigated the relationship between GSK-3β inhibition and NF-κB in apoptosis of pediatric primary leukemia cells obtained from 39 newly diagnosed ALL children in China.

Methods

Bone marrow mononuclear cells (BMMC) were isolated by density gradient centrifugation from the heparinized aspirates of children with ALL. We used immunofluorescence staining to detect nuclear GSK-3β in these cells. After treatment with chemically distinct GSK-3β inhibitors in vitro, NF-κB transcriptional activity was identified by means of western blotting and electrophoretic mobility shift assay (EMSA). NF-κB-mediated apoptosis was detected by Annexin V-PE/7-AAD double-staining flow cytometry. The expression level of the survivin gene was detected by reverse-transcriptase polymerase chain reaction (RT-PCR).

Results

GSK-3β significantly accumulates in the nuclei of ALL cells than in the nuclei of control cells. Cell death induced by GSK-3β inhibition in ALL cells was mediated by a downregulation of NF-κB p65 transcriptional activity. GSK-3β inhibition significantly decreased the expression of the NF-κB target gene survivin.

Conclusions

These results indicate that inhibition of GSK-3β downregulates the NF-κB activation pathway, leading to suppression of the expression of an NF-κB-regulated gene and promotion of apoptosis in ALL cells in vitro. Furthermore, our findings suggest that GSK-3β or NF-κB is a potential therapeutic target in the treatment of pediatric ALL.
XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells
Authors: Xing Zhaoquan , Zhou Zunlin , Yu Rong , Li Shuling , Li Chunde , Nilsson Sten , Liu Zhaoxu
Published: January 2011

Background

Somatostatin prevents cell proliferation by inducing apoptosis. Downregulation of the XAF1 transcript may occur during the development of prostate cancer. It is interesting to evaluate the potential regulatory effects of somatostatin on XAF1 expression during the development of prostate cancer cells.

Methods

XAF1 mRNA and protein expression in human prostate epithelial cells RWPE-1, androgen dependent prostate cancer LNCaP, and androgen independent DU145 and PC3 cells were evaluated using RT-PCR and Western blot. The regulation of XAF1 mRNA and protein expression by somatostatin and its analogue Octreotide was evaluated.

Results

Substantial levels of XAF1 mRNA and proteins were detected in RWPE-1 cells, whereas prostate cancer cells LNCaP, DU145 and PC3 exhibited lower XAF1 expression. Somatostatin and Octreotide up-regulated XAF1 mRNA and protein expression in all prostate cancer cell lines.

Conclusions

XAF1 down-regulation may contribute to the prostate cancer development. The enhanced XAF1 expression by somatostatin indicates a promising strategy for prostate cancer therapy.
Split tendon transfers for the correction of spastic varus foot deformity: a case series study
Authors: Vlachou Maria , Dimitriadis Dimitris
Published: January 2011

Background

Overactivity of anterior and/or posterior tibial tendon may be a causative factor of spastic varus foot deformity. The prevalence of their dysfunction has been reported with not well defined results. Although gait analysis and dynamic electromyography provide useful information for the assessment of the patients, they are not available in every hospital. The purpose of the current study is to identify the causative muscle producing the deformity and apply the most suitable technique for its correction.

Methods

We retrospectively evaluated 48 consecutive ambulant patients (52 feet) with spastic paralysis due to cerebral palsy. The average age at the time of the operation was 12,4 yrs (9‐18) and the mean follow‐up 7,8 yrs (4‐14). Eigtheen feet presented equinus hind foot deformity due to gastrocnemius and soleus shortening. According to the deformity, the feet were divided in two groups (Group I with forefoot and midfoot inversion and Group II with hindfoot varus). The deformities were flexible in all cases in both groups. Split anterior tibial tendon transfer (SPLATT) was performed in Group I (11 feet), while split posterior tibial tendon transfer (SPOTT) was performed in Group II (38 feet). In 3 feet both procedures were performed. Achilles tendon sliding lengthening (Hoke procedure) was done in 18 feet either preoperatively or concomitantly with the index procedure.

Results

The results in Group I, were rated according to Hoffer's clinical criteria as excellent in 8 feet and satisfactory in 3, while in Group II according to Kling's clinical criteria were rated as excellent in 20 feet, good in 14 and poor in 4. The feet with poor results presented residual varus deformity due to intraoperative technical errors.

Conclusion

Overactivity of the anterior tibial tendon produces inversion most prominent in the forefoot and midfoot and similarly overactivity of the posterior tibial tendon produces hindfoot varus. The deformity can be clinically unidentifiable in some cases when Achilles shortening co‐exists producing foot equinus. By identifying the muscle causing the deformity and performing the appropriate technique, very satisfying results were achieved in the majority of our cases. In three feet both muscles contributed to a combined deformity and simultaneous SPLATT and SPOTT were considered necessary. For complex foot deformities where the component of cavus co‐exists, supplementary procedures are required along with the index operation to obtain the best result.
Recovering mitochondrial DNA lineages of extinct Amerindian nations in extant homopatric Brazilian populations
Authors: Gonçalves Vanessa F , Parra Flavia C , Gonçalves-Dornelas Higgor , Rodrigues-Carvalho Claudia , Silva Hilton P , Pena Sergio DJ
Published: January 2011

Background

Brazilian Amerindians have experienced a drastic population decrease in the past 500 years. Indeed, many native groups from eastern Brazil have vanished. However, their mitochondrial mtDNA haplotypes, still persist in Brazilians, at least 50 million of whom carry Amerindian mitochondrial lineages. Our objective was to test whether, by analyzing extant rural populations from regions anciently occupied by specific Amerindian groups, we could identify potentially authentic mitochondrial lineages, a strategy we have named 'homopatric targeting'.

Results

We studied 173 individuals from Queixadinha, a small village located in a territory previously occupied by the now extinct Botocudo Amerindian nation. Pedigree analysis revealed 74 unrelated matrilineages, which were screened for Amerindian mtDNA lineages by restriction fragment length polymorphism. A cosmopolitan control group was composed of 100 individuals from surrounding cities. All Amerindian lineages identified had their hypervariable segment HVSI sequenced, yielding 13 Amerindian haplotypes in Queixadinha, nine of which were not present in available databanks or in the literature. Among these haplotypes, there was a significant excess of haplogroup C (70%) and absence of haplogroup A lineages, which were the most common in the control group. The novelty of the haplotypes and the excess of the C haplogroup suggested that we might indeed have identified Botocudo lineages. To validate our strategy, we studied teeth extracted from 14 ancient skulls of Botocudo Amerindians from the collection of the National Museum of Rio de Janeiro. We recovered mtDNA sequences from all the teeth, identifying only six different haplotypes (a low haplotypic diversity of 0.8352 ± 0.0617), one of which was present among the lineages observed in the extant individuals studied.

Conclusions

These findings validate the technique of homopatric targeting as a useful new strategy to study the peopling and colonization of the New World, especially when direct analysis of genetic material is not possible.
Hydrogen peroxide induced genomic instability in nucleotide excision repair-deficient lymphoblastoid cells
Authors: Gopalakrishnan Kalpana , Low Grace Kah Mun , Ting Aloysius Poh Leong , Srikanth Prarthana , Slijepcevic Predrag , Hande M Prakash
Published: January 2011

Background

The Nucleotide Excision Repair (NER) pathway specialises in UV-induced DNA damage repair. Inherited defects in the NER can predispose individuals to Xeroderma Pigmentosum (XP). UV-induced DNA damage cannot account for the manifestation of XP in organ systems not directly exposed to sunlight. While the NER has recently been implicated in the repair of oxidative DNA lesions, it is not well characterised. Therefore we sought to investigate the role of NER factors Xeroderma Pigmentosum A (XPA), XPB and XPD in oxidative DNA damage-repair by subjecting lymphoblastoid cells from patients suffering from XP-A, XP-D and XP-B with Cockayne Syndrome to hydrogen peroxide (H2O2).

Results

Loss of functional XPB or XPD but not XPA led to enhanced sensitivity towards H2O2-induced cell death. XP-deficient lymphoblastoid cells exhibited increased susceptibility to H2O2-induced DNA damage with XPD showing the highest susceptibility and lowest repair capacity. Furthermore, XPB- and XPD-deficient lymphoblastoid cells displayed enhanced DNA damage at the telomeres. XPA- and XPB-deficient lymphoblastoid cells also showed differential regulation of XPD following H2O2 treatment.

Conclusions

Taken together, our data implicate a role for the NER in H2O2-induced oxidative stress management and further corroborates that oxidative stress is a significant contributing factor in XP symptoms. Resistance of XPA-deficient lymphoblastoid cells to H2O2-induced cell death while harbouring DNA damage poses a potential cancer risk factor for XPA patients. Our data implicate XPB and XPD in the protection against oxidative stress-induced DNA damage and telomere shortening, and thus premature senescence.
De-escalation as part of a global strategy of empiric antibiotherapy management. A retrospective study in a medico-surgical intensive care unit
Authors: Morel Jérôme , Casoetto Julie , Jospé Richard , Aubert Gérald , Terrana Raphael , Dumont Alain , Molliex Serge , Auboyer Christian
Published: January 2011

Introduction

Most data on de-escalation of empirical antimicrobial therapy has focused on ventilator-associated pneumonia. In this retrospective monocentric study, we evaluated de-escalation as part of a global strategy of empiric antibiotherapy management irrespective of the location and the severity of the infection. The goal of this trial was to assess the application of a de-escalation strategy and the impact in terms of re-escalation, recurrent infection and to identify variables associated with de-escalation.

Methods

All consecutive patients treated with empiric antibiotic therapy and hospitalized in the intensive care unit for at least 72 hours within a period of 16 months were included. We compared the characteristics and outcome of patients who have experienced de-escalation therapy with those who have not.

Results

A total of 116 patients were studied corresponding to 133 infections. Antibiotic therapy was de-escalated in 60 cases (45%). De-escalation, primarily accomplished by a reduction in the number of antibiotics used, was observed in 52% of severe sepsis or septic shock patients. Adequate empiric antibiotic and use of aminoglycoside were independently linked with de-escalation. De-escalation therapy was associated with a significant reduction of recurrent infection (19% vs 5% P = 0.01). Mortality was not changed by de-escalation.

Conclusions

As part of a global management of empiric antibiotherapy in an intensive care unit, de-escalation might be safe and feasible in a large proportion of patients.
Outcome of severe lactic acidosis associated with metformin accumulation
Authors: Friesecke Sigrun , Abel Peter , Roser Markus , Felix Stephan B , Runge Soeren
Published: January 2011

Introduction

Metformin associated lactic acidosis (MALA) may complicate metformin therapy, particularly if metformin accumulates due to renal dysfunction. Profound lactic acidosis (LA) generally predicts poor outcome. We aimed to determine if MALA differs in outcome from LA of other origin (LAOO).

Methods

We conducted a retrospective analysis of all patients admitted with LA to our medical ICU of a tertiary referral center during a 5-year period. MALA patients and LAOO patients were compared with respect to parameters of acid-base balance, serum creatinine, hospital outcome, Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) score, using Pearson's Chi-square or the Mann-Whitney U-test.

Results

Of 197 patients admitted with LA, 10 had been diagnosed with MALA. With MALA, median arterial blood pH was significantly lower (6.78 [range 6.5 to 6.94]) and serum lactate significantly higher (18.7 ± 5.3 mmol/L) than with LAOO (pH 7.20 [range 6.46 to 7.35], mean serum lactate 11.2 ± 6.1 mmol/L). Overall mortality, however, was comparable (MALA 50%, LAOO 74%). Furthermore, survival of patients with arterial blood pH < 7.00 (N = 41) was significantly better (50% vs. 0%) if MALA (N = 10) was the underlying condition compared to LAOO (N = 31).

Conclusions

Compared to similarly severe lactic acidosis of other origin, the prognosis of MALA is significantly better. MALA should be considered in metformin-treated patients presenting with lactic acidosis.
Relationship between alcohol use disorders, cortisol concentrations, and cytokine levels in patients with sepsis
Authors: de Wit Marjolein , Wiaterek Gregory K , Gray Nicole D , Goulet Keith E , Best Al M , Clore John N , Sweeney Lori B
Published: January 2011

Introduction

Patients with alcohol use disorders (AUD) are at increased risk of developing sepsis and have higher mortality. AUD are associated with higher cortisol and anti-inflammatory cytokine profile. Higher cortisol increases risk of death in septic patients. The relationship between AUD and cortisol in septic patients is unknown. We aimed to study this relationship and postulated that AUD would be associated with higher cortisol and anti-inflammatory cytokine profile.

Methods

This was a prospective cohort study of 40 medical intensive care unit (ICU) patients admitted with sepsis. Cortisol, anti-inflammatory interleukin (IL) 10, and pro-inflammatory IL1β, IL6, tumor necrosis factor (TNF) α were measured.

Results

Thirteen (32%) out of 40 patients had AUD. AUD patients had higher cortisol by univariate (39 microg/dl versus 24,P= 0.04) and multivariable analyses (44 microg/dl versus 23,P= 0.004). By univariate analyses, AUD patients had higher IL10 (198 picog/dl versus 47,P= 0.02) and IL6 (527 picog/ml versus 156,P= 0.048), but similar IL1β and TNFα. By multivariable analyses, AUD patients had higher IL10 (182 picog/dl versus 23,P= 0.049) but similar IL1β, IL6, and TNFα. AUD patients had lower IL1β/IL10 (univariate 0.01 versus 0.10,P= 0.04; multivariable 0.01 versus 0.03,P= 0.04), lower TNFα/IL10 (univariate 0.15 versus 0.52,P= 0.03; multivariable 0.11 versus 0.63,P= 0.01), but similar IL6/IL10.

Conclusions

AUD are common diagnoses among medical ICU patients with sepsis. Patients with AUD have higher cortisol concentrations and have differences in cytokine expression. Future studies should seek to determine if these differences may explain the higher severity of illness seen in patients with sepsis and AUD.

Trial registration

ClinicalTrials.gov:NCT00615862
Pre-hospital cooling of patients following cardiac arrest is effective using even low volumes of cold saline
Authors: Škulec Roman , Truhlář Anatolij , Šeblová Jana , Dostál Pavel , Černý Vladimír
Published: January 2011

Introduction

Pre-hospital induction of therapeutic mild hypothermia (TH) may reduce post-cardiac arrest brain injury in patients resuscitated from out-of-hospital cardiac arrest. Most often, it is induced by a rapid intravenous administration of as much as 30 ml/kg of cold crystalloids. We decided to assess the pre-hospital cooling effectivity of this approach by using a target dose of 15-20 ml/kg of 4°C cold normal saline in the setting of the physician-staffed Emergency Medical Service. The safety and impact on the clinical outcome have also been analyzed.

Methods

We performed a prospective observational study with a retrospective control group. A total of 40 patients were cooled by an intravenous administration of 15-20 ml/kg of 4°C cold normal saline during transport to the hospital (TH group). The pre-hospital decrease of tympanic temperature (TT) was analyzed as the primary endpoint. Patients in the control group did not undergo any pre-hospital cooling.

Results

In the TH group, administration of 12.6 ± 6.4 ml/kg of 4°C cold normal saline was followed by a pre-hospital decrease of TT of 1.4 ± 0.8°C in 42.8 ± 19.6 min (p < 0.001). The most effective cooling was associated with a transport time duration of 38-60 min and with an infusion of 17 ml/kg of cold saline. In the TH group, a trend toward a reduced need for catecholamines during transport was detected (35.0 vs. 52.5%, p = 0.115). There were no differences in demographic variables, comorbidities, parameters of the cardiopulmonary resuscitation and in other post-resuscitation characteristics. The coupling of pre-hospital cooling with subsequent in-hospital TH predicted a favorable neurological outcome at hospital discharge (OR 4.1, CI95% 1.1-18.2, p = 0.046).

Conclusions

Pre-hospital induction of TH by the rapid intravenous administration of cold normal saline has been shown to be efficient even with a lower dose of coolant than reported in previous studies. This dose can be associated with a favorable impact on circulatory stability early after the return of spontaneous circulation and, when coupled with in-hospital continuation of cooling, can potentially improve the prognosis of patients.

Trial Registration

ClinicalTrials (NCT): NCT00915421
Lack of effect of glutamine administration to boost the innate immune system response in trauma patients in the intensive care unit
Authors: Pérez-Bárcena Jon , Crespí Catalina , Regueiro Verónica , Marsé Pedro , Raurich Joan M , Ibáñez Jordi , García de Lorenzo-Mateos Abelardo , Bengoechea José A
Published: January 2011

Introduction

The use of glutamine as a dietary supplement is associated with a reduced risk of infection. We hypothesized that the underlying mechanism could be an increase in the expression and/or functionality of Toll-like receptors (TLR), key receptors sensing infections. The objective of this study was to evaluate whether glutamine supplementation alters the expression and functionality of TLR2 and TLR4 in circulating monocytes of trauma patients admitted to the intensive care unit (ICU).

Methods

We designed a prospective, randomized and single-blind study. Twenty-three patients received parenteral nutrition (TPN) with a daily glutamine supplement of 0.35 g/kg. The control group (20 patients) received an isocaloric-isonitrogenated TPN. Blood samples were extracted before treatment, at 6 and 14 days. Expression of TLR2 and TLR4 was determined by flow cytometry. Monocytes were stimulated with TLR specific agonists and cytokines were measured in cell culture supernatants. Phagocytic ability of monocytes was also determined.

Results

Basal characteristics were similar in both groups. Monocytes from patients treated with glutamine expressed the same TLR2 levels as controls before treatment (4.9 ± 3.5 rmfi vs. 4.3 ± 1.9 rmfi, respectively; P = 0.9), at Day 6 (3.8 ± 2.3 rmfi vs. 4.0 ± 1.7 rmfi, respectively; P = 0.7) and at Day 14 (4.1 ± 2.1 rfim vs. 4.6 ± 1.9 rmfi, respectively; P = 0.08). TLR4 levels were not significantly different between the groups before treatment: (1.1 ± 1 rmfi vs 0.9 ± 0.1 rmfi respectively; P = 0.9), at Day 6 (1.1 ± 1 rmfi vs. 0.7 ± 0.4 rmfi respectively; P = 0.1) and at Day 14 (1.4 ± 1.9 rmfi vs. 1.0 ± 0.6 rmfi respectively; P = 0.8). No differences in cell responses to TLR agonists were found between groups. TLR functionality studied by phagocytosis did not vary between groups.

Conclusions

In trauma patients in the intensive care unit, TPN supplemented with glutamine does not improve the expression or the functionality of TLRs in peripheral blood monocytes.

Trial registration

ClinicalTrials.gov Identifier: NCT01250080.
Respiratory support withdrawal in intensive care units: families, physicians and nurses views on two hypothetical clinical scenarios
Authors: Fumis Renata RL , Deheinzelin Daniel
Published: January 2011

Introduction

Evidence suggests that dying patients' physical and emotional suffering is inadequately treated in intensive care units. Although there are recommendations regarding decisions to forgo life-sustaining therapy, deciding on withdrawal of life support is difficult, and it is also difficult to decide who should participate in this decision.

Methods

We distributed a self-administered questionnaire in 13 adult intensive care units (ICUs) assessing the attitudes of physicians and nurses regarding end-of-life decisions. Family members from a medical-surgical ICU in a tertiary cancer hospital were also invited to participate. Questions were related to two hypothetical clinical scenarios, one with a competent patient and the other with an incompetent patient, asking whether the ventilator treatment should be withdrawn and about who should make this decision.

Results

Physicians (155) and nurses (204) of 12 ICUs agreed to take part in this study, along with 300 family members. The vast majority of families (78.6%), physicians (74.8%) and nurses (75%) want to discuss end-of-life decisions with competent patients. Most of the physicians and nurses desire family involvement in end-of-life decisions. Physicians are more likely to propose withdrawal of the ventilator with competent patients than with incompetent patients (74.8% × 60.7%, P = 0.028). When the patient was incompetent, physicians (34.8%) were significantly less prone than nurses (23.0%) and families (14.7%) to propose decisions regarding withdrawal of the ventilator support (P < 0.001).

Conclusions

Physicians, nurses and families recommended limiting life-support therapy with terminally ill patients and favored family participation. In decisions concerning an incompetent patient, physicians were more likely to maintain the therapy.
Predictive network modeling of the high-resolution dynamic plant transcriptome in response to nitrate
Authors: Krouk Gabriel , Mirowski Piotr , LeCun Yann , Shasha Dennis E , Coruzzi Gloria M
Published: January 2011

Background

Nitrate, acting as both a nitrogen source and a signaling molecule, controls many aspects of plant development. However, gene networks involved in plant adaptation to fluctuating nitrate environments have not yet been identified.

Results

Here we use time-series transcriptome data to decipher gene relationships and consequently to build core regulatory networks involved in Arabidopsis root adaptation to nitrate provision. The experimental approach has been to monitor genome-wide responses to nitrate at 3, 6, 9, 12, 15 and 20 minutes using Affymetrix ATH1 gene chips. This high-resolution time course analysis demonstrated that the previously known primary nitrate response is actually preceded by a very fast gene expression modulation, involving genes and functions needed to prepare plants to use or reduce nitrate. A state-space model inferred from this microarray time-series data successfully predicts gene behavior in unlearnt conditions.

Conclusions

The experiments and methods allow us to propose a temporal working model for nitrate-driven gene networks. This network model is tested both in silico and experimentally. For example, the over-expression of a predicted gene hub encoding a transcription factor induced early in the cascade indeed leads to the modification of the kinetic nitrate response of sentinel genes such as NIR, NIA2, and NRT1.1, and several other transcription factors. The potential nitrate/hormone connections implicated by this time-series data are also evaluated.
Novel genes exhibit distinct patterns of function acquisition and network integration
Authors: Capra John A , Pollard Katherine S , Singh Mona
Published: January 2011

Background

Genes are created by a variety of evolutionary processes, some of which generate duplicate copies of an entire gene, while others rearrange pre-existing genetic elements or co-opt previously non-coding sequence to create genes with 'novel' sequences. These novel genes are thought to contribute to distinct phenotypes that distinguish organisms. The creation, evolution, and function of duplicated genes are well-studied; however, the genesis and early evolution of novel genes are not well-characterized. We developed a computational approach to investigate these issues by integrating genome-wide comparative phylogenetic analysis with functional and interaction data derived from small-scale and high-throughput experiments.

Results

We examine the function and evolution of new genes in the yeast Saccharomyces cerevisiae. We observed significant differences in the functional attributes and interactions of genes created at different times and by different mechanisms. Novel genes are initially less integrated into cellular networks than duplicate genes, but they appear to gain functions and interactions more quickly than duplicates. Recently created duplicated genes show evidence of adapting existing functions to environmental changes, while young novel genes do not exhibit enrichment for any particular functions. Finally, we found a significant preference for genes to interact with other genes of similar age and origin.

Conclusions

Our results suggest a strong relationship between how and when genes are created and the roles they play in the cell. Overall, genes tend to become more integrated into the functional networks of the cell with time, but the dynamics of this process differ significantly between duplicate and novel genes.
Time-varying boundary conditions in simulation of seismic wave propagation
Authors: Fletcher Robin P. , Robertsson Johan O.
Published: January 2011

We propose two new boundary conditions to regulate coherent reflections from the model boundaries in numerical solutions of wave equations. Both boundary conditions have the common feature that the boundary condition is varied with respect to time. The first boundary condition expands or contracts the computational model during a modeling simulation. The effect is to cause a Doppler shift in the reflected wavefield that can be used to shift energy outside a frequency band of interest. In addition, when the computational domain is expanding, the range of possible incidence angles on the boundary is restricted. This can be used to increase the effectiveness of many existing absorbing boundary conditions that are more effective for incidence angles close to normal. The second boundary condition is an extension of random boundaries. By carefully changing the realization of a random boundary over time, a more diffusive wavefield can be simulated. We show results with 2D numerical simulations of the scalar wave equation for both these boundary conditions. The first boundary condition has application to modeling, but both these boundary conditions have potential application within algorithms that rely upon modeling kernels, such as reverse-time migration and full-waveform inversion.