Azygos vein preservation revisited: impact on early outcomes after repair of esophageal atresia/tracheoesophageal fistula in newborns.
Since the first successful repair of esophageal atresia/tracheoesophageal fistula (EA-TEF) was performed approximately 8 decades ago, surgeons have made considerable technical advances in solving intraoperative surgical challenges and reducing postoperative complications. According to some surgeons, preserving the Azygos vein makes this modification attractive. This study aimed to evaluate the benefits of preserving the Azygos vein during surgery for esophageal atresia with tracheoesophageal fistula and to highlight its advantages in reducing anastomotic leak, stricture, and other postoperative outcomes. This prospective comparative series was conducted between April 2020 and April 2023. The study included all newborns with EA-TEF eligible for primary repair. Patients were randomized to either Group A or B. Group A underwent Azygos vein preservation, whereas the remaining patients (Group B) underwent Azygos vein disconnection. Sixty-four patients were included in this study. Thirty-two patients (Group A) underwent Azygos vein preservation during EA-TEF repair, and the remaining thirty-two patients (Group B) underwent Azygos vein ligation and disconnection. Both groups were comparable in terms of demographics, clinical data, and operative findings (P > 0.05). Pneumonitis occurred in 4 patients in Group A and 16 patients in Group B. Anastomotic leaks occurred in two (6.2%) patients in Group A and six (18.7%) patients in Group B. There were two deaths in Group A and six deaths in Group B, with a significant difference between the two groups (P = 0.0485). Preserving the Azygos vein during esophageal atresia repair reduces the occurrence of postoperative pneumonia, leakage, and stenosis, and decreases postoperative mortality. Therefore, we declare that this modification is a significant and valuable addition to the current surgical procedures.


[Longitudinal reference intervals of maternal-fetal Doppler parameters].
To create longitudinal reference intervals for pulsatility index (PI) of the umbilical (UA), middle cerebral (MCA), uterine (UtA) arteries and ductus venosus (DV) in a Brazilian cohort. A longitudinal observational study performed from February 2010 to May 2012. Low risk pregnancies were scanned fortnightly from 18 to 40 weeks for the measurements of PI of the UA, MCA, DV and UtA. Linear mixed models were used for the elaboration of longitudinal reference intervals (5th, 50th and 95th percentiles) of these measurements. PI obtained for the placental and abdominal portions of the umbilical artery were compared by the t-test for independent samples. Two-sided p values of less than 0.05 were considered statistically significant. A total of 164 patients underwent 1,242 scans. There was significant decrease in PI values of all vessels studied with gestational age (GA). From the 18(th) to the 40(th) week of pregnancy, the median PI values of UA (abdominal and placental ends of the cord), MCA, DV and the mean PI of the UtA ranged from 1.19 to 0.74, 1.33 to 0.78, 1.56 to 1.39, 0.58 to 0.41, and 0.98 to 0.66, respectively. The following equations were obtained for the prediction of the medians: PI-UA=1.5602786 - (0.020623 x GA); Logarithm of the PI-MCA=0.8149111 - (0.004168 x GA) - [0.02543 x (GA - 28.7756)²]; Logarithm of the PI-DV=-0.26691- (0.015414 x GA); PI-UtA = 1.2362403 - (0.014392 x GA). There was a significant difference between the PI-UA obtained at the abdominal and placental ends of the umbilical cord (p<0.001). Longitudinal reference intervals for the main gestational Doppler parameters were obtained in a Brazilian cohort. These intervals could be more adequate for the follow-up of maternal-fetal hemodynamic modifications in normal and abnormal pregnancies, a fact that still requires further validation.


Human papillomavirus vaccine update.
With the approval of Gardasil (Merck and Co., Inc., Whitehouse Station, NJ) in June of 2006 and the pending approval of Cervarix (GlaxoSmithKline, London, UK), two prophylactic human papillomavirus (HPV) vaccines will be available for clinical use. Randomized controlled trials have shown that both vaccines are safe and highly effective in preventing persistent infection and lesions caused by HPV 16 and 18--the types responsible for 70% of cervical cancers worldwide. Determining an effective vaccination strategy is now the most pressing issue facing clinicians, parents, public health officials, and policy makers. We discuss the appropriate age of vaccination, vaccine acceptance, implementation strategies in low resource settings, and the future of screening.


Light and laser therapies for the treatment of sebaceous gland hyperplasia a review of the literature.
Sebaceous gland hyperplasia (SGH) is a benign cutaneous condition that presents primarily on the face and increases with UVB exposure and ageing. These lesions are a common cosmetic concern but are difficult to treat, as the entire sebaceous gland needs to be destroyed to prevent recurrence. Traditional methods of treatment include: cryosurgery, electrodessication, curettage, shave excision and topical trichloroacetic acid. These methods have an increased risk of skin discoloration and scarring to the area of treatment that may lead to inferior cosmetic outcomes. Alternatively, oral isotretinoin can treat SGH, but is a known teratogen in pregnancy and has high relapse rates with discontinuation. A systematic review of the literature was performed to look at photodynamic therapy (PDT) and laser treatment for SGH. According to the results of this study, PDT, lasers and combinations of the two treatments were found to offer alternatives to the more conventional techniques with better outcomes. In particular, the use of wavelength-specific laser for the sebaceous gland of 1720 nm were found to have better outcomes and provide minimal damage to surrounding tissues. Additionally, combination PDT with aminolevulinic acid and pre-treatment with carbon dioxide laser ablation or pulse-dyed laser offered higher cure rates over stand-alone laser or PDT treatments in a shorter number of sessions with similar transient side-effects. However, further large-scale prospective studies with adequate follow-up are required to confirm these findings and those for sebaceous gland-specific lasers.


Inheritance of congenital heart disease.
Congenital heart defects (CHD) are the most common developmental anomalies and are the leading noninfectious cause of mortality in newborn babies. It has been estimated that between four and ten live-born infants per 1000 have a cardiac malformation (0.4 to 1.0%), 40% of which are diagnosed in the first year of life. The European Registration of Congenital Anomalies (EUROCAT) reported a prevalence of 58.9/10,000 live births in the northern part of the Netherlands (0.6%). Hoffman estimated that the true prevalence of CHD may be as high as 53 per 1000 pregnancies (5.3%), including a 20% occurrence of heart defects in spontaneous abortion, a 10% occurrence in stillbirth, and a 1% occurrence in live birth.


A novel fully differential biopotential amplifier with dc suppression.
Fully differential amplifiers yield large differential gains and also high common mode rejection ratio (CMRR), provided they do not include any unmatched grounded component. In biopotential measurements, however, the admissible gain of amplification stages located before dc suppression is usually limited by electrode offset voltage, which can saturate amplifier outputs. The standard solution is to first convert the differential input voltage to a single-ended voltage and then implement any other required functions, such as dc suppression and dc level restoring. This approach, however, yields a limited CMRR and may result in a relatively large equivalent input noise. This paper describes a novel fully differential biopotential amplifier based on a fully differential dc-suppression circuit that does not rely on any matched passive components, yet provides large CMRR and fast recovery from dc level transients. The proposed solution is particularly convenient for low supply voltage systems. An example implementation, based on standard low-power op amps and a single 5-V power supply, accepts input offset voltages up to +/-500 mV, yields a CMRR of 102 dB at 50 Hz, and provides, in accordance with the AAMI EC38 standard, a reset behavior for recovering from overloads or artifacts.


Polymorphism in the ELOVL6 gene is associated with a major QTL effect on fatty acid composition in pigs.
The ELOVL fatty acid elongase 6 (ELOVL6), the only elongase related to de novo lipogenesis, catalyzes the rate-limiting step in the elongation cycle by controlling the fatty acid balance in mammals. It is located on pig chromosome 8 (SSC8) in a region where a QTL affecting palmitic, and palmitoleic acid composition was previously detected, using an Iberian x Landrace intercross. The main goal of this work was to fine-map the QTL and to evaluate the ELOVL6 gene as a positional candidate gene affecting the percentages of palmitic and palmitoleic fatty acids in pigs. The combination of a haplotype-based approach and single-marker analysis allowed us to identify the main, associated interval for the QTL, in which the ELOVL6 gene was identified and selected as a positional candidate gene. A polymorphism in the promoter region of ELOVL6, ELOVL6:c.-533C>T, was highly associated with the percentage of palmitic and palmitoleic acids in muscle and backfat. Significant differences in ELOVL6 gene expression were observed in backfat when animals were classified by the ELOVL6:c.-533C>T genotype. Accordingly, animals carrying the allele associated with a decrease in ELOVL6 gene expression presented an increase in C16:0 and C16:1(n-7) fatty acid content and a decrease of elongation activity ratios in muscle and backfat. Furthermore, a SNP genome-wide association study with ELOVL6 relative expression levels in backfat showed the strongest effect on the SSC8 region in which the ELOVL6 gene is located. Finally, different potential genomic regions associated with ELOVL6 gene expression were also identified by GWAS in liver and muscle, suggesting a differential tissue regulation of the ELOVL6 gene. Our results suggest ELOVL6 as a potential causal gene for the QTL analyzed and, subsequently, for controlling the overall balance of fatty acid composition in pigs.


Universal Intimate-Partner Violence Assessment in the Pediatric Emergency Department and Urgent Care Setting: A Retrospective Review.
The aim of this study was to examine universal intimate-partner violence (IPV) assessment in the pediatric acute care setting. We reviewed universal IPV assessment over 1 year in 2 emergency departments and 3 urgent care centers within a children's hospital system. Written IPV assessment used 2 questions (ie, safety concerns at home, information desired); "yes" to either was considered positive. We identified positive assessments via preexisting quality report. We collected demographics, resource utilization, and reason for positive screen by chart review. Positive assessment for IPV was determined by chart documentation. Intimate-partner violence assessment was documented in 169,399 visits (96% of all visits); 511 (0.3%) were positive. Four hundred ninety cases were reviewed; 21 cases were excluded (incomplete data). One hundred twenty positive assessments were classified as misunderstood ("yes" marked in error); these were associated with nonwhite race (P < 0.001). We identified IPV in 169 (46%) of the remaining 370 positive assessments. Intimate-partner violence identification was associated with white race (P = 0.004), female caregiver (P < 0.001), and English as primary home language (P = 0.045). Non-IPV concerns triggered 239 positive assessments; concerns included child maltreatment (n = 125), mental/behavioral health (n = 46), other violence (n = 33), and parenting (n = 21). Intimate-partner violence was identified by social work in 82 cases triggered by non-IPV concerns. Resources utilized included social work (99%), non-IPV resources (59%), IPV advocate (21%), law enforcement (0.8%), and child protective services (1.6%). Universal IPV assessment in the pediatric acute care setting is feasible and may enable resource provision for IPV and non-IPV concerns.


Schistosoma japonicum: excretory-secretory products of the eggs during miracidial development.
The release pattern of excretory-secretory (E-S) products of Schistosoma japonicum eggs was investigated using eggs cultured in a chemically defined medium (MEMSE-J) for 16 days. The amount of protein released in culture supernatants was greater in 0- to 4-day and 12- to 16-day cultures than in 4- to 12-day cultures. The protein composition of E-S products and soluble extracts of newly laid eggs (N-SEA) and in vitro matured eggs (M-SEA) was analyzed by SDS-PAGE. Silver staining patterns of N-SEA and M-SEA were found to be similar except for the band at approximately 66 kDa, which appeared in highest concentrations in N-SEA. Western blot analysis with human infected sera showed antibody recognition of a 140- to 160-kDa antigen present in E-S products from mature eggs, while E-S products from immature eggs were unreactive. When either [35S]methionine or [3H]glucosamine was added to the culture medium, newly synthesized proteins or glycoproteins of the SEA and E-S products were labeled. Incorporation of both isotopes into SEA appears to correlate with developmental activity of the eggs. In contrast, release of E-S proteins and glycoproteins is more apparent as the miracidium matures. These results suggested that the source of E-S products from immature eggs is likely to be the collapsing vitelline cells and that of E-S products from mature eggs to be mainly miracidial secretions.


Limits of commercial molecular tests for diagnosis of pulmonary tuberculosis.
Several studies report high specificity, but variable sensitivity, of Amplified Mycobacterium tuberculosis Direct Test (AMTDT, Gen-Probe) based on ribosomal ribonucleic acid (rRNA) amplification and Amplicor Mycobacterium tuberculosis test (Amplicor, Roche) based on deoxyribonucleic acid (DNA) amplification for diagnosis of pulmonary tuberculosis. We have retrospectively evaluated these assays on selected acid-fast bacilli (AFB)-positive and -negative smear specimens and compared the results obtained from nucleic acid amplification with those of AFB staining of semi-quantitative cultures as determined by radiometric Bactec and Löwenstein-Jensen cultures. In comparison to cultures, Amplicor and AMTDT assays exhibited identical overall sensitivities of 80%, while the staining had a lower sensitivity of 62%. The sensitivities of Amplicor and AMTDT were 98% and 100%, respectively, for the AFB-positive specimens, and 50 and 46%, respectively for the AFB-negative specimens in comparison to cultures. The sensitivities of both assays appeared similar, and were directly related to the number of bacilli in the specimens studied. The low sensitivity (50%) for smear-negative specimens showed that current amplification assays may be unsuitable to replace cultures for diagnosis of tuberculosis. The decision to perform these molecular techniques should result from close co-operation between clinicians and microbiologists, taking into account the sensitivity results reported here, as well as the expense of the assays.


The implications of changing patterns in oral health for dental education.
Reports from many countries indicate that there has recently been a significant reduction in the prevalence of dental caries. Survey questionnaires were sent to 131 dental schools in 58 countries to determine the perceptions of dental educators to changing oral disease patterns. The educators were asked to indicate changes which had occurred in their respective curricula relative to the disease trends. They were asked to speculate on future curricular changes. Thirty-six schools in 21 countries replied. Most respondents indicated a decrease in the prevalence of dental caries, but little perception of changes in other oral diseases. Whereas, many adjustments have been made in dental curricula, there is little to indicate that the changes are related to variations in oral disease patterns. A new dilemma faces dental education for there is a need to broaden the scope of skills to be attained by the dental student to support a wide range of dental practice, while maintaining skills in restorative dentistry. More intensive continuous epidemiological studies of oral diseases need to be conducted. Dental school administrators need to be informed about oral disease trends and should adjust their curricula accordingly.


[Age-specific aspects of hemodynamic and morphological changes of the pulmonary vessels in tetralogy of Fallot].
The results of investigations of 50 patients with tetralogy of Fallot aged from 5 months to 15 years, made prior to surgery, and of 14 others, examined after palliative operations, furnished grounds for assessing hemodynamic and morphological changes in the pulmonary vessels as viewed in an age-specific aspect. The patients underwent catheterization of the heart, angiocardiography and histological investigation of the pulmonary tissue. In each age group the characteristics of the cardiac cycle in the right ventricle, minute volume and cardiac index, hemodynamic indices of the lesser circulation, pulmonary and greater circulation vessels resistance were analyzed. In the age category of up to 6 years the development of compensatory-adaptive reactions of the organism were recorded. The pressure in the pulmonary artery remained normal. Morphological alterations in the pulmonary arterial trunks were seen to occur already in the early childhood.


Preceptor preferences for participating in electronic preceptor development.
New guidelines require preceptors to deliver approximately 30% of the doctor of pharmacy curricula. With preceptor's increasing responsibilities, colleges are faced with the task of training preceptors as educators. Identifying preceptor's training format preferences (i.e. electronic vs. live) should contribute to the more effective and efficient creation of training materials and programs. A preceptor training video was created and made available electronically and was distributed to 400 preceptors with a brief 2-part questionnaire about preceptor training preferences, electronic training preferences after viewing the video, and available technology resources for participating in electronic training. 38.25% of the questionnaires were returned. The majority of respondents (57%) preferred electronic to live preceptor developing training and the majority (53%) had not previously attended the live annual preceptor development conference offered by the college. 51.6% participants reviewed the electronic training video created by the OU College of Pharmacy. Of the respondents who did not watch the video, 73% cited having too little time, problems accessing the video, or technical reasons for not watching the training video. The majority of responders in all age groups preferred electronic training to face-to-face training except those ages 61-65 and the majority (55.7%) would participate in on-line training again in the future. The majority of respondents have the technical resources to participate in electronic training. Preceptors have limited time to participate in preceptor development training, although they view training as an important activity. This study reveals three main findings: (1) the majority of preceptors prefer electronic preceptor development training programs regardless of age; (2) would participate in future electronic training after having participated in electronic training; and (3) have the available resources to participate in electronic training. Future preceptor development programs should have flexible formats to accommodate preferences for live and electronic programming.


Expression of claudin 1, claudin 4, and claudin 7 in colorectal cancer and its relation with CLDN DNA methylation patterns.
Altered claudin expression has been described in colon, prostatic, ovarian, and breast carcinoma. However, the role of epigenetic modifications in these genes and their role in colorectal cancer is unknown. We aimed our study to investigate whether claudin protein expression and methylation of CLDN can influence the tumorigenesis of colorectal cancer. A total of 31 patients diagnosed with colorectal carcinoma was used in this study. Immunohistochemical staining was used to study protein expression in both tumor and the adjacent nonneoplastic mucosa of claudin 1, 4, and 7. To detect the DNA methylation pattern of CLDN1, 4, and 7, genomic DNA was extracted from both the tumor and the adjacent nonneoplastic mucosa. Methylation analysis was carried out using bisulfite pyrosequencing. Cell membrane staining intensity of all claudins was found significantly lower in colorectal cancer tissues when compared to paired normal mucosa (p ≤ 0.001). For claudin 4, the percentage of cells staining positively was also significantly reduced (p = 0.04). In normal mucosa, cytoplasm showed no staining for claudins in any patient, whereas in paired colorectal cancer tissues, significant cytoplasmic staining appeared both for claudin 1 (p = 0.04) and claudin 4 (p = 0.01). Tumor samples were significantly hypomethylated in CLDN1 (p < 0.05). In conclusion, our results show that CLDN1 is significantly hypomethylated in tumor samples and that the membrane staining intensity for claudin 1, 4, and 7 is significantly lower in colorectal cancer tissues than in adjacent nonneoplastic tissue. Colorectal cancer cells showed dystopic cytoplasmic location of claudins.


[Fluctuational intramolecular mobility of proteins using physical labels].
An analysis of spin,- fluorescence, triplet- and Mössbauer labeling techniques is given as well as the method of radical pair recombination for investigation of globular proteins molecular dynamics in the temperature range of 50-300 K and correlation time tau c = 10(-2) - 10(11) s-1. Based on experimental evidence and literature data a conclusion is drawn on the existence of protein microheterogeneity at negative temperatures. A dynamic model of a globular protein is proposed. It is supposed to be a system of tightly-packed polypeptide proteins blocks connected by hinge-like linkage with a few degrees of freedom. The system is sunk in viscous amorphous medium composed of superficial protein groups and bound water molecules. The correlation between the protein molecular dynamics and enzymes activities is discussed.


HSD10 disease in a female: A case report and review of literature.
HSD10 disease is a rare X-linked mitochondrial disorder caused by pathogenic variants in the HSD17B10 gene. The phenotype results from impaired 17β-hydroxysteroid dehydrogenase 10 (17β-HSD10) protein structure and function. HSD10 is a multifunctional protein involved in enzymatic degradation of isoleucine and branched-chain fatty acids, the metabolism of sex hormones and neurosteroids, as well as in regulating mitochondrial RNA maturation. HSD10 disease is characterised by progressive neurologic impairment. Disease onset is varied and includes neonatal-onset, infantile-onset and late-onset in males. Females can also be affected. Our index case is a 45-month-old female, who initially presented at 11 months of age with global developmental delay. She subsequently began to lose previously acquired cognitive and motor skills starting around 29 months of age. Brain MRI showed abnormalities in the basal ganglia indicative of possible mitochondrial disease. Urine organic acid analysis revealed elevations of 2-methyl-3-hydroxybutyric acid and tiglyglycine. HSD17B10 gene sequencing revealed a likely pathogenic variant, NM_001037811.2:c.439C>T (p.Arg147Cys) inherited from her mother, expected to be causative of HSD10 disease. Her X-chromosome inactivation study is consistent with a skewed X-inactivation pattern. We report a female patient with HSD10 disease caused by a missense pathogenic variant, Arg147Cys in the HSD17B10 gene. The patient is the fifth severely affected female with this disease. This case adds to the small number of known affected families with this highly variable disease in the literature. These findings support the possibility of X-inactivation patterns influencing the penetrance of HSD10 disease in females.


BID-dependent release of mitochondrial SMAC dampens XIAP-mediated immunity against Shigella.
The X-linked inhibitor of apoptosis protein (XIAP) is a potent caspase inhibitor, best known for its anti-apoptotic function in cancer. During apoptosis, XIAP is antagonized by SMAC, which is released from the mitochondria upon caspase-mediated activation of BID. Recent studies suggest that XIAP is involved in immune signaling. Here, we explore XIAP as an important mediator of an immune response against the enteroinvasive bacterium Shigella flexneri, both in vitro and in vivo. Our data demonstrate for the first time that Shigella evades the XIAP-mediated immune response by inducing the BID-dependent release of SMAC from the mitochondria. Unlike apoptotic stimuli, Shigella activates the calpain-dependent cleavage of BID to trigger the release of SMAC, which antagonizes the inflammatory action of XIAP without inducing apoptosis. Our results demonstrate how the cellular death machinery can be subverted by an invasive pathogen to ensure bacterial colonization.


Enhanced oxygen permeability in membrane-bottomed concave microwells for the formation of pancreatic islet spheroids.
Oxygen availability is a critical factor in regulating cell viability that ultimately contributes to the normal morphogenesis and functionality of human tissues. Among various cell culture platforms, construction of 3D multicellular spheroids based on microwell arrays has been extensively applied to reconstitute in vitro human tissue models due to its precise control of tissue culture conditions as well as simple fabrication processes. However, an adequate supply of oxygen into the spheroidal cellular aggregation still remains one of the main challenges to producing healthy in vitro spheroidal tissue models. Here, we present a novel design for controlling the oxygen distribution in concave microwell arrays. We show that oxygen permeability into the microwell is tightly regulated by varying the poly-dimethylsiloxane (PDMS) bottom thickness of the concave microwells. Moreover, we validate the enhanced performance of the engineered microwell arrays by culturing non-proliferated primary rat pancreatic islet spheroids on varying bottom thickness from 10 μm to 1050 μm. Morphological and functional analyses performed on the pancreatic islet spheroids grown for 14 days prove the long-term stability, enhanced viability, and increased hormone secretion under the sufficient oxygen delivery conditions. We expect our results could provide knowledge on oxygen distribution in 3-dimensional spheroidal cell structures and critical design concept for tissue engineering applications. In this study, we present a noble design to control the oxygen distribution in concave microwell arrays for the formation of highly functional pancreatic islet spheroids by engineering the bottom of the microwells. Our new platform significantly enhanced oxygen permeability that turned out to improve cell viability and spheroidal functionality compared to the conventional thick-bottomed 3-D culture system. Therefore, we believe that this could be a promising medical biotechnology platform to further develop high-throughput tissue screening system as well as in vivo-mimicking customised 3-D tissue culture systems.


A Method of Predicting Posture-related Pain Using Biomechanical Parameters for Patients with Lumbar Spinal Disc Herniation.
Lumbar spinal disc herniation is a disease in which the protruding nucleus pulposus presses on the nerve due to actions that place loads on the disc, causing pain in the lower back and lower limbs. About 80% of treatments of disc herniation are conservative treatments, and although it is necessary to live with pain for a long time, there have been no studies that clearly define the relationship between pain and biomechanical parameters. In this study, we proposed a method of identifying biomechanical parameters that predict posture-related pain in patients with lumbar spinal disc herniation. The pain values were quantitatively evaluated by the Numerical Rating Scale (NRS) and the biomechanical parameters were analyzed by OpenSim. Lasso regression was performed to narrow down the biomechanical parameters that were related to pain and derive the mathematical model of the relationship. Therefore, many of the parameters of the obtained mathematical model were related to the lumbar spine and were consistent with areas that be related to lumbar spinal disc herniation.


Excess Cost and Healthcare Resources Associated With Delayed Diagnosis of Charcot Foot.
The purpose of the present study was to demonstrate the effect of a delayed diagnosis of Charcot foot on acute care cost and usage. We used International Classification of Disease, Ninth Revision, Clinical Modification codes, and the California Office for Statewide Health Planning and Development 2009 to 2012 public patient discharge files to identify patients with type 2 diabetes mellitus and Charcot foot. The costs and length of stay were compared for those with a diagnosis of Charcot foot on admission compared with those who received a delayed diagnosis of Charcot foot before discharge. Patient demographic data, diagnoses often mistaken for Charcot foot, and procedures often performed for Charcot foot were assessed to determine the potential effect on costs and length of stay in Charcot foot subjects. A delayed Charcot foot diagnosis was associated with 10.8% greater inpatient costs and 12.1% longer length of stay. These patients required greater resource usage owing to the significantly greater number of procedures performed. A significantly greater number of patients underwent lower extremity amputation when the diagnosis was delayed, resulting in a 30.4% increase in costs and 31.6% longer length of stay. A greater rate of diabetic foot ulcers, foot infections, and osteomyelitis was also observed; however, the cost was only affected by osteomyelitis, and the length of stay was not significantly affected. A delayed diagnosis of Charcot foot at admission resulted in significantly increased acute care costs and longer lengths of stay.


Evolution in techniques for endoscopic brow lift with deep temporal fixation only and lower blepharoplasty-transconjunctival fat repositioning.
As we become more confident with our surgical skills following our fellowship training, some of our approaches and techniques will be modified or changed. My primary evolutionary change involves procedures of the upper third of the face, primarily the brow lift and treatment of lower eyelid fat techniques. Traditional methods of forehead and brow rejuvenation, such as coronal, pretrichal, and direct brow lifts, have provided facial plastic surgeons with effective brow elevation for many years. In the past decade, the endoscopic brow lift has rapidly become accepted as part of the surgical armamentarium and is frequently the technique of choice. In general, the temporal dissection, temporal fixation, forehead subperiosteal or subgaleal dissection with release, and treatment to the brow depressor musculature have been standardized. Methods of bony fixation remain a controversial topic as there are numerous methods. We advocate deep temporal fixation only without bone fixation to achieve effective, long-term brow elevation. Traditionally, lower eyelid herniated fat is removed, which may cause a sunken or hollow lid appearance, especially in patients with a tear trough deformity (nasojugal groove). Lower eyelid transconjunctival fat repositioning, defined as the subperiosteal repositioning of the medial and central lower eyelid herniated orbital fat into the nasojugal fold, may prevent the surgical, hollow lower eyelid appearance while treating the herniated fat. Fat repositioning may be combined with an endoscopic subperiosteal midface-lift, transcutaneous skin pinch, and transconjunctival orbicularis oculi excision. This technique offers a powerful tool in the surgical armamentarium of the facial plastic surgeon.


Aortic endograft sizing in trauma patients with hemodynamic instability.
To investigate changes in aortic diameter in hemodynamically unstable trauma patients and the implications for sizing of thoracic endovascular aortic repair (TEVAR) in patients with traumatic thoracic aortic injury (TTAI). We retrospectively evaluated all trauma patients that were admitted with hemodynamic instability (mean arterial pressure <95 mm Hg and a pulse >or=100 beats/min) and underwent computed tomography (CT) of the thorax and abdomen both at admission and at another moment (control CT scan), at the Yale New Haven Hospital between 2002 and 2009. The CT examinations were reviewed in a blinded fashion and the aortic diameter was measured at six different levels by a cardiovascular radiologist. Differences in aortic diameter between the initial CTs obtained in the trauma bay and the control CTs were compared using the paired Student t test. Forty-three patients were identified, including 32 males. Mean age was 37 +/- 16 years, mean injury severity score was 26 +/- 15, the mean pulse and blood pressure were 122 beats/min and 103/63 mm Hg, respectively. Overall, the mean aortic diameter was significantly larger at the control CT examinations compared with the initial CT examinations while hemodynamically unstable, at all evaluated levels. Among patients with a pulse >or=130/min, the mean increase in aortic diameter was most consistent at the level of the mid descending thoracic aorta (DTA, +12.6%, P = .003) and at the level of the infrarenal aorta (+12.6%, P = .004). The aortic diameter decreases dramatically in trauma patients with hemodynamic instability. This decrease in aortic diameter could theoretically lead to inaccurate aortic measurements and undersizing of the endograft in hemodynamically unstable TTAI patients requiring TEVAR. Further research is needed to better predict the actual aortic diameters in individual hemodynamically unstable patients requiring endovascular aortic repair.


Current research in empirical therapy for febrile neutropenia in cancer patients: what should be necessary and what is going on.
Fever is an important complication in neutropenic patients and standard of care calls for empirical broad-spectrum antibiotics, followed by 'empirical' antifungal therapy in persisting fever. Emergence of infections due to resistant bacteria, especially Gram-negatives, and usefulness of empirical antifungal therapy represent the major concerns in this field. Clinical trials registered in 5 international databases were referred for randomized clinical trials (RCTs) of empirical antibacterial therapy or empirical antifungal therapy in neutropenic cancer patients. The majority of RCTs compared antibiotics without major differences in the spectrum of activity, especially in the wake of the present epidemiology with an increase of infections and mortality due to resistant Gram-negatives; oral therapy and home care were analyzed in 3 RCTs. As regards empirical antifungal therapy, 1 ongoing study is comparing 'standard' empirical treatment vs diagnostic-driven approach. In an era of increasing antibiotic resistance the comparison of different strategies more than that of different drugs will probably represent the future in studies in this field. The next future will tell us if a diagnostic-driven approach is safe for fungal infections, or if we should continue to treat them only on the basis of the persistence of febrile neutropenia.


Information dynamics of in vitro selection-amplification systems.
Selection-amplifications systems provide a means of engineering biomacromolecules with new properties. The combination of stringent functional selection with the ability to amplify single molecules confers great specificity on the evolving population. Yet such systems like many complicated chemical kinetic mechanisms can show a range of unstable and metastable behavior. These instabilities can be investigated using the Shannon entropy of the evolving population. It is shown that the Shannon entropy provides a Lyapounov function for exploring dynamic stability. A simple model of in vitro evolution is presented and stability conditions are established. It is seen that fairly simple directed evolution models can exhibit a range of dynamical behavior.


[Gender differences in the influence of housework on health].
To analyze the influence of domestic workload on the health of the working population of Catalonia, taking into account its differential impact on males and females. The study population were the 2,164 men and 1,215 women interviewed in the Catalonian Health Survey (ESCA) of 1994, with a paid work who were the main responsible for the family unit. The dependent variable was the self-perceived health status that was dichotomized for the bivariate and multivariate analysis. The domestic workload was measured with the number of people living at home (2, 3, 4 or more than 4), living with children younger than 15 and living with older than 65. The adjusting variables were age and occupational social class. The analysis was separated for men and women and crude, adjusted for age, and for all the predictor variables odds ratios (OR) were calculated with their 95% confidence intervals (95%CI). There was no relation between domestic workload and health status among men. Among women the risk or poor health status increased with the number of people living at home with adjusted OR associated to living with more than four persons of 2.35 (95%CI = 1. 33-4.15), as compared with living only with the spouse. Living with older than 65 was protector for women (adjusted OR = 0.63; 95%CI = 0. 39-1.03). The risk of poor health status associated to the domestic workload among women with paid work, suggests the need of increasing community resources for caring children, as well as, increasing the participation of men in the domestic work. Future health surveys should collect information about the number of people of different age strata living at home.


Use of neuroleptic-induced extrapyramidal symptoms to predict future vulnerability to side effects.
Susceptibility to neuroleptic-induced extrapyramidal syndromes varies widely, even within age and sex subgroups. Individual vulnerability to extrapyramidal syndromes has been assumed to explain this, but the utility of past history for predicting future occurrence of extrapyramidal syndromes has not been studied extensively. This investigation was undertaken to determine whether patients' previous histories of extrapyramidal syndromes predict future episodes of extrapyramidal syndromes and to compare the importance of this predictive factor with patient age, sex, neuroleptic dose, and anticholinergic dose as predictors of extrapyramidal syndromes. The charts of 62 schizophrenic patients with multiple neuroleptic treatment episodes were reviewed. Extrapyramidal syndromes, neuroleptic drug doses, and anticholinergic drug doses during the first 21 days of each treatment episode were recorded. Previous extrapyramidal syndromes correctly predicted extrapyramidal syndromes in subsequent treatments for 84% of the patients. Variations in neuroleptic potency, neuroleptic dose, and anticholinergic dose partially explained incorrect predictions. These results support the hypothesis that patients with a history of extrapyramidal syndromes are at greater risk for future extrapyramidal syndromes. If confirmed, these results strongly support individual susceptibility as a major predictor of extrapyramidal syndromes and indicate that prophylaxis of extrapyramidal syndromes should be considered for patients who have previously suffered extrapyramidal syndromes from similarly prescribed neuroleptic therapy.


[Antimicrobial prescription in family health units in Southern Brazil].
This paper describes antimicrobial prescription, clinical indications, and seasonal characteristics in primary health care. We performed a cross-sectional study in family health units in Bagé, Rio Grande do Sul State, Brazil, in July 2005 and January 2006. All medical prescriptions (n = 2,877) were analyzed, and the prevalence rates for antimicrobial prescription in winter and summer were 30.4% (95%CI: 28.5-32.4) and 21% (95%CI: 19.1-22.9), respectively. The most frequently prescribed antimicrobials were amoxicillin and sulfamethoxazole-trimethoprim. The main clinical indications for antimicrobial prescription were non-specific upper respiratory tract infections (22.5%), throat infections (20.8%), urinary tract infections (13.3%), otitis (8.5%), and sinusitis (7.5%). We observed differences between summer and winter in prescriptions for the same diseases. Seasonal differences between treatment profiles for the same diseases show the absence of a consistent antimicrobial prescription pattern in primary health care, contrary to World Health Organization guidelines, which advocate the establishment of protocols for antimicrobial use at all levels of care, as a strategy to prevent inadequate usage and the occurrence of strains that are resistant to available antimicrobials.


Severe Extraarticular Manifestations in a Community-based Cohort of Patients with Rheumatoid Arthritis: Risk Factors and Incidence in Relation to Treatment with Tumor Necrosis Factor Inhibitors.
The aims of this study were to evaluate whether treatment with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) affects the risk of developing severe extraarticular rheumatoid arthritis (ExRA) manifestations and to investigate potential predictors for developing ExRA. A dynamic community-based cohort of patients with RA was studied (n = 1977). Clinical records were reviewed and cases of severe ExRA were identified. Information on exposure to TNF inhibitors was obtained from a regional register. Exposure to TNF inhibitors was analyzed in a time-dependent fashion and the incidence of severe ExRA in exposed patients was compared with the incidence in unexposed patients. Cox regression models were used to assess potential predictors of severe ExRA. During treatment with TNF inhibitors, there were 17 patients with new onset of severe ExRA in 2400 person-years at risk (PY; 0.71/100 PY, 95% CI 0.41-1.13) compared with 104 in 15,599 PY (0.67/100 PY, 95% CI 0.54-0.81) in patients without TNF inhibitors. This corresponded to an incidence rate ratio of 1.06 (95% CI 0.60-1.78). The age- and sex-adjusted HR for ExRA in anti-TNF-treated patients was 1.21 (95% CI 1.02-1.43), with similar findings in models adjusted for time-dependent Health Assessment Questionnaire and propensity for anti-TNF treatment. Male sex, positive rheumatoid factor (RF), long disease duration, and greater disability were predictors for ExRA. This study suggests that patients treated with TNF inhibitors are at a slightly increased risk of developing severe ExRA. RF-positive patients with disabling disease of long duration were more likely to develop severe ExRA.


Inefficient lymph node sensitization during respiratory viral infection promotes IL-17-mediated lung pathology.
Development of bronchus-associated lymphoid tissue has been suggested to enhance local antiviral immune responses; however, ectopic lymph node formation often corresponds to chronic inflammatory diseases. These studies investigated the role of ectopic pulmonary lymph nodes upon respiratory syncytial virus (RSV) infection using CCR7-deficient mice, which develop bronchus-associated lymphoid tissue early in life. CCR7(-/-) mice exhibited impaired secondary lymph node formation, enhanced effector T cell responses and pathogenic mucus production in the lung after RSV infection. IL-17 production from CD4 T cells in CCR7(-/-) mice was most remarkably enhanced. Wild-type animals reconstituted with CCR7(-/-) bone marrow recapitulated the pathogenic lung phenotype in CCR7(-/-) mice, whereas CCR7(-/-) animals reconstituted with wild-type bone marrow had normal lymph node development, diminished IL-17 production and reduced lung pathology. Mixed bone marrow chimeras revealed an alteration of immune responses only in CCR7(-/-) T cells, suggesting that impaired trafficking promotes local effector cell generation. Lymphotoxin-α-deficient mice infected with RSV were used to further examine locally induced immune responses and demonstrated increased mucus production and amplified cytokine responses in the lung, especially IL-17. Neutralization of IL-17 in CCR7(-/-) or in lymphotoxin-α-deficient animals specifically inhibited mucus hypersecretion and reduced IL-13. Thus, immune cell trafficking to secondary lymph nodes is necessary for appropriate cytokine responses to RSV as well as modulation of the local environment.


Long-term incidence of dry eye in an older population.
To estimate the ten-year incidence of dry eye in an older population and examine its association with various risk factors. The 43 to 86 year old population of Beaver Dam, WI, was examined in 1988 to 1990 (n = 4926) and 1993 to 1995 (n = 3722). Dry eye data were first collected in 1993 to 1995. Subsequent examinations or interviews occurred in 1998 to 2000 (n = 2827) and 2003 to 2005 (n = 2124). The incidence cohort comprised 2414 subjects not reporting dry eye in 1993 to 1995. Risk factor information, ascertained in 1993 to 1995, included demographics, medical history, cardiovascular disease risk factors, medications, and life-style factors. Ten-year cumulative incidence was estimated by the product-limit method. Over the 10-year period, 482 subjects developed a history of dry eye for an incidence of 21.6% (95% confidence interval, 19.9 to 23.3%). Incidence increased significantly (p < 0.001) with age. Incidence was greater in women (25.0%) than men (17.2%, p < 0.001). After adjusting for age, incidence was greater (p < 0.05) in subjects with arthritis, allergy or thyroid disease not treated with hormone, using antihistamines, antianxiety medications, antidepressants, oral steroids or vitamins, and poorer self-rated health. Incidence was less (p < 0.05) in subjects consuming alcohol. It was not significantly associated with blood pressure, hypertension, serum total or high density lipoprotein cholesterol, body mass, diabetes, gout, osteoporosis, cardiovascular disease, smoking, caffeine use, or taking calcium channel blockers or anticholesterol medications. In a multivariable model with time-varying covariates, increased incidence was associated with age, female gender, poorer self-rated health, antidepressant or oral steroid use, and thyroid disease untreated with hormone. It was lower for those using angiotensin-converting enzyme inhibitors or with a sedentary lifestyle. Dry eye incidence is substantial. However, there are few associated risk factors. Some drugs (antihistamines, antianxiety drugs, antidepressants, oral steroids) are associated with greater risk, while angiotensin-converting enzyme inhibitors may be associated with lower risk.


Presentation of a Clinical Practice Protocol for Patients with Swallowing Disorders.
To describe the implementation process of a Clinical Practice Protocol for Patients with Swallowing Disorders (CPSD) in a public hospital of high technological density in the Federal District of Brazil. This is an Experience Report study which describes the implementation process of a Clinical Practice Protocol for Patients with Swallowing Disorders in a public hospital of high technological density in the Federal District. The protocol was implemented in three stages: Stage 1 - literature search on the procedures that characterize the best propaedeutic and therapeutic practices; Stage 2 - discussion with a multidisciplinary team about the adjustments needed to implement the CPSD; and Stage 3 - Final proposal for the protocol implementation considering the particularities of the service. The final proposal of the Clinical Practice Protocol for Patients with Swallowing Disorders (CPSD) provides a predefined, systematic method to monitor patients with swallowing disorders in high technological density health facilities. In addition to being inexpensive, the CPSD fosters decision-making, favors early detection of disorders, and assists managers with evaluating the quality of the service offered.


Carbon monoxide poisoning in Jerusalem: epidemiology and risk factors.
To describe the epidemiology of carbon monoxide (CO) poisoning in Jerusalem and identify risk factors for such poisoning. A retrospective descriptive analysis of patients with CO poisoning who presented to the Hadassah hospitals in Jerusalem from 1994 to 2006. All patients with suspected CO poisoning were examined and those with confirmed cases [carboxyhemoglobin (COHb) level >5%] were included. Sources of exposure, seasonal variation, and demographic characteristics were analyzed. There were 292 patients (49% males) with 40 family clusters that accounted for 149 patients (51%); 230 patients (79%) presented during the winter months. All but one had unintentional CO intoxication. The main sources of exposure were faulty gas heaters (n = 135), fire (n = 102), and other residential heating systems (n = 40). The estimated annual incidence of CO poisoning decreased from 6.45 per 100,000 in 1994-2000 to 3.53 per 100,000 in 2001-2006. High-risk intoxication (COHb level >25%) occurred in 84 patients (29%). Factors associated with severe intoxication were male gender, individual patients (compared with those in clusters), and faulty gas heaters (compared with other sources). Males exposed to CO may have a more severe intoxication. The lower risk in patients presenting in clusters could be explained by the assumption that severe presentation in one patient alerts the others who are less severely affected. The implementation of safer standards for residential heating systems and CO detectors together with the public education may explain the decline in the incidence of CO poisoning.


Responses of Polyamine-Metabolic Genes to Polyamines and Plant Stress Hormones in Arabidopsis Seedlings.
In plants, many of the enzymes in polyamine metabolism are encoded by multiple genes, whose expressions are differentially regulated under different physiological conditions. For comprehensive understanding of their regulation during the seedling growth stage, we examined the expression of polyamine metabolic genes in response to polyamines and stress-related plant hormones in Arabidopsis thaliana. While confirming previous findings such as induction of many of the genes by abscisic acid, induction of arginase genes and a copper amine oxidase gene, CuAOα3, by methyl jasmonate, that of an arginine decarboxylase gene, ADC2, and a spermine synthase gene, SPMS, by salicylic acid, and negative feedback regulation of thermospermine biosynthetic genes by thermospermine, our results showed that expressions of most of the genes are not responsive to exogenous polyamines. We thus examined expression of OsPAO6, which encodes an apoplastic polyamine oxidase and is strongly induced by polyamines in rice, by using the promoter-GUS fusion in transgenic Arabidopsis seedlings. The GUS activity was increased by treatment with methyl jasmonate but neither by polyamines nor by other plant hormones, suggesting a difference in the response to polyamines between Arabidopsis and rice. Our results provide a framework to study regulatory modules directing expression of each polyamine metabolic gene.


A comparison of imaging software and conventional cell counting in determining melanocyte density in photodamaged control sample and melanoma in situ biopsies.
Objective methods for distinguishing melanoma in situ (MIS) from photodamaged skin (PS) are needed to guide treatment in patients with melanocytic proliferations. Melanocyte density (MD) could serve as an objective histopathological criterion in difficult cases. Calculating MD via manual cell counts (MCC) with immunohistochemical (IHC)-stained slides has been previously published. However, the clinical application of this method is questionable, as quantification of MD via MCC on difficult cases is time consuming, especially in high volume practices. ImageJ is an image processing software that uses scanned slide images to determine cell count. In this study, we compared MCC to ImageJ calculated MD in microphthalmia transcription factor-IHC stained MIS biopsies and control PS acquired from the same patients. We found a statistically significant difference in MD between PS and MIS as measured by both MCC and ImageJ software (P < 0.01). Additionally, no statistically significant difference was found when comparing MD measurements recorded by ImageJ vs those determined by the MCC method. MD as determined by ImageJ strongly correlates with the MD calculated by MCC. We propose the use of ImageJ as a time-efficient, objective, and reproducible tool to assess MD.


[Intraocular manifestations of systemic cancer].
Systemic cancer may present intraocular features in three forms: as a sign of the presence of lymphoreticular tumors, of solid tumors or as a paraneoplastic syndrome.


Cardiovascular changes during acute episodic repetitive hypoxic and hypercapnic breathing in rats.
It has been shown that chronic repetitive ambient hypoxia, simulating pulmonary gas disturbances observed in apnoea, leads to systemic hypertension in rats. However, the relative roles of hypoxia (HO), hypercapnia (HC), gas stress and vigilance on the cardiovascular changes have not yet been demonstrated. The aim of this study was to investigate the acute haemodynamic changes observed during the repetitive inhalation of various gas mixtures in rats for HO alone and HO+HC, and to analyse the effects of vigilance and of the stress of gas administration. We studied 6 unanaesthetized Wistar rats chronically instrumented with an aortic catheter. Nitrogen, nitrogen+CO2 mixtures and compressed air were randomly administered in a Plexiglass chamber for 10 s and then flushed by compressed air for 20 s. Two cycles were repeated every min for 10 to 12 min. The inhaled gas fractions (FI,O2,FI,CO2) were monitored by O2 and CO2 analysers. Blood pressure (BP) was measured by a P23XL transducer. The blood gases were analysed by a 1306 IL meter. In control experiments, with compressed air alone, there were no significant acute changes in heart rate (HR) and BP. During HO there were no changes in HR or BP at FI,O2 values from 0.05-0.14, whilst at FI,O2 values from 0-0.05 systolic blood pressure (SBP) rose significantly (+25.3 +/- 25.7 (SD) mmHg) and HR decreased (-93.8 +/- 124.1 bpm). During HOHC, SBP rose (+35.1 +/- 26.4 mmHg) and HR decreased (-139.3 +/- 75.7 bpm), significantly more than in HO alone. SBP was linearly correlated with Pa,O2 during HO (r = 0.53) and also during HOHC (r = 0.44) and was not directly related to Pa,CO2 which has, nevertheless, an additive effect to HO. SBP rose with each challenge significantly more when the rats were awake than when asleep (behavioural sleep). We conclude that in this acute repetitive inhalation model, the rise in SBP is not related to gas stress or to Pa,CO2 but to a decrease in Pa,O2 and is enhanced by wakefulness.


Secular trends in frailty: a comparative study of 75-year olds born in 1911-12 and 1930.
while there is a trend towards a compression of disability, secular trends in physiological frailty have not been investigated. The aim of this paper was to report physiological frailty in two cohorts of 75-year olds examined in 1987 and 2005. a repeated cross-sectional study : Two population-based birth cohorts of community-dwelling 75-year olds from Gothenburg, Sweden, born in 1911-12 (n = 591) and 1930 (n = 637) were examined with identical methods in 1987 and 2005. Measures were three frailty criteria from Fried's frailty phenotype: low physical activity, slow gait speed and self-reported exhaustion. seventy-five-year olds examined in 2005 were less frail according to the criteria low physical activity compared with those examined in 1987 (3 versus 18%, P < 0.001).This was seen both in women and in men, and among those with basic and more than basic educational level. Further, men with basic education were less frail in 2005 compared with those in 1987 in slow gait speed (non-significant when adjusted for body height) and low self-rated fitness, while no cohort differences were seen in men with more than basic education. Women with more than basic education were less frail in 2005 compared with those in 1987 in slow gait speed and self-rated fitness, while no cohort difference was seen in women with basic education. less 75-year olds were physiologically frail in 2005 compared with those in 1987, with the exception of women with low educational level, suggesting that this is a disadvantaged group that needs to receive particular attention with regard to physiological frailty.


An effective erythropoietin dose regimen protects against severe nerve injury-induced pathophysiological changes with improved neural gene expression and enhances functional recovery.
The functional recovery following non-severing peripheral nerve injury (PNI) is often incomplete. Erythropoietin (EPO) is a pleiotropic hormone and it has been shown to protect peripheral nerves following mild and even moderate severity injuries. However, the effectiveness of EPO in severe PNI is largely unknown. In this study, we sought to investigate the neuroprotective effect of a new dose regimen of EPO in severe sciatic nerve crush injury (SSCI). Adult male mice (8 animals/group) were randomly assigned to sham (normal saline, 0.1 ml/mouse), SSCI (normal saline, 0.1 ml/mouse) and SSCI with EPO (5000 IU/kg) groups. SSCI was performed using calibrated forceps for 30 sec. EPO or normal saline was administered intraperitoneally immediately after the SSCI and at post-injury day1 and 2. The functional recovery after injury was assessed by sciatic function index (SFI), von Frey Test (VFT), and grip strength test. Mice were euthanized on day 7 and 21 and nerves at injury/peri-injury site were processed for gene (quantitative real-time PCR) and protein (immunohistochemistry) expression analysis. EPO significantly improved SFI, VFT, and hind limb paw grip strength from post-injury day 7. EPO demonstrated significant regulatory effects on mRNA expression of inflammatory (IL-1β and TNF-α), anti-inflammatory (IL-10), angiogenesis (VEGF and eNOS), and myelination (MBP) genes. The protein expression of IL-1β, F4/80, CD31, NF-κB p65, NF-H, MPZ, and DHE (redox-sensitive probe) was also significantly modulated by EPO treatment. In conclusion, the new dose regimen of EPO augments sciatic nerve functional recovery by mitigating inflammatory, anti-inflammatory, oxidative stress, angiogenesis, and myelination components of SSCI.


Development and testing of low-volume hyperoncotic, hyperosmotic spray-dried plasma for the treatment of trauma-associated coagulopathy.
Trauma-associated coagulopathy carries an extremely high mortality. Fresh-frozen plasma (FFP) is the mainstay of treatment; however, its availability in the battlefield is limited. We have already shown that lyophilized, freeze-dried plasma (FDP) reconstituted in its original volume can reverse trauma-associated coagulopathy. To enhance the logistical advantage (lower volume and weight), we developed and tested a hyperoncotic, hyperosmotic spray-dried plasma (SDP) product in a multiple injuries/hemorrhagic shock swine model. Plasma separated from fresh porcine blood was stored as FFP or preserved as FDP and SDP. In in vitro testing, SDP was reconstituted in distilled water that was either equal (1 × SDP) or one-third (3 × SDP) the original volume of FFP. Analysis included measurements of prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen levels, and activity of selected clotting factors. In in vivo testing, swine were subjected to multiple injuries (femur fracture and grade V liver injury) and hemorrhagic shock (60% arterial hemorrhage, with the "lethal triad" of acidosis, coagulopathy, and hypothermia) and were treated with FFP, FDP, or 3 × SDP (n=4-5/group). Coagulation profiles (PT, PTT, and thromboelastography) were measured at baseline, post-shock, post-crystalloid, treatment (M0), and during 4 hours of monitoring (M1-4). In vitro testing revealed that clotting factors were preserved after spray drying. The coagulation profiles of FFP and 1 × SDP were similar, with 3 × SDP showing a prolonged PT/PTT. Multiple injuries/hemorrhagic shock produced significant coagulopathy, and 3 × SDP infusion was as effective as FFP and FDP in reversing it. Plasma can be spray dried and reconstituted to one-third of its original volume without compromising the coagulation properties in vivo. This shelf-stable, low-volume, hyperoncotic, hyperosmotic plasma is a logistically attractive option for the treatment of trauma-associated coagulopathy in austere environments, such as a battlefield.


An investigation of a reference posture used in determining rearfoot kinematics for both healthy and patellofemoral pain syndrome individuals.
The choice of a reference posture is important when investigating rearfoot motion in clinical populations. The reference posture used may affect the magnitude of the peak angles and therefore may not enable comparison of the rearfoot kinematics across different populations. This study examined the relationship between the rearfoot frontal plane pattern of motion and three reference postures during the stance phase of walking in healthy and patellofemoral pain syndrome (PFPS) subjects. The three reference postures investigated were: Relaxed Standing posture, subtalar joint neutral position (STJN) and when the calcaneus and the lower leg were vertically aligned (Vertical Alignment). The rearfoot inversion/eversion during the stance phase was measured in 14 healthy subjects and 13 subjects with diagnosed PFPS using three dimensional motion analysis with the three different reference postures. The graphs of rearfoot inversion/eversion motion were overlaid with the angle at the rearfoot in the static posture and any intersection between the static angle and rearfoot motion was noted. An ANOVA showed significant differences in static posture between the groups for Relaxed Standing (p = 0.01), and STJN (p = 0.02). For both groups, with Relaxed Standing as a reference posture, the mean rearfoot pattern of motion did not intersect the Relaxed Standing static angle during the stance phase. The use of Vertical Alignment reference posture, however, showed an intersection of this reference posture through the rearfoot pattern of motion. The use of the Vertical Alignment reference posture also generated a typical rearfoot motion pattern for both groups and therefore it may be an appropriate reference posture for both healthy and PFPS individuals. Key PointsThe use of the three reference postures resulted in shifting of the curve of the rearfoot frontal plane pattern of motion. The shift of the curve is important in identifying the magnitude of rearfoot peak motion during the stance phase.The use of Vertical Alignment reference posture only, generated a typical rearfoot motion pattern for both groups and therefore it may be an appropriate reference posture for both healthy and PFPS individualsThe use of Relaxed Standing and STJN as reference postures would not be recommended due to their poor test retest reliability.


Altered features of monocytes in adult onset leukoencephalopathy with axonal spheroids and pigmented glia: A clue to the pathomechanism of microglial dyshomeostasis.
Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an autosomal-dominant type of leukoencephalopathy caused by gene mutation of colony stimulating factor 1 receptor, which is expressed mainly on monocyte lineage cells such as monocytes in the peripheral blood and microglia in the brain. Hence, microglial dysfunction is regarded as critical in the pathogenesis of ALSP. However, functional changes in these cells have not been elucidated. In this study, we report the phenotypic and functional alterations of monocytes in four patients with ALSP. Flow cytometric analysis revealed altered expression of antigen presentation- and migration-related molecules, an inflammatory shift in cytokine production and phagocytic impairment in ALSP monocytes. We speculate that the observed altered features of monocytes are mostly shared by microglial cells, leading to the clinical history and pathological characteristics of ALSP. Our analysis of PB monocytes provides novel insights into the pathogenesis of ALSP.


Dose Conversion Coefficients Based on Taiwanese Reference Phantoms and Monte Carlo Simulations for Use in External Radiation Protection.
Reference phantoms are widely applied to evaluate the radiation dose for external exposure. However, the frequently used reference phantoms are based on Caucasians. Dose estimation for Asians using a Caucasian phantom can result in significant errors. This study recruited 40 volunteers whose body sizes are close to the average Taiwanese population. Magnetic resonance imaging was performed to obtain the organ volume for construction of the Taiwanese reference man (TRM) and Taiwanese reference woman (TRW). The dose conversion coefficients (DCC) resulting from photo beams in anterior-posterior, posterior-anterior, right-lateral, left-lateral, and isotropic irradiation geometries were estimated. In the anterior-posterior geometry, the mean DCC differences among organs between the TRM and ORNL phantom at 0.1, 1, and 10 MeV were 7.3%, 5.8%, and 5.2%, respectively. For the TRW, the mean differences from the ORNL phantom at the three energies were 10.6%, 7.4%, and 8.3%. The DCCs of the Taiwanese reference phantoms and the ORNL phantom presented similar trends in other geometries. The torso size of the phantom and the mass and geometric location of the organ have a significant influence on the DCC. The Taiwanese reference phantoms can be used to establish dose guidelines and regulations for radiation protection from external exposure.


An intracellular symbiont and other microbiota associated with field-collected populations of sawflies (Hymenoptera: Symphyta).
Six species of sawfly (Hymenoptera: Symphyta) from four taxonomic families (Agridae, Diprionidae, Pamphiliidae, and Tenthredinidae) were collected from locations across Canada and surveyed for their associated microbiota. Total DNA was extracted from individual insects, and polymerase chain reaction (PCR) was used to amplify the conserved 16S rRNA gene from microbiota. Denaturing gradient gel electrophoresis (DGGE) and restriction fragment length polymorphism (RFLP) were undertaken to separate bacterial clones associated with the host insect. Sequencing of the PCR-DGGE and PCR--RFLP products revealed a dominance of alpha- and gamma-Proteobacteria, with most sequences showing high similarity to bacteria previously identified from other insect species and environmental samples. Additionally, a strain of the bacterial endosymbiont Wolbachia and a Wolbachia bacteriophage were identified from the mountain ash sawfly (Pristiphora geniculata).


Increased Interleukin-10 Expression by the Inhibition of Ca2+-Activated K+ Channel KCa3.1 in CD4+CD25+ Regulatory T Cells in the Recovery Phase in an Inflammatory Bowel Disease Mouse Model.
Inflammatory bowel diseases (IBD) are chronic inflammatory diseases of the gastrointestinal tract arising from abnormal responses of the innate and adaptative immune systems. Interleukin (IL)-10-producing CD4+CD25+ regulatory T (Treg) cells play a protective role in the recovery phase of IBD. In the present study, the effects of the administration of the selective Ca2+-activated K+ channel KCa3.1 inhibitor TRAM-34 on disease activities were examined in chemically induced IBD model mice. IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage in the colon, was significantly lower in mice administered 1 mg/kg TRAM-34 than in vehicle-administered mice. Quantitative real-time polymerase chain reaction examinations showed that IL-10 expression levels in the recovery phase were markedly increased by the inhibition of KCa3.1 in mesenteric lymph node (mLN) Treg cells of IBD model mice compared with vehicle-administered mice. Among several positive and negative transcriptional regulators (TRs) for IL-10, three positive TRs-E4BP4, KLF4, and Blimp1-were upregulated by the inhibition of KCa3.1 in the mLN Treg cells of IBD model mice. In mouse peripheral CD4+CD25+ Treg cells induced by lectin stimulation, IL-10 expression and secretion were enhanced by the treatment with TRAM-34, together with the upregulation of E4BP4, KLF4, and Blimp1. Collectively, the present results demonstrated that the pharmacological inhibition of KCa3.1 decreased IBD symptoms in the IBD model by increasing IL-10 production in peripheral Treg cells and that IL-10high Treg cells produced by the treatment with KCa3.1 inhibitor may contribute to efficient Treg therapy for chronic inflammatory disorders, including IBD. SIGNIFICANCE STATEMENT: Pharmacological inhibition of Ca2+-activated K+ channel KCa3.1 increased IL-10 expression in peripheral Treg cells, together with the upregulation of the transcriptional regulators of IL-10: Krüppel-like factor 4, E4 promoter-binding protein 4, and/or B lymphocyte-induced maturation protein 1. The manipulation of IL-10high-producing Treg cells by the pharmacological inhibition of KCa3.1 may be beneficial in the treatment of chronic inflammatory diseases such as inflammatory bowel disease.


Fast Talairach Transformation for magnetic resonance neuroimages.
We introduce and validate the Fast Talairach Transformation (FTT). FTT is a rapid version of the Talairach transformation (TT) with the modified Talairach landmarks. Landmark identification is fully automatic and done in 3 steps: calculation of midsagittal plane, computing of anterior commissure (AC) and posterior commissure (PC) landmarks, and calculation of cortical landmarks. To perform these steps, we use fast and anatomy-based algorithms employing simple operations. FTT was validated for 215 diversified T1-weighted and spoiled gradient recalled (SPGR) MRI data sets. It calculates the landmarks and warps the Talairach-Tournoux atlas fully automatically in about 5 sec on a standard computer. The average distance errors in landmark localization are (in mm): 1.16 (AC), 1.49 (PC), 0.08 (left), 0.13 (right), 0.48 (anterior), 0.16 (posterior), 0.35 (superior), and 0.52 (inferior). Extensions to FTT by introducing additional landmarks and applying nonlinear warping against the ventricular system are addressed. Application of FTT to other brain atlases of anatomy, function, tracts, cerebrovasculature, and blood supply territories is discussed. FTT may be useful in a clinical setting and research environment: (1) when the TT is used traditionally, (2) when a global brain structure positioning with quick searching and labeling is required, (3) in urgent cases for quick image interpretation (eg, acute stroke), (4) when the difference between nonlinear and piecewise linear warping is negligible, (5) when automatic processing of a large number of cases is required, (6) as an initial atlas-scan alignment before performing nonlinear warping, and (7) as an initial atlas-guided segmentation of brain structures before further local processing.


Dendritic development of retinal ganglion cells after prenatal intracranial infusion of tetrodotoxin.
The dendritic form of a cell may be established by many factors both intrinsic and environmental. Blockade of action potentials along the course of axons and in their postsynaptic targets dramatically alters the development of axonal morphology. The extent to which blockade of target cell activity retrogradely alters the dendritic morphology of the presynaptic cells is unknown. To determine whether the establishment of dendritic form by developing retinal ganglion cells depends on activity within their targets, the sodium channel blocker, tetrodotoxin (TTX), was administered via minipumps to the diencephalon of cat fetuses from embryonic day 43 (E43) to E57. At E57 retinae were removed and living retinal ganglion cells injected in vitro with Lucifer yellow to reveal their dendritic morphology. In the TTX-treated animals both alpha and beta types of retinal ganglion cells were present, as were putative gamma cells. Overall, the dendrites of retinal ganglion cells in TTX-treated animals appeared qualitatively and quantitatively similar to those of untreated animals. The only significant change in the TTX-treated cases was a small increase in the number of dendritic spines on the non-beta cells. These results indicate that the acquisition of basic dendritic form of developing ganglion cells is not influenced by the action potential activity within their targets, and that it is also independent of the terminal branching patterns of their axons.


Takotsubo syndrome during treatment with 5-fluorouracil.
Fluoropyrimidines have been linked to cardiovascular toxicity. A woman in her forties with locally advanced rectal cancer received curative-intent treatment according to the RAPIDO protocol. Shortly after starting the first 5-fluorouracil infusion she developed chest/epigastric pain, nausea and vomiting. Electrocardiogram showed mild ST elevation in multiple contiguous leads. Troponin I was elevated. Transthoracic echocardiogram (TTE) displayed signs suggestive of myocardial infarction. Coronary angiogram indicated no obstructive coronary artery disease. Ventriculography demonstrated apical hypokinesia and basal hyperkinesia. MRI revealed no signs of myocardial infarction or myocarditis. The patient was diagnosed with Takotsubo syndrome, possibly induced by 5-fluorouracil. Follow-up TTE three weeks later was normal. Subsequently, she received treatment with tegafur/gimeracil/oteracil (Teysuno®) in place of 5-fluorouracil, combined with oxaliplatin. No further cardiotoxicity was observed during three cycles. The patient was diagnosed with Takotsubo syndrome following 5-fluorouracil infusion, likely to represent 5-fluorouracil-induced cardiotoxicity. Following replacement of 5-fluorouracil with Teysuno®, she experienced no signs of cardiotoxicity.


Loss of caveolin-1 causes blood-retinal barrier breakdown, venous enlargement, and mural cell alteration.
Blood-retinal barrier (BRB) breakdown and related vascular changes are implicated in several ocular diseases. The molecules and mechanisms regulating BRB integrity and pathophysiology are not fully elucidated. Caveolin-1 (Cav-1) ablation results in loss of caveolae and microvascular pathologies, but the role of Cav-1 in the retina is largely unknown. We examined BRB integrity and vasculature in Cav-1 knockout mice and found a significant increase in BRB permeability, compared with wild-type controls, with branch veins being frequent sites of breakdown. Vascular hyperpermeability occurred without apparent alteration in junctional proteins. Such hyperpermeability was not rescued by inhibiting eNOS activity. Veins of Cav-1 knockout retinas exhibited additional pathological features, including i) eNOS-independent enlargement, ii) altered expression of mural cell markers (eg, down-regulation of NG2 and up-regulation of αSMA), and iii) dramatic alterations in mural cell phenotype near the optic nerve head. We observed a significant NO-dependent increase in retinal artery diameter in Cav-1 knockout mice, suggesting that Cav-1 plays a role in autoregulation of resistance vessels in the retina. These findings implicate Cav-1 in maintaining BRB integrity in retinal vasculature and suggest a previously undefined role in the retinal venous system and associated mural cells. Our results are relevant to clinically significant retinal disorders with vascular pathologies, including diabetic retinopathy, uveoretinitis, and primary open-angle glaucoma.


An In Vitro Study on the Effect of Amorphous Calcium Phosphate and Fluoride Solutions on Color Improvement of White Spot Lesions.
The ability of remineralizing agents to improve the color of white spot lesions (WSL) is an important aspect that should be investigated. The aim of this study was to evaluate the effects of 0.05% amorphous calcium phosphate (ACP), 0.5% ACP, and 0.05% fluoride solutions, as well as artificial saliva on the color improvement of white spot lesions (WSLs). In this in vitro study, 50 human premolar teeth were randomly classified into five groups. At baseline, all the samples were assessed by using a colorimeter (E0). Then, white spot lesions were induced on the surface of the teeth by means of a pH-cycling model, and the colorimeter was used again (E1). Afterwards, samples of the 1st and 2nd groups were kept in 0.05% ACP and 0.5% ACP solutions for 1 min/day, respectively. The 3rd group specimens were placed in 0.05% fluoride solution for 1 min/day. The other two groups were kept in artificial saliva and distilled in water separately. All the samples were assessed by the colorimeter for a third time (E2). We found no significant difference between the groups in ∆E1. There was also no significant difference among 0.05% ACP solution, 0.5% ACP solution, 0.05% fluoride solution, and artificial saliva considering ∆E2. However, a significant difference was noted between the above-mentioned solutions and distilled water in ∆E2. With respect to ∆E3, there were considerable differences between ACP solution and artificial saliva. The same results were obtained for the difference between fluoride solution and artificial saliva. However, no significant difference was found among 0.05% ACP, 0.5% ACP, and 0.05% fluoride solutions in terms of ∆E3. In Conclusion, ACP is as effective as fluoride in the color improvement of WSLs and the recommended treatment for this purpose is daily use of 0.05% ACP, 0.5% ACP or 0.05% fluoride solutions.


The explanatory models and coping strategies for alcohol use disorders: an exploratory qualitative study from India.
The explanatory models (EM) and coping strategies for mental health problems influence treatment seeking and the subsequent patient journey. The goal of this study was to explore the EMs and coping strategies for alcohol use disorders (AUD). We conducted semi structured interviews with 29 men with AUD and 10 significant others (SO) in two sites in India. Thematic analysis was used to analyse data. The former were predominantly married, literate and employed; the latter were predominantly wives, literate and employed. Alcohol consumption and AUDs are seen to be mainly associated with psychosocial stress, with other factors being peer influences, availability of disposable income and drinking for pleasure. They are perceived to result in a range of adverse impacts on social life, family life, personal health and family finances. Various coping strategies were deployed by men with AUD and their significant others, for example avoidance, substitution, distraction, religious activities, support from AA/friends/family, restricting means to buy alcohol and anger management. Reduction/cessation in drinking, improved family relationships, improved emotional/physical wellbeing and better occupational functioning were the most desired treatment outcomes. There are considerable similarities, as well as some key differences, observed between the EMs for AUD in India and those reported from other cultures which have implications for the global applicability and contextual adaptations of evidence based interventions for AUD.


[Lesions of the coronary arteries in nonspecific aortoarteritis].
Clinical and angiographic signs of coronary arterial lesions associated with nonspecific aorto-arteritis are considered. Three kinds of coronary arterial affection are described: affected arterial opening, combined affection of the opening and proximal arterial portions and affected distal portions. It is concluded that the diagnosis of coronary arterial lesions in this condition can be based on combined investigation including continuous ECG recording for 10 or 12 days, bicycle ergometry and selective coronarography.


Emergency assessment of hemostasis in the bleeding patient.
Emergency hemostasis testing is typically used to determine which blood products are needed to correct hemostatic defects associated with bleeding. Rapid assessment of hemostasis can be performed using standard or viscoelastic hemostasis tests in the clinical laboratory, satellite laboratory, or using point-of-care methods. The major drawback of standard coagulation testing is that most clinical laboratories are focused more on accuracy than on turnaround time. Improving turnaround times may require revision of the entire approach to performing the testing in the clinical laboratory including specimen processing, testing, and reporting. An advantage to rapid central laboratory testing is the availability to all areas of the hospital, not just the emergency department or operating rooms. Use of point-of-care assays can improve turnaround times, but point-of-care tests typically show more variation and lower precision. Viscoelastic global hemostasis tests can be used for rapid assessment as well, but care needs to be taken in the interpretation of the results. Viscoelastic testing is currently the only method that can detect severe fibrinolysis. Platelet function testing is useful for detection of hereditary platelet function problems and some antiplatelet medication monitoring, but is less useful for preoperative bleeding risk assessment or diagnosing the cause of acquire bleeding syndromes. This review will highlight different approaches to the rapid assessment of hemostasis.


Partner notification program and possibility of including it in the HIV prevention strategies in Japan.
This article discusses the possibility of implementing partner notification program as a part of HIV prevention strategy in Japan. Relevant factors, like HIV seroprevalence, general population attitudes toward HIV, legislation, resources, barriers, behavioral changes, cost and effectiveness are analyzed in Japanese perspectives. Effectiveness of this program is also predicted based on the two informal contact tracing program in Japan. At the same time a review was made on the global perspectives of partner notification program and operational procedures are also outlined. Published literatures were investigated regarding prevalence of new HIV infection among the partners who underwent testing (11-39%), cost per new HIV positive case found (US $810-3,205), and secondary infection rate (11-20%) in Japan. Having considered all relevant factors we recommend that the partner notification program be implemented, initially in a limited area, then all over Japan. Further analysis on cost-benefit of this program remains to be done.


Polyethylene glycol-conjugated superoxide dismutase attenuates septic lung injury in guinea pigs.
Reactive oxygen species (ROS), including superoxide anions, play an important role in mediating acute lung injury. We examined whether polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) attenuates lung injury in Escherichia coli-treated guinea pigs. Twenty-four guinea pigs were divided into four groups: (1) control group; (2) septic group, in which live E. coli (2 x 10(9)/kg) were injected intravenously; (3) pretreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 15 min before E. coli; and (4) posttreatment group, in which PEG-SOD (2,000 IU/kg) was injected intravenously 30 min after E. coli. Lung injury was assessed by the concentration ratio of 125I-labeled albumin in lung tissue and bronchoalveolar lavage (BAL) fluid relative to plasma (L/P and BAL/P), lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid. Plasma half-life of PEG-SOD in normal guinea pigs was 13.5 h. L/P, lung wet-to-dry weight ratio, and the number of neutrophils in BAL fluid decreased in both pretreatment and posttreatment groups compared with the septic group. BAL/P decreased in the pretreatment group but not in the posttreatment group compared with the septic group. After the animal model studies, we investigated the effect of PEG-SOD on the human neutrophil extracellular generation of ROS stimulated by phorbol myristate acetate (PMA) in lucigenin-dependent chemiluminescence (CL). PEG-SOD at concentrations greater than or equal to 0.1 U/ml inhibited PMA-induced CL in a dose-dependent manner. We also examined the effect of PEG-SOD on the neutrophil intracellular generation of ROS using flow cytometry to assess intracellular hydroethidine oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)


A Multicatalytic Approach to the Hydroaminomethylation of α-Olefins.
We report an approach to conducting the hydroaminomethylation of diverse α-olefins with a wide range of alkyl, aryl, and heteroarylamines at relatively low temperatures (70-80 °C) and pressures (1.0-3.4 bar) of synthesis gas. This approach is based on simultaneously using two distinct catalysts that are mutually compatible. The hydroformylation step is catalyzed by a rhodium diphosphine complex, and the reductive amination step, which is conducted as a transfer hydrogenation with aqueous, buffered sodium formate as the reducing agent, is catalyzed by a cyclometallated iridium complex. By adjusting the ratio of CO to H2 , we conducted the reaction at one atmosphere of gas with little change in yield. A diverse array of olefins and amines, including hetreroarylamines that do not react under more conventional conditions with a single catalyst, underwent hydroaminomethylation with this new system, and the pharmaceutical ibutilide was prepared in higher yield and under milder conditions than with a single catalyst.


Prospective study of violence risk reduction by a mental health court.
Although many mental health courts (MHCs) have been established to reduce criminal justice involvement of persons with mental disorders, research has not kept pace with the widespread implementation of these courts. Whereas early MHCs were restricted to persons charged with nonviolent misdemeanors, many MHCs now accept persons with more serious charges for whom ameliorating risk of violence is a greater concern. This study evaluated the relationship between MHC participation and risk of violence by using a prospective design. It was hypothesized that MHC participation would decrease the risk of violence during a one year follow-up compared with a matched comparison group. The sample included 169 jail detainees with a mental disorder who either entered an MHC (N=88) or received treatment as usual (N=81). Seventy-two percent had been charged with felonies. Participants were interviewed at baseline and during a one-year follow up, and their arrest records were reviewed. Propensity-adjusted logistic regression evaluated the relationship between MHC participation and risk of violence, controlling for potential confounders such as history of violence, demographic characteristics, baseline treatment motivation, and time at risk in the community. MHC participation was associated with reduction in risk of violence (odds ratio=.39). During follow-up, 25% of the MHC group perpetrated violence, compared with 42% of the treatment-as-usual group. MHC participation can reduce the risk of violence among justice-involved persons with mental disorders. The findings support the conclusion that the MHC model can be extended beyond persons charged with nonviolent misdemeanors in a way that enhances public safety.


Innovative health service delivery models in low and middle income countries - what can we learn from the private sector?
The poor in low and middle income countries have limited access to health services due to limited purchasing power, residence in underserved areas, and inadequate health literacy. This produces significant gaps in health care delivery among a population that has a disproportionately large burden of disease. They frequently use the private health sector, due to perceived or actual gaps in public services. A subset of private health organizations, some called social enterprises, have developed novel approaches to increase the availability, affordability and quality of health care services to the poor through innovative health service delivery models. This study aims to characterize these models and identify areas of innovation that have led to effective provision of care for the poor. An environmental scan of peer-reviewed and grey literature was conducted to select exemplars of innovation. A case series of organizations was then purposively sampled to maximize variation. These cases were examined using content analysis and constant comparison to characterize their strategies, focusing on business processes. After an initial sample of 46 studies, 10 case studies of exemplars were developed spanning different geography, disease areas and health service delivery models. These ten organizations had innovations in their marketing, financing, and operating strategies. These included approaches such a social marketing, cross-subsidy, high-volume, low cost models, and process reengineering. They tended to have a narrow clinical focus, which facilitates standardizing processes of care, and experimentation with novel delivery models. Despite being well-known, information on the social impact of these organizations was variable, with more data on availability and affordability and less on quality of care. These private sector organizations demonstrate a range of innovations in health service delivery that have the potential to better serve the poor's health needs and be replicated. There is a growing interest in investing in social enterprises, like the ones profiled here. However, more rigorous evaluations are needed to investigate the impact and quality of the health services provided and determine the effectiveness of particular strategies.


Mitoxantrone, etoposide, and cyclosporine therapy in pediatric patients with recurrent or refractory acute myeloid leukemia.
To determine the remission rate and toxicity of mitoxantrone, etoposide, and cyclosporine (MEC) therapy, multidrug resistance-1 (MDR1) status, and steady-state cyclosporine (CSA) levels in children with relapsed and/or refractory acute myeloid leukemia. MEC therapy consisted of mitoxantrone 6 mg/m(2)/d for 5 days, etoposide 60 mg/m(2)/d for 5 days, and CSA 10 mg/kg for 2 hours followed by 30 mg/kg/d as a continuous infusion for 98 hours. Because of pharmacokinetic interactions, drug doses were decreased to 60% of those found to be effective without coadministration of CSA. MDR1 expression was evaluated by reverse transcriptase polymerase chain reaction, flow cytometry, and the ability of CSA at 2.5 micromol/L to increase intracellular accumulation of (3)H-daunomycin in blasts from bone marrow specimens. The remission rate was 35% (n = 23 of 66). Overall, 35% of patients (n = 23) achieved complete remission (CR), 12% of patients (n = 8) achieved partial remission, and 9% of patients (n = 6) died of infection. Exposure to CSA levels of greater than 2,400 ng/mL was achieved in 95% of patients (n = 56 of 59). Toxicities included infection, cardiotoxicity, myelosuppression, stomatitis, and reversible increases in serum creatinine and bilirubin. In most who had relapsed while receiving therapy or whose induction therapy had failed, response was not significantly different for MDR1-positive and MDR1-negative patients. Serum levels of CSA capable of reversing multidrug resistance are achievable in children with acceptable toxicity. The CR rate of 35% achieved in this study is comparable to previously reported results using standard doses of mitoxantrone and etoposide. The use of CSA may have improved the response rate for the MDR1-positive patients so that it was not different from that for the MDR1-negative patients.


A reference methylome database and analysis pipeline to facilitate integrative and comparative epigenomics.
DNA methylation is implicated in a surprising diversity of regulatory, evolutionary processes and diseases in eukaryotes. The introduction of whole-genome bisulfite sequencing has enabled the study of DNA methylation at a single-base resolution, revealing many new aspects of DNA methylation and highlighting the usefulness of methylome data in understanding a variety of genomic phenomena. As the number of publicly available whole-genome bisulfite sequencing studies reaches into the hundreds, reliable and convenient tools for comparing and analyzing methylomes become increasingly important. We present MethPipe, a pipeline for both low and high-level methylome analysis, and MethBase, an accompanying database of annotated methylomes from the public domain. Together these resources enable researchers to extract interesting features from methylomes and compare them with those identified in public methylomes in our database.


Polycystic Ovary Syndrome Fuels Cardiovascular Inflammation and Aggravates Ischemic Cardiac Injury.
Reducing cardiovascular disease burden among women remains challenging. Epidemiologic studies have indicated that polycystic ovary syndrome (PCOS), the most common endocrine disease in women of reproductive age, is associated with an increased prevalence and extent of coronary artery disease. However, the mechanism through which PCOS affects cardiac health in women remains unclear. Prenatal anti-Müllerian hormone treatment or peripubertal letrozole infusion was used to establish mouse models of PCOS. RNA sequencing was performed to determine global transcriptomic changes in the hearts of PCOS mice. Flow cytometry and immunofluorescence staining were performed to detect myocardial macrophage accumulation in multiple PCOS models. Parabiosis models, cell-tracking experiments, and in vivo gene silencing approaches were used to explore the mechanisms underlying increased macrophage infiltration in PCOS mouse hearts. Permanent coronary ligation was performed to establish myocardial infarction (MI). Histologic analysis and small-animal imaging modalities (eg, magnetic resonance imaging and echocardiography) were performed to evaluate the effects of PCOS on injury after MI. Women with PCOS and control participants (n=200) were recruited to confirm findings observed in animal models. Transcriptomic profiling and immunostaining revealed that hearts from PCOS mice were characterized by increased macrophage accumulation. Parabiosis studies revealed that monocyte-derived macrophages were significantly increased in the hearts of PCOS mice because of enhanced circulating Ly6C+ monocyte supply. Compared with control mice, PCOS mice showed a significant increase in splenic Ly6C+ monocyte output, associated with elevated hematopoietic progenitors in the spleen and sympathetic tone. Plasma norepinephrine (a sympathetic neurotransmitter) levels and spleen size were consistently increased in women with PCOS when compared with those in control participants, and norepinephrine levels were significantly correlated with circulating CD14++CD16- monocyte counts. Compared with animals without PCOS, PCOS animals showed significantly exacerbated atherosclerotic plaque development and post-MI cardiac remodeling. Conditional Vcam1 silencing in PCOS mice significantly suppressed cardiac inflammation and improved cardiac injury after MI. Our data documented previously unrecognized mechanisms through which PCOS could affect cardiovascular health in women. PCOS may promote myocardial macrophage accumulation and post-MI cardiac remodeling because of augmented splenic myelopoiesis.


Sentinel lymph node biopsy for head and neck malignancies utilizing simultaneous radioisotope gamma probe and indocyanine green fluorescence navigation.
We depict an innovative surgical approach for sentinel lymph node biopsy (SLNB) in head and neck malignancies that utilizes both near-infrared (NIR) imaging with indocyanine green (ICG) dye and hand-held gamma probe intraoperatively to isolate and excise SLNs. Twenty-one patients presented to our institution with cutaneous melanoma, cutaneous squamous cell carcinoma (SCC), and oral cavity SCC tumors that met criteria for SLNB based on tumor depth and histology. The video offers a step-by-step approach for this technique along with descriptions of recommended equipment. Among 21 patients, two patients had positive SLNs on final pathology. One patient developed a local recurrence over an average of 16.2 months of follow-up (SD = 15.6). SLNB with ICG and radionucleotide co-localization may enhance the identification of sentinel nodes without compromising outcomes in the hands of surgeons well-versed in the technique.


PGK1 a potential marker for peritoneal dissemination in gastric cancer.
Peritoneal carcinomatosis, which is caused by the dissemination of cancer cells into the abdominal cavity is a frequent finding in patients with primary gastric cancer, and it is associated with a poor prognosis. The mechanisms that mediate peritoneal carcinomatosis in diffuse primary gastric tumours require definition. We therefore compared the gene expression profile in diffuse primary gastric cancer patients with and without peritoneal carcinomatosis (n=13). Human specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated using oligonucleotide microarrays. Differentially expressed genes of interest were further evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). The results reveal a significant overexpression of phosphoglycerate kinase 1 (PGK1), the chemokine CXCR4 and its ligand CXCL12 in specimens from diffuse gastric cancer patients with peritoneal carcinomatosis. Overexpression of PGK1 is known to increase the expression of CXCR4. CXCR4 on its part can increase CXCL12 expression. Elevated levels of CXCR4 and CXCL12 are associated with an increase in the metastatic rate and play an important role in the metastatic homing of malignant cells. The overexpression of PGK1 and its signalling targets may be a expression-pathway in diffuse primary gastric carcinomas promoting peritoneal dissemination and may function as prognostic markers and/or be potential therapeutic targets to prevent the migration of gastric carcinoma cells into the peritoneum.