Auditory brainstem development of naked mole-rats (Heterocephalus glaber).
Life underground often leads to animals having specialized auditory systems to accommodate the constraints of acoustic transmission in tunnels. Despite living underground, naked mole-rats use a highly vocal communication system, implying that they rely on central auditory processing. However, little is known about these animals' central auditory system, and whether it follows a similar developmental time course as other rodents. Naked mole-rats show slowed development in the hippocampus suggesting they have altered brain development compared to other rodents. Here, we measured morphological characteristics and voltage-gated potassium channel Kv3.3 expression and protein levels at different key developmental time points (postnatal days 9, 14, 21 and adulthood) to determine whether the auditory brainstem (lateral superior olive and medial nucleus of the trapezoid body) develops similarly to two common auditory rodent model species: gerbils and mice. Additionally, we measured the hearing onset of naked mole-rats using auditory brainstem response recordings at the same developmental timepoints. In contrast with other work in naked mole-rats showing that they are highly divergent in many aspects of their physiology, we show that naked mole-rats have a similar hearing onset, between postnatal day (P) 9 and P14, to many other rodents. On the other hand, we show some developmental differences, such as a unique morphology and Kv3.3 protein levels in the brainstem.


[Evaluation of electrophysiological neuromonitoring in the diagnosis of brain death: Part III. Compressed spectral arrays].
Electrophysiological neuromonitoring of compressed spectral array (CSA) EEG, brainstem auditory evoked potentials (BAEP) and short-latency somatosensory evoked potentials (SEP) can provide precise and immediate information concerning functional integrity of severe brain damage. We applied this neuromonitoring system in 185 cases of severe brain damage in order to evaluate its reliability in the diagnosis of brain death. This report considers the relationships between CSA and neurological, conventional EEG (CEEG), BAEP and SEP findings, and the significance of CSA in the assessment of brain death. CSA monitoring of 59 patients (37 brain-dead in group A and 22 non brain-dead in group B) was performed and analysed. Brain damage was caused by cerebrovascular insult in 31 cases, head injury in 25, meningitis in 2, dan anoxia in 1. Mean patient age was 49 (ages 5-84). There were no significant differences in causes and age distribution between the two groups. CSA monitoring, using 5 or 7 microV/mm, of two channels (Cz-A1 and Cz-A2) of EEG activity was performed. Power spectral analysis (0-16 Hz) was carried out at 10 to 120 second epochs. Automatic BAEP (54 patients) and/or SEP (33 patients) monitoring was performed simultaneously 10 to 30 minutes. CSA was classified into three patterns: 1) "Electrocerebral silence; ECS" revealed bilateral absence of the CSA power spectra for periods longer than 40 seconds. 2) "Biological activity; BA" showed continuous peaks of activity. 3) "Equivocal; EQ" pattern showed intermittent peaks of activity, and unilateral loss of power spectra or bilateral loss within 30 seconds. CSA findings indicated the loss of CSA "BA" pattern (LCBP) in 36 group A patients (17 "ECS" and 19 "EQ"). All but two revealing LCBP had satisfied the neurological criteria of brain death (deep coma, absent brainstem reflexes and apnea) during CSA monitoring. "BA" was always present in 22 group B and one group A patients had not fulfilled neurological criteria of brain death. The CEEG results of all group A patients demonstrating "ECS" of CSA were of the classification Hockaday grade Va or Vb. Four patients classified as grade IV b demonstrated "EQ" An examination of CSA and neurological brainstem function of 28 group A patients revealed LCBP preceded the loss of brainstem reflexes and apnea in 15 patients or was coincided with them in 13.(ABSTRACT TRUNCATED AT 400 WORDS)


Sagittal abdominal diameter as a new predictor for incident diabetes.
Obesity, particularly visceral adiposity, is a major risk factor for type 2 diabetes. The commonly used obesity indicators, BMI, waist girth, and waist-to-hip ratio (WHR), have limited ability to measure the visceral adipose tissue. Sagittal abdominal diameter (SAD) has been shown to predict the amount of visceral fat. So far no study has been published on its ability to predict diabetes occurrence. We assessed and compared the prediction of the four obesity indicators for diabetes incidence in a prospective study based on 5,168 participants from the nationally representative Health 2000 study. During a mean follow-up lasting 8.1 years, 222 incident diabetes cases occurred. In multivariate models adjusted for lifestyle factors, BMI, waist girth, WHR, and SAD were significant predictors of diabetes incidence. The relative risks (95% CI) between high and low levels were 15.0 (6.94-32.6), 11.4 (5.39-23.8), 12.5 (6.47-24.2), and 14.7 (6.89-31.2), respectively. Pairwise interaction analysis showed that the co-occurrence of high BMI and high SAD was associated with the highest diabetes incidence, with a relative risk of 37.0 (11.2-122). After adjustment for waist girth and the components of the metabolic syndrome, the relative risk was 9.88 (2.81-34.7). The corresponding population-attributable fraction estimate was 84% (49-95). The combination of SAD and BMI measurements yields a new predictor of diabetes incidence.


Hydrocortisone may act through the angiotensin II receptor-2 level in patients with catecholamine-resistant septic shock.
This study aimed to compare the serum angiotensin II and its receptor levels (AT1, AT2) in septic patients with catecholamine-responsive or resistant. The effect of hydrocortisone treatment on angiotensin II levels in the catecholamine-resistant septic patients was evaluated. This prospective observational study enrolled 40 patients diagnosed with septic shock based on sepsis-3 criteria. Patients were divided into two groups according to the noradrenalin infusion rate required to keep the mean arterial pressure above 65 mmHg: control group and hydrocortisone group (control group: below 0.5 µg/kg/min, hydrocortisone group: above 0.5 µg/kg/min). Serum angiotensin II, AT1, AT2 levels were measured at the time of diagnosis (A), one hour after hydrocortisone treatment (B), and three days later (C). In the catecholamine-resistant group, angiotensin II and AT1 levels were higher than the catecholamine-responder group in all periods. The sensitivity and specificity of AT-1 was observed to be high in all periods. AT2 levels decreased after hydrocortisone treatment in the catecholamine-resistant group and cut-off value was found 11%. It was concluded that angiotensin II and AT1 can be used as a biomarker of refractory septic shock and hydrocortisone may provide their blood pressure correcting effect by reducing AT2 level in these patients. AT2 can be a therapeutic target in the catecholamine-resistant septic shock patients.


Cerebral small vessel disease and chronic kidney disease.
Chronic kidney disease, defined by a decreased glomerular filtration rate or albuminuria, is recognized as a major global health burden, mainly because it is an established risk factor for cardiovascular and cerebrovascular diseases. The magnitude of the effect of chronic kidney disease on incident stroke seems to be higher in persons of Asian ethnicity. Since the kidney and brain share unique susceptibilities to vascular injury due to similar anatomical and functional features of small artery diseases, kidney impairment can be predictive of the presence and severity of cerebral small vessel diseases. Chronic kidney disease has been reported to be associated with silent brain infarcts, cerebral white matter lesions, and cerebral microbleeds, independently of vascular risk factors. In addition, chronic kidney disease affects cognitive function, partly via the high prevalence of cerebral small vessel diseases. Retinal artery disease also has an independent relationship with chronic kidney disease and cognitive impairment. Stroke experts are no longer allowed to be ignorant of chronic kidney disease. Close liaison between neurologists and nephrologists can improve the management of cerebral small vessel diseases in kidney patients.


Zoledronic acid at the time of castration prevented castration-induced bone metastasis in mice.
Androgen deprivation therapy (ADT) is known to cause bone loss in a majority of patients with castration-resistant prostate cancer (CRPC). A study published in this issue of Endocrine-Related Cancer by Ottewell and colleagues shows that ADT increased bone resorption and triggered growth of disseminated prostate cancer (CaP) cells to form bone metastasis using an in vivo model. However, prevention of bone decay by weekly administration of zoledronic acid (ZOL) at the time of castration prevented ADT-induced tumor growth in bone. Recently, two publications from Japan have demonstrated that ZOL combined with ADT improved outcomes for patients with treatment-naïve CaP with bone metastasis. The mechanistic cause for these patients having an improved overall survival compared with those who were treated with ZOL after ADT initiation or before metastasis development was never explained. Ottewell and colleague's study now suggests that it is the bone loss caused by ADT that promoted bone metastasis, and if ZOL is administered at the time of ADT initiation, it would prevent this bone loss and prolong skeletal-related event-free survival.


Mandatory vaccination and no fault vaccine injury compensation schemes: An identification of country-level policies.
To prevent the spread of infectious diseases, governments have implemented a number of policies, including a range of mandatory vaccination policies. In addition, some governments have implemented no fault vaccine injury compensation schemes as a legal mechanism of recourse for individuals experiencing adverse events following vaccination. We aimed to identify countries with mandatory vaccination policies that also have no fault compensation schemes. To identify countries with mandatory childhood vaccination policies, we utilized existing publications, lists and databases, also conducting multiple country searches and policy detail verification. We then investigated compensation schemes for each country with childhood vaccination mandates, using an existing study and database/internet searches. Of the 62 countries we identified with mandatory childhood vaccination policies, we found evidence that only 7 (11%) had also implemented no fault compensation schemes. No-fault compensation schemes are one government approach to address unintended consequences of vaccination. Few countries have implemented these schemes, including those with mandatory vaccination policies. Mandatory vaccination invokes a strong need to protect those who fall victim to extremely rare cases of provable no-fault vaccine injury. Countries that mandate childhood vaccination without providing no fault compensation schemes could be seen as abrogating the social contract. This is particularly important when public policies limit parental choice regarding whether to vaccinate.


Possible link between unique chemokine and homing receptor expression at diagnosis and relapse location in a patient with childhood T-ALL.
Childhood acute lymphoblastic leukemia (ALL) is often associated with extramedullary infiltration by leukemic cells at diagnosis or at relapse. To understand the mechanisms behind the dissemination of T-cell ALL (T-ALL) cells this study investigated the homing receptor expression on the blast cells of 11 pediatric T-ALL patients at diagnosis. One patient revealed a unique profile with high expression of the chemokine receptor CCR9 and the integrin CD103 on the T-ALL cells. Both of these molecules are specifically associated with homing to the gut. This finding was clinically significant as the patient later suffered a relapse that was confined to the gut. Immunohistochemistry revealed that the leukemic cells in the gut still expressed CCR9 and colocalized with a high expression of the CCR9 ligand, CCL25. These findings suggest that the original expression of CCR9 and CD103 on the leukemic cells contributed to the relapse location in the gut of this patient.


Psychometric features related to the acute phase and final outcome of anorexia nervosa.
The MMPI responses of a poor and good final outcome group from a follow-up study of anorexia nervosa were compared with responses of a group of anorexic patients in the acute phase. The poor outcome group produced elevated scores in the psychopathological range except on scales 4, 5 and 9. No elevations occurred in the good outcome group and the MMPI thus discriminated significantly between different kinds of final outcome of anorexia nervosa. The profile of the patients in the acute phase at time of testing was not significantly different from the poor outcome group profile. In order to improve the predictive validity of the MMPI related to anorexia nervosa, the paper points to possible directions for further research.


Stress testing in persons above the age of 65 years: applicability and diagnostic value of a standardized maximal symptom-limited testing protocol.
A standardized symptom-limited stress test on a bicycle ergometer in semisupine position is examined in regard to its applicability in patients over the age of 65. The test protocol allows for exercise at full capacity in the elderly. Its value for diagnosis of coronary heart disease is equivalent with its value in the younger patients' group. In 167 patients above 65 years, there occurred only one case of pulmonary rales with exercise, no other complication could be observed (0.568%). Standardized, symptom-limited stress testing appears to be a simple, highly diagnostic and safe method for testing exercise capacity or diagnosing coronary heart disease in the elderly as in younger persons.


Parametric empirical Bayes estimates of disease prevalence using stratified samples from community populations.
Studies of chronic diseases in a community setting often employ stratified sample designs to enable the study to attain multiple research goals at a reasonable cost. One important goal is estimation of disease prevalence in the whole community and in important subgroups. Some adjustment for the sample design is necessary; if the design has many strata with very disparate sampling fractions, simply upweighting observed stratum prevalences may lead to unstable estimators. We propose a parametric empirical Bayes estimator in the spirit of the work of Efron and Morris, and we compare it to the direct upweighted estimator and a regression-smoothed estimator. Simulation studies in realistic settings suggest that the new estimator performs best, giving estimates with low bias and good precision under a variety of models.


Impact of dexmedetomidine on secondary hyperparathyroidism recurrence in uremic patients who received parathyroidectomy with auto-transplantation: a retrospective propensity-matched study.
Recurrence of secondary hyperparathyroidism (SHPT) remains a big challenge in uremic patients who underwent total parathyroidectomy with auto-transplantation (tPTX-AT). However, the relationship between perioperative intervention and recurrence of SHPT remains unclear. Dexmedetomidine has been used safely and effectively in uremic patients' anesthesia. The aim of the study was to explore the effect of dexmedetomidine on the recurrence of SHPT and identify the possible mechanism of action. Records of patients who underwent tPTX-AT between 2017 and 2018 were retrospectively analyzed. The study consisted of patients who received dexmedetomidine intra-operatively and the control patients who did not receive dexmedetomidine. The primary endpoint was the difference in the recurrence of SHPT one year after the surgery between the two groups. The secondary endpoint was health-related quality of life scores. Analysis included propensity score matching and multivariable logistic regression. Of 354 patients, 133 patients received dexmedetomidine intra-operatively, and the total recurrence rate of SHPT was 10.2%. After propensity score matching, we found that patients' age, dexmedetomidine infusion, comorbidity of diabetes, and preoperative serum phosphorus were independent factors for SHPT recurrence, and that patients who received dexmedetomidine had an estimated 3.80-fold decrease in the risk of SHPT recurrence (odds ratio, 0.263; 95% confidence interval, 0.081 to 0.854; P=0.026). Patients receiving intraoperative dexmedetomidine infusion exhibited a better quality of life in terms of physical functioning and general health, and less emotional role limitations compared with those in the control group. In uremic patients who received tPTX-AT, there was an association between dexmedetomidine use and decreased risk of SHPT recurrence one year after the surgery. Further studies are needed to accurately assess the effects and mechanism of action of dexmedetomidine on the prognosis of this population.


Diagnostic and therapeutic studies in childhood serous otitis media. Results of treatment with an antihistamine-adrenergic combination.
Fifty-five children with their first recognized episodes of serous otitis media were followed over a three-month period. The efficacy of an antihistamine-adrenergic combination (diphenhydramine and pseudoephedrine), the comparative value of various diagnostic studies of middle ear function, and the prognostic importance of information obtained at the first visit were assessed. Compared double-blindly to a placebo, the pharmaceutical preparations did not appear to influence the clinical course, although more drug patients experienced lethargy or relief of symptoms not directly concerned with middle ear function (mainly upper respiratory congestion). The color and extent of motility of the tympanic membrane, but no other pneumatic otoscopic findings, were related to audiometry, whereas tympanometry correlated with the amount of motility and the presence or absence of visible fluid behind the membrane. The patients with the most severe hearing losses or with visible middle ear fluid at their initial visits improved the most, and those who began to be followed in the summer the least. The last finding may be due to a general but unexplained deterioration of childhood serous otitis media during the fall.


The positive predictive value of diagnostic ultrasound for occult herniae.
The aim of this study is to ascertain the accuracy of diagnostic ultrasound in the assessment of the occult abdominal and groin herniae. The authors have previously demonstrated its efficacy in diagnosing the type of clinical groin herniae but occult herniae provide a further diagnostic problem. A total of 113 consecutive patients were referred prospectively for ultrasound examinations with clinically suspected occult herniae. All positive scans were offered surgery whilst the negative results were offered further imaging or other diagnostic tests depending on the clinical criteria. The end point for negative scans was based on 18-month follow-up or resolution of symptoms. Overall, 59 scans showed positive results for herniae and 56 of these had surgery. In the other three patients, two refused an operation, and one had no hernia detected at operation. In the remaining 57 scans, ultrasound offered alternative soft tissue diagnoses in 23 patients and surgical/endoscopic diagnoses accounted for a further 8 patients. Ultrasound offered a diagnosis for the symptomology in 82 patients (70.6%) of which 59 were herniae. The positive predictive value for hernia is 98.3%. Twenty-six patients with no diagnosis or confirmation of herniae on follow-up showed symptom resolution in 22 cases, and four patients were treated by the pain clinic.


Prevalence of and risk factors associated with carotid artery stenosis: the Tromsø Study.
To assess prevalence, distribution, ultrasound characteristics and determinants of carotid artery stenosis in a large, population-based study of both women and men. A total of 6,727 persons aged 25-84 years were screened for extracranial stenosis with Duplex ultrasound of the right carotid artery. Risk factors were compared in 225 persons with stenosis and 5,514 persons without. The prevalence of carotid stenosis was higher in men than in women, where 3.8% (95% CI, 3.2-4.6%) had carotid stenosis, compared to 2.7% (95% CI, 2.2-3.3%) in women (p = 0.001). The prevalence gradually increased by age in both genders. Cholesterol, HDL cholesterol, fibrinogen, systolic blood pressure levels and current smoking were independently associated with carotid artery stenosis in both women and men. The presence of carotid stenosis was significantly associated with a history of cerebrovascular disease, coronary heart disease and peripheral artery disease. For each 10% increase in the degree of carotid stenosis, the risk of having had a cerebrovascular event increased by 26%. The prevalence of carotid stenosis in the general population, as measured by ultrasound, is low. Age, male gender, smoking, total cholesterol, HDL cholesterol (inverse), fibrinogen and systolic blood pressure are all independent predictors of carotid artery stenosis.


Multicomponent geriatric intervention for elderly inpatients with delirium: a randomized, controlled trial.
Delirium is a common syndrome with poor prognosis affecting elderly inpatients. Treatment is mainly based on common sense with wide variations in practice. We investigated whether intensified, multicomponent geriatric treatment could improve the prognosis of delirious patients. We performed a randomized, controlled trial of 174 patients with delirium in six general medicine units from an acute hospital in Helsinki, Finland. The intervention group received individually tailored geriatric treatment. The primary endpoint was the sum of those deceased individuals and the patients permanently institutionalized. Secondary endpoints included the number of days in hospitals and other institutions, delirium intensity, and cognition. The mean age of patients was 83 years, and 31% had previous dementia. The intervention group (N = 87) received significantly more acetylcholinesterase inhibitors (58.6% vs 9.2%), atypical antipsychotics (69.8% vs 30.2%), specialist consultations (49.4% vs 28.7%), hip protectors (88.5% vs 3.4%), physiotherapy (87.4% vs 47.1%), and fewer conventional neuroleptics (8.0% vs 23.0%) than did the control group (N = 87). During the 1-year follow-up, 60.9% of the intervention group and 64.4% of controls were either deceased or permanently institutionalized (p =.638). The intervention group spent a mean of 126 days in institutions, and the control group 140 days (p =.688). Delirium was, however, alleviated more rapidly during hospitalization, and cognition improved significantly at 6 months in the intervention group. Faster alleviation of delirium and improved cognition justify good, comprehensive geriatric care for these patients although treatment produced no significant improvements in hard endpoints of prognosis.


Identification and tissue-specific expression of amphioxus GM2 activator protein gene from amphioxus Branchiostoma belcheri.
An amphioxus cDNA, AmphiGM2AP, encoding GM2 activator protein was isolated from the gut cDNA library of Branchiostoma belcheri. It is 907 bp long, and its longest open reading frame codes for a precursor protein consisting of 242 amino acid residues with a signal peptide of 14 amino acids. The deduced amino acid sequence includes a conserved domain typical of GM2APs between residues 53 and 224, a single N-linked glycosylation site at position 65 and 8 conserved cysteines. Phylogenetic analysis showed that amphiGM2AP forms a club together with invertebrate GM2APs, indicating that AmphiGM2AP is evolutionarily closely related to invertebrate GM2APs rather than vertebrate ones. Both Northern blotting and in situ hybridization histochemistry analyses revealed a tissue-specific expression pattern of AmphiGM2AP in adult amphioxus with the strongest expression in the digestive system, which is in contrast to the widespread expression pattern of human, mouse and sheep GM2AP genes. It is suggested that AmphiGM2AP is possibly involved in the take-in of digested food components like lipid molecules.


Between Galen, Geddes, and the Gael: Arthur Brock, modernity, and medical humanism in early-twentieth-century Scotland.
Arthur Brock (1879-1947) is generally remembered as the physician who treated poet Wilfred Owen for shell shock and as the translator of Galen and other ancient physicians. He was also a key figure in the early-twentieth-century humanist revival within medicine. Brock's interest in humanism, I argue, was inspired by a broader concern about modernity and by a desire to return medicine and society to the more harmonious, organic existence that he believed was characteristic of ancient Greece and could still be found among "primitive" peoples, such as the Scottish Gaels. This article explores Brock's anxieties about modernity and its relations to his interests in ancient and "primitive" peoples; to his medical thought and practice; to his interests in history, sociology, language, and translation; and to his involvement in the social and political life of Edinburgh and North Queensferry, where he moved in 1925. Crucially, it shows how all these interests and activities were influenced by Brock's mentor, Edinburgh polymath Patrick Geddes. The article concludes with a discussion of Brock's place in early-twentieth-century medical humanism.


Comparison of Different Bone Filling Materials and Resorbable Membranes by Means of Micro-Tomography. A Preliminary Study in Rabbits.
The purpose of this work was to evaluate the behavior of different membranes and bone filling materials used to fill critical defects in rabbit calvaria. Four defects were prepared in the cranial calvaria of female rabbits. They were randomly divided into three subgroups according to the type of barrier membrane to be used. Four animals carried cross-linked bovine collagen membranes (Mem-Lok, Bio-Horizons, Birmingham, AL, USA)), four human fascia lata membranes (Tissue, Inbiomed SA, Córdoba, Argentina) and four human chorioamniotic membranes (Tissue. Inbiomed SA, Córdoba, Argentina). The defects were filled with the deproteinized bovine bone particulate Bio-Oss® (Geistlich-Pharma AG, Wolhusen, Switzerland), with particulate human hydroxyapatite MinerOss® (Bio-Horizons, Birmingham, AL, USA), with particulate dental material (Tissue Bank Foundation, Inbiomed S.A., Córdoba, Argentina), and the last one was left without the addition of filler material. In the first group of four specimens, a resorbable cross-linked bovine collagen membrane was placed over the skull and defects, without additional fixing. In the second group, a human fascia lata membrane was placed, without additional fixing. In the third group, a human chorioamniotic membrane was placed, without additional fixing. The animals were sacrificed at 4 and 8 weeks. The highest percentages of relative radiological density (average) were recorded considering the amnio-chorionic membranes (83.63%) followed by collagen (81.44%) and finally the fascia lata membranes (80.63%), but the differences were not statistically significant (p > 0.05). The sites grafted with a decellularized tooth (96.83%) and Bio-Oss (88.42%), recorded the highest percentages of radiological density but did not differ significantly from each other (subset 2). The three membranes used did not show statistical differences between them, in any of the two time periods used. There were statistical differences between the filling materials evidencing the presence of a large quantity of calcified material in the defects treated with particulate tooth and deproteinized bovine bone and while smaller amounts of calcified material were registered in the case of defects treated with human hydroxyapatite and those that were not treated.


[The planning of therapeutic trials in leukemias].
The planning of therapeutic trials in leukemias presents special problems due to the very variable spontaneous courses. The chronic forms are better accessible to an individual comparison. With the multitude of objective criteria relatively few difficulties arise if long enough periods of therapy are planned and performed. The criteria for the composition of homogeneous collectives as the basis for the much more difficult group comparison are discussed. In the absence of a subdivision into stages the duration of the past history can be used as a substitute criterion. Non-homogeneity in this regard leads to erroneous results, a practical example for which is given. Important is also the consideration of therapeutic and non-therapeutic contributory causes to be regarded already in the planning. The documentation of the findings should be made on special form sheets, a personal model of which is brought up for discussion. Finally the cooperation of several clinics in the therapeutic sector is discussed and the special problems of such a procedure outlined.


A review of NSAID complications: gastrointestinal and more.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed medications in the world. Their use is associated with significant morbidity, commonly including gastrointestinal, renal, and hepatic effects. Other less common effects include otic, central nervous system (CNS), ophthalmic, allergic, and dermatologic effects. Recognizing and diagnosing potential complications are imperative to obtain favorable outcomes in patients on NSAIDs. Among the NSAIDs currently on the market, there exists a wide variability of incidence of organ-specific side effects. Some of these side effects are class specific, but most are not. Much research also is being performed in the field of COX-2-specific inhibitory agents, which would theoretically reduce the gastrointestinal insult of these drugs. Patient awareness through education is crucial in decreasing morbidity and preventing the adverse effects of these drugs.


ATM-mediated PTEN phosphorylation promotes PTEN nuclear translocation and autophagy in response to DNA-damaging agents in cancer cells.
PTEN (phosphatase and tensin homolog), a tumor suppressor frequently mutated in human cancer, has various cytoplasmic and nuclear functions. PTEN translocates to the nucleus from the cytoplasm in response to oxidative stress. However, the mechanism and function of the translocation are not completely understood. In this study, topotecan (TPT), a topoisomerase I inhibitor, and cisplatin (CDDP) were employed to induce DNA damage. The results indicate that TPT or CDDP activates ATM (ATM serine/threonine kinase), which phosphorylates PTEN at serine 113 and further regulates PTEN nuclear translocation in A549 and HeLa cells. After nuclear translocation, PTEN induces autophagy, in association with the activation of the p-JUN-SESN2/AMPK pathway, in response to TPT. These results identify PTEN phosphorylation by ATM as essential for PTEN nuclear translocation and the subsequent induction of autophagy in response to DNA damage.


Clinical expression and morbidity of systemic lupus erythematosus during a post-diagnostic 5-year follow-up: a male:female comparison.
The aim of this study was to analyse the prevalence of the most relevant clinical features of the diagnosis of systemic lupus erythematosus (SLE) in a sample of male patients with lupus as well as the incidence of the main causes of morbidity in a 5-year period after the diagnosis. A further aim of this study was to investigate the impact of gender on expression and morbidity of SLE. Data were collected from the medical records of 59 male and 535 female patients with SLE who were diagnosed at the hospitals in the region of Thessaloniki. Several differences in the expression and morbidity of the disease were found in relation to the gender of the patient. Male patients had a higher prevalence of thromboses, nephropathy, strokes, gastrointestinal tract symptoms and antiphospholipid syndrome when compared with female patients, but tended to present less often with arthralgia, hair loss, Raynaud's phenomenon and photosensitivity as the initial clinical manifestations. During the 5-year follow-up, positive associations have been found between male gender and the incidence of tendonitis, myositis, nephropathy and infections, particularly of the respiratory tract. In conclusion, this study has provided information regarding the features of clinical expression and morbidity in male patients, and has shown that gender is a possible factor that can influence the clinical expression of SLE.


Digital amputation caused by climbing-rope entanglement.
Digital avulsions and amputations are not uncommon in outdoor activities. Rope entanglement is often the cause, though specific descriptions of the mechanism of injury have not been reported. We report a common scenario where entanglement during a fall resulted in an amputation injury. Although any roping activity may cause a loop formation leading to digital entrapment and subsequent amputation injury, activities involving soft and loose ropes may increase the chances of injury. Rope slack is to be avoided to minimize the likelihood of entanglement. This case report describes a digital amputation during an indoor climbing incident and also describes a possible mechanism for such injuries.


Structure of the transcription regulator CcpA from Lactococcus lactis.
Catabolite control protein A (CcpA) functions as master transcriptional regulator of carbon catabolism in Firmicutes. It belongs to the family of bacterial repressor/regulator proteins. Here, the crystal structure of the 76 kDa homodimeric CcpA protein from Lactococcus lactis subsp. lactis IL1403 is presented at 1.9 A resolution in the absence of cognate DNA. The phases were derived by molecular replacement and the structure was refined to crystallographic R and R(free) factors of 0.177 and 0.211, respectively. The presence of a sulfate molecule in the direct vicinity of a putative effector-binding site in the monomer allowed the derivation of a model for the possible binding of small organic effector molecules.


Synthesis of molybdenum complexes that contain "hybrid" triamidoamine ligands, [(hexaisopropylterphenyl-NCH2CH2)2NCH2CH2N-aryl]3-, and studies relevant to catalytic reduction of dinitrogen.
In the Buchwald-Hartwig reaction between HIPTBr (HIPT = 3,5-(2,4,6-i-Pr3C6H2)2C6H3 = hexaisopropylterphenyl) and (H2NCH2CH2)3N, it is possible to obtain a 65% isolated yield of (HIPTNHCH2CH2)2NCH2CH2NH2. A second coupling then can be carried out to yield a variety of "hybrid" ligands, (HIPTNHCH2CH2)2NCH2CH2NHAr, where Ar = 3,5-Me2C6H3, 3,5-(CF3)2C6H3, 3,5-(MeO)2C6H3, 3,5-Me2NC5H3, 3,5-Ph2NC5H3, 2,4,6-i-Pr3C6H2, or 2,4,6-Me3C6H2. The hybrid ligands may be attached to Mo to yield [hybrid]MoCl species. From the monochloride species, a variety of other species such as [hybrid]MoN, {[hybrid]MoN2}Na, and {[hybrid]Mo(NH3)}+ can be prepared. [Hybrid]MoN2 species were prepared through oxidation of {[hybrid]MoN2}Na species with ZnCl2, but they could not be isolated. [Hybrid]Mo=N-NH species could be observed as a consequence of the protonation of {[hybrid]MoN2}- species, but they too could not be isolated as a consequence of a facile decomposition to yield dihydrogen and [hybrid]MoN2 species. Attempts to reduce dinitrogen catalytically led to little or no ammonia being formed from dinitrogen. The fact that no ammonia was formed from dinitrogen in the case of Ar = 3,5-Me2C6H3, 3,5-(CF3)2C6H3, or 3,5-(MeO)2C6H3 could be attributed to a rapid decomposition of intermediate [hybrid]Mo=N-NH species in the catalytic reaction, a decomposition that was shown in separate studies to be accelerated dramatically by 2,6-lutidine, the conjugate base of the acid employed in the attempted catalytic reduction. X-ray structures of [(HIPTNHCH2CH2)2NCH2CH2N{3,5-(CF3)2C6H3}]MoCl and [(HIPTNHCH2CH2)2NCH2CH2N(3,5-Me2C6H3)]MoN2}Na(THF)2 are reported.


The Spectrum of Pulmonary Toxicity in Pancreatic Cancer Patients Receiving Gemcitabine Combination Chemotherapy.
Gemcitabine is widely utilized in the treatment of pancreatic, ovarian, and non small cell lung cancers. Gemcitabine is associated with a wide spectrum of lung toxicities, ranging from dyspnea 25% of patients to severe pulmonary toxicity in up to 5% of patients. There is a dearth of information specific to pulmonary toxicity in the setting of gemcitabine combination chemotherapy. Given the potential severity, it is important to identify it early by excluding more common etiologies. We share two case reports of patients with pancreatic cancer who developed severe pulmonary toxicity during gemcitabine combination chemotherapy. Both cases emphasize the heightened risk of pulmonary toxicity in patients receiving gemcitabine chemotherapy combinations, and a need to be vigilant to initiate appropriate therapies immediately.


The analysis of mortality from cardiovascular diseases in Pomeranian province.
Descriptive epidemiology characterises frequency of appearance of given event (here decease) in dependence of many factors concerning a person, region or time of existence of given salubrious phenomena. The source of information was the official death registry that provides complete records of all deaths that took place in Pomeranian province. This description of sanitary situation of people from particular area enables doing comparison between regions, facilitates researching etiological factors, planning work of medical workers and programming preventive rules. Cardiovascular diseases during last fifty years are the main reason of death of people from developed countries which is also Poland. The aim of this work is to find out differences in health condition between citizens of Pomeranian province and other people in Poland and countries of European Union. In Pomeranian province in 2002 the highest mortality from cardiovascular diseases was observed for Sztum county (587.5/100,000) and was 72.5% of all deaths in this region. Similarly, there was high mortality these reasons in Tczew county (442.1/100,000), Malbork county (406.9/ 100,000) and also in Tricity (424.8/100,000). The lowest mortality from cardiovascular diseases was observed in Gdańsk county (257.2/100,000) and was only 40% of all deaths in this region. Relatively low mortality was in Czluchow county (288.9/100,000). Frequency of death from cardiovascular diseases in Pomeranian province has become lower from year 2000 (361.0/100,000) to year 2002 (347.9/100,000). It was lower than in other parts of Poland (449.8/100,000 in year 2000) but higher than in countries of European Union (257.8/100,000 in year 2000). Mortality from cardiovascular diseases has decreased during last few years. Also there are distinctions in this phenomena among regions of Pomeranian province, other parts of Poland and countries of European Union. From these reasons health care should be differentiated to address the differences in spatial patterns of risk observed.


Fragile X premutation in a woman with cognitive impairment, tremor, and history of premature ovarian failure.
Few women with Fragile X tremor ataxia syndrome (FXTAS) have been reported. They have milder manifestations at a later age than men. This gender difference may be related to the X inactivation pattern in women. We describe a woman who presented to her geriatrician with poor memory and was found to have ataxia and tremor. Additional queries yielded history of premature ovarian failure. Genetic testing showed heterozygous fragile X mental retardation gene premutation with 103 CGG repeats in the abnormal allele and 31 CGG repeats in the normal allele. Also, the X inactivation pattern was skewed with the active X chromosome predominantly having the premutation allele. We believe that FXTAS is more common in women than is generally thought and that many such patients masquerade as dementia of old age. Action tremor and ataxia associated with a history suggestive of premature ovarian failure should raise suspicions for FXTAS.


Diversity of Ants and Termites of the Botanical Garden of the University of Lomé, Togo.
Ants and termites are used as bioindicators in many ecosystems. Little knowledge is available about them in Togo, especially ants. This study aimed to find out how ants and termites could be used to assess the restoration of former agricultural land. These insect groups were sampled within six transects of 50 × 2 m2 (using pitfall traps, monoliths, baits for ants and hand sampling for termites) in two consecutive habitats: open area (grassland) and covered area (an artificial forest). Seventeen termite species and 43 ant species were collected. Seven ant species were specific to the covered area against four for the open area, while four unshared species of termite were found in the open area against three in the covered area. The presence of unshared species was linked to vegetation, as Trinervitermes (Holmgren, 1912), a grass feeding termite, was solely found in open area. Also, for some ant species like Cataulacus traegaordhi (Santschi, 1914), Crematogaster (Lund, 1831) species, Oecophylla longinoda (Latreille, 1802) and Tetraponera mocquerysi (Brown, 1960), all arboreal species, vegetation was a determining factor for their presence. The occurrence of these species together with Basidentitermes mactus (Sjöstedt, 1911), Strumigenys bernardi (Brown, 1960) and S. sistrura (Bolton, 1983), suggest a more advanced level of restoration of the covered area.


Efficacy of mefloquine treatment and genetic profiles in uncomplicated Plasmodium falciparum malaria in southern Lao PDR.
We conducted a 28-day follow-up of 17 Laotian patients diagnosed with uncomplicated Plasmodium falciparum malaria treated with mefloquine (Mephaquine, MQ) alone to determine the efficacy. All patients were completely cured with MQ, without reappearance of asexual stage parasitemia at follow-up. Of the 7 isolates tested for genotypic analysis, one isolate was a Y86 mutant type of the pfmdr1 gene, the others were N86 wild. These findings suggest no MQ resistance in the study area possibly because the drug is rarely used in southern Lao PDR.


When cats' ways of life interact with their viruses: a study in 15 natural populations of owned and unowned cats (Felis silvestris catus).
In natural populations, virus circulation is influenced by host behavior and physiological characteristics. Cat populations exhibit a great variability in social and spatial structure, the existence of different ways of life within a same population may also result in different epidemiological patterns. To test this hypothesis, we used a logistic regression to analyze the risk factors of Feline immunodeficiency virus (FIV), feline herpes virus (FHV), feline calicivirus (FCV), and feline parvovirus (FPV) infection in owned (fed and sheltered) and unowned (neither fed nor sheltered, unsocialized) cats living in a rural environment in the North Eastern part of France. A serological survey was carried out in 492 non-vaccinated and non-sterilized individuals from 15 populations living in the same area. The prevalence of feline leukemia virus (FeLV) was also studied, but too few were infected to analyze the risk factors of this virus. For each virus, the epidemiological pattern was different in owned and unowned cats. Unowned cats were more frequently infected by directly transmitted viruses like FIV, FHV and FCV (21.22%, 67.66%, 86.52% in unowned cats vs 9.55%, 53.88%, 77.18% in owned cats, respectively), a difference that may be explained by a more solitary and more aggressive behavior in unowned adults, and/or possibly by a higher sensitivity related to a more stressful life. On the contrary, owned cats were more frequently infected with FPV (36.41% in owned cats vs 15.61% in unowned cats), possibly as a result of their concentration around human settlements. The present study showed that owned and unowned cats living in a same area have behavioral and physiological characteristics sufficiently different to influence virus circulation. Pooling different types of cats in a single sample without taking it into account could give a wrong picture of the epidemiology of their viruses. The conclusion of this work can be extended to any epidemiological studies led in wildlife species with flexible behavior as any variations in social or spatial structure, between or within populations, could result in different virus circulation.


Albumin in the mg/l-range activates NF-kappaB in renal proximal tubule-derived cell lines via tyrosine kinases and protein kinase C.
Albuminuria represents one of the most unfavourable diagnostic factors for the prognosis of nephropathies. We investigated albumin-induced NF-kappaB activation and the potential contribution of tyrosine kinase and protein kinase C. Therefore we exposed proximal tubule-derived human (IHKE-1), opossum (OK) and porcine (LLC-PK1) cell lines to serum albumin at concentrations of 10 - 500 mg/l. DNA-binding activity of NF-kappaB increased concentration-dependently in the presence of albumin. In OK and LLC-PK1 cells, NF-kappaB activity increased during the first 45 min and reached a plateau thereafter. In IHKE-1, cells NF-kappaB activity reached a plateau after 90 min with a maximum at 180 min exposure to albumin. The albumin-induced increase in NF-kappaB DNA-binding activity was inhibited by herbimycin A (tyrosine kinase inhibitor) and BIM (protein kinase C inhibitor). Reporter gene assays demonstrated that albumin stimulates NF-kappaB mediated reporter gene activation in LLC-PK1 cells, which was partially inhibited by herbimycin A and BIM. Our data indicate, that albumin exposure induces a rapid increase in NF-kappaB protein activity in renal proximal tubule cells of different species via a tyrosine kinase- and protein kinase C-dependent pathway, at concentrations occurring during mild glomerular injury.


Review of specialist dietitian services in patients with inherited metabolic disease in the United Kingdom.
Dietary management forms the mainstay of treatment for many inherited metabolic diseases (IMDs) and specialist dietitians play a crucial role in the multi-disciplinary core team for these patients. Professional concerns have been expressed that the current clinical workforce is inadequate for meeting current and future service demands. The aim of this work was to describe the provision of specialist dietetics to patients with IMD as part of a national needs assessment and review. The 24 main specialist providers and 27 specialist dietitians were surveyed by a questionnaire. A focus group of three specialist dietitians was also held to explore the roles of specialist dietitians in greater depth. Responses were received from all 24 specialist service providers and 63% of 27 specialist dietitians. The majority of service providers (92%) have specialist dietitians, but only eight services had more than one whole time equivalent (33%). Key roles were management of complex dietary regimens, prevention and management of metabolic crises, education, co-ordination of care, clinical audit and research. Although highly qualified, there is currently no clear formal career structure or training pathway for dietitians in IMDs. Specialist dietitians have important clinical and leadership roles in managing IMD but specialist services are thinly spread. There is a need for access to formal education, training and support programmes. The clinical workforce needs expansion to provide more comprehensive and equitable services.


Robust peak recognition in intracranial pressure signals.
The waveform morphology of intracranial pressure pulses (ICP) is an essential indicator for monitoring, and forecasting critical intracranial and cerebrovascular pathophysiological variations. While current ICP pulse analysis frameworks offer satisfying results on most of the pulses, we observed that the performance of several of them deteriorates significantly on abnormal, or simply more challenging pulses. This paper provides two contributions to this problem. First, it introduces MOCAIP++, a generic ICP pulse processing framework that generalizes MOCAIP (Morphological Clustering and Analysis of ICP Pulse). Its strength is to integrate several peak recognition methods to describe ICP morphology, and to exploit different ICP features to improve peak recognition. Second, it investigates the effect of incorporating, automatically identified, challenging pulses into the training set of peak recognition models. Experiments on a large dataset of ICP signals, as well as on a representative collection of sampled challenging ICP pulses, demonstrate that both contributions are complementary and significantly improve peak recognition performance in clinical conditions. The proposed framework allows to extract more reliable statistics about the ICP waveform morphology on challenging pulses to investigate the predictive power of these pulses on the condition of the patient.


HbMyb1, a Myb transcription factor from Hevea brasiliensis, suppresses stress induced cell death in transgenic tobacco.
Tapping panel dryness (TPD) is a complex physiological syndrome found widely in rubber tree (Hevea brasiliensis) plantations that causes severe yield loss in natural rubber-producing countries. In an earlier study, we confirmed that there is a negative correlation between HbMyb1 expression and TPD severity. To further investigate the function of HbMyb1 in TPD, HbMyb1 was over-expressed in tobacco controlled by a CaMV 35S promoter. In transgenic plants expressing HbMyb1, cell death induced by UV-B irradiation, paraquat and the hypersensitive reaction to necrotrophic fungal infection (Botrytis cinerea) was suppressed with a close correlation between HbMyb1 protein levels and the extent of suppression. In addition the nuclear condensation and degradation were observed in laticifer cells of TPD trees, while the nucleus of laticifer cells of healthy trees was morphologically normal. On the basis of the results described above, we propose that HbMyb1 maybe suppress stress induced cell death in rubber trees.


Visual Assessment of CT Findings in Smokers With Nonobstructed Spirometric Abnormalities in The COPDGene® Study.
Within the COPD Genetic Epidemiology (COPDGene®) study population of cigarette smokers, 9% were found to be unclassifiable by the Global Initiative for chronic Obstructive Lung Disease (GOLD) criteria. This study was to identify the differences in computed tomography (CT) findings between this nonobstructed (GOLDU) group and a control group of smokers with normal lung function. This research was approved by the institutional review board of each institution. CT images of 400 participants in the COPDGene® study (200 GOLDU, 200 smokers with normal lung function) were retrospectively evaluated in a blinded fashion. Visual CT assessment included lobar analysis of emphysema (type, extent), presence of paraseptal emphysema, airway wall thickening, expiratory air trapping, centrilobular nodules, atelectasis, non-fibrotic and fibrotic interstitial lung disease (ILD), pleural thickening, diaphragmatic eventration, vertebral body changes and internal thoracic diameters (in mm). Univariate comparisons of groups for each CT parameter and multiple logistic regression were performed to determine the imaging features associated with GOLDU. When compared with the control group, GOLDU participants had a significantly higher prevalence of unilateral diaphragm eventration (30% vs. 16%), airway wall thickening, centrilobular nodules, reticular abnormality, paraseptal emphysema (33% vs. 17%), linear atelectasis (60% vs. 35.6%), kyphosis (12% vs. 4%), and a smaller internal transverse thoracic diameter (255 ± 22.5 [standard deviation] vs. 264.8 ± 22.4, mm) (all p<0.05). With multiple logistic regression, all of these CT parameters, except non-fibrotic ILD and kyphosis, remained significantly associated with GOLDU status (p<0.05). In cigarette smokers, chest wall abnormalities and parenchymal lung disease, which contribute to restrictive physiologic impairment, are associated with GOLD-nonobstructed status.


Comparison of four diagnostic tests for the identification of serum antibodies in small ruminants infected with Mycoplasma agalactiae.
To determine the diagnostic capability of a newly developed Western blot (WB) assay for the detection of serum antibodies against Mycoplasma agalactiae compared with conventional serological tests, and to identify the best test for routine diagnostic use. The serological test methods used were: two commercial indirect enzyme-linked immunosorbent assays (ELISA), viz ELISA-1, using a bacterial antigen preparation, and ELISA-2, using a recombinant protein (lipoprotein p48) antigen; the complement fixation test (CFT); and a newly developed WB assay, the latter both using a bacterial antigen preparation. Thirty sera from goats infected with M. agalactiae and 97 sera from non-infected sheep were tested using all four methods. Staining patterns in the WB were quite variable. An immuno-dominant band of 41 kDa was detected in 63% of sera from infected animals. The same band also appeared, although mostly very weakly, in 10% of sera from non-infected animals. When suspicious or very weak reactors were omitted, the diagnostic sensitivity (DSE) and diagnostic specificity (DSP), respectively, for the four assays were: WB=56.7%, 97.9%; ELISA-1=76.7%, 99.0%; ELISA-2=56.7%, 100%; and CFT=40.0%, 94.8%. ELISA-1 performed best in this comparison. While the WB can be used, it did not have a technical advantage over the ELISA. The CFT should be discouraged as the primary screening method for contagious agalactia and should be replaced by ELISA-1. Results from this study confirm that serological test methods for contagious agalactia are useful for the detection of infected flocks but will not detect every individual infected animal.


Epidemiology, costs, and the economic burden of fibromyalgia.
The assumption that fibromyalgia is associated with a major impact on the utilization of both healthcare and nonhealthcare resources has not been thoroughly supported by evidence-based data. Despite the differences between healthcare and sociopolitical systems in various countries, more recent results from epidemiological research now clearly demonstrate the socioeconomic burden of fibromyalgia and its comorbidities. The costs of the disease, calculated in single studies and countries, allow estimates for populations in other countries. The alarming results highlight the urgent need both for more research (including pathophysiology and epidemiology) and for the acceptance of emerging treatment challenges.


[The glioneuronal interrelations in the nervous system of the crayfish].
The glio-neuronal interrelations in the nerves, connective and ganglia were studied in the crayfish Astacus leptodactylus as a representative of invertebrates. The outer membranes of the ganglia, connectives and nerves are formed by specialized cells with morphological features of the loose connective tissue cells. In the ganglia between the outer membrane and the neuropile there is another type of the connective tissue cells--Leydig's 1st type cells. The sheaths of axon bundles in the connectives and neuropile are formed by the bodies and processes of glial cells. Their processes also cover solitary axons. The neuron bodies are surrounded by glial cells forming trophospongium. Axons of greater diameter are surrounded by a greater amount of glial layers. Specific features of the structure of myelin-like neurite sheaths were found. The ratio of the length of the membrane of gliocytes covering the neurite to the length of the neurite circle on sections of motor fibers of the nerve is 1:15.7; of sensory fibers of the nerve--1:2.1; of connective neurites--1:1.9; of axons inside the ganglion--1:0.4; in the neuropile--1:0.01.


Facial and Nasolabial Aesthetics of Complete UCLP Submitted to 2-Stage Palate Repair With Vomer Flap.
To evaluate the aesthetics of nasolabial appearance and facial profile of children with unilateral cleft lip and palate (UCLP) submitted to 2-stage palate repair with vomerine flap. Retrospective. Single center. Forty patients with UCLP, mean age of 7.81 years of both sexes, rehabilitated at a single center by 1 plastic surgeon. Lip and anterior palate repair with nasal alar repositioning was performed at 3 to 6 months of age by Millard technique and vomer flap, respectively. Posterior palate was repaired at 18 months by Von Langenbeck technique. Four cropped digital facial photographs of each patient were evaluated by 3 orthodontists to score the nasolabial aesthetics and profile. Frequencies of each score as well means and medians were calculated. Kappa test was used for evaluating inter- and intrarater reproducibility. The nasal form and deviation was scored as good/very good in 70%, fair in 22.5%, and poor in 7.5% of the sample. The nasal-subnasal aesthetic was considered good/very good in 55%, fair in 30%, and poor in 15% of the sample. The lip vermilion border and the white part of surgical scar aesthetics were good/very good in 77.5% and 80%, fair in 17.5% for both categories, and poor in 5% and 2.5% of the cases, respectively. In all, 67.5% showed convex facial profile, 20% was straight, and 12.5% was concave profile. Two-stage palatoplasty presented an adequate aesthetical results for the majority of patients with UCLP in the mixed dentition.


Psychodynamic Psychotherapy Process Research: A quick ride through what you should know about process (research).
This paper gives an overview of psychoanalytic process research, which brings to light the complexity of psychotherapy sessions. This complexity is so rich that many instruments intended to make the process measurable failed in the past because they initially used a strategy of complexity reduction. This method however did not help to further our understanding of the complexity involved. Three former presidents of the Society for Psychotherapy Research (Stiles, Hill, Elliot 2015) decided to solve the following equivalence paradox: many therapies work successfully though they all follow different theories, produce a heterogeneity of processes and often enough a misfit between what theories maintain to be a good process and their realization in the treatment room. As theories are often compared to maps, a driver would wonder which route to take. But therapists-as-drivers go undaunted - and nevertheless achieve their goals together with their patients. Norcross and Wampold (2018) found that good therapists invent new therapies with every new patient. They hypothesize that it is because of conversation. This is in accord with the 3 former presidents' proposal to return to detailed single case analyses including the micro-analytic power of conversation analysis of which a few insights are outlined in this article.


1.7 µm figure-9 Tm-doped ultrafast fiber laser.
The evolution of multiphoton microscopy is critically dependent on the development of ultrafast laser technologies. The ultrashort pulse laser source at 1.7 µm waveband is attractive for in-depth three-photon imaging owing to the reduced scattering and absorption effects in biological tissues. Herein, we report on a 1.7 µm passively mode-locked figure-9 Tm-doped fiber laser. The nonreciprocal phase shifter that consists of two quarter-wave plates and a Faraday rotator introduces phase bias between the counter-propagating beams in the nonlinear amplifying loop mirror. The cavity dispersion is compensated to be slightly positive, enabling the proposed 1.7 µm ultrafast fiber laser to deliver the dissipative soliton with a 3-dB bandwidth of 20 nm. Moreover, the mode-locked spectral bandwidth could be flexibly tuned with different phase biases by rotating the wave plates. The demonstration of figure-9 Tm-doped ultrafast fiber laser would pave the way to develop the robust 1.7 µm ultrashort pulse laser sources, which could find important application for three-photon deep-tissue imaging.


Interactions between gemini surfactant alkanediyl-alpha,omega-bis(dodecyldimethylammonium bromide) and polyelectrolyte NaPAA.
Interactions between cationic gemini surfactant alkanediyl-alpha,omega-bis(dodecyldimethylammonium bromide) (12-n-12, n=3,4,6) and oppositely charged polyelectrolyte sodium polyacrylate (NaPAA) in aqueous solution have been investigated by measuring fluorescence, conductivity, UV-vis transmittance, dynamic lighting scattering, and transmission electron microscopy. Micelle-like structure and 12-n-12/NaPAA complex are observed to form due to the electrostatic and hydrophobic interactions, and the effective diameter of the complex reduces with increasing 12-n-12 concentration. The microstructures of 12-n-12/NaPAA solution determined from fluorescence and electron microscopy measurements are in good agreement. The spacer length is found to play an important role in the interactions of 12-n-12 with NaPAA.


Freedom to speak up - the role of freedom to speak up guardians and the National Guardian's Office in England.
Following the events at Mid Staffordshire NHS Foundation Trust, Sir Robert Francis was commissioned to undertake a public inquiry. During this process, from speaking to NHS workers and from the evidence submitted to the inquiry, he found that staff had tried to speak up about their concerns, but that they had been ignored, or victimised as a result. This experience was not confined to Mid Staffordshire and a further report, Freedom to speak up, was commissioned. Freedom to speak up made two recommendations, which were accepted by all NHS organisations and the Department of Health. The report included principles and actions about the culture and practice in the NHS, the appointment of freedom to speak up guardians in NHS trusts and foundation trusts and a national guardian to lead this network, undertake case reviews and provide support and challenge to the system. In this article, I will describe the work of freedom to speak up guardians and the National Guardian's Office, the impact of these on workers in NHS trusts and other organisations, and the next steps in the journey to make speaking up business as usual.


The effect of sleep-disordered breathing on stages of sleep in patients with Alzheimer's disease.
Patients with Alzheimer's disease (AD) commonly have poor sleep and a high reported incidence of sleep-disordered breathing (SDB). This study examined how the presence of SDB affected sleep stages in AD patients. Sixty-six volunteers with mild - moderate AD underwent home polysomnography. Results showed that patients with SDB spent less of the night in REM sleep than those with no SDB, but there were no differences in other sleep stages. The findings suggest that the decreased amount of REM sleep may be due to the presence of AD and SDB. Treating these patients' SDB may increase their amount of REM sleep, which may result in improved daytime functioning. Controlled trials of SDB treatment in AD are needed to answer this question.


Intracranial pressure monitoring in Reye's syndrome.
The neurologic damage caused by rapidly rising intracranial pressure can be halted or reversed only if specific therapy is instituted early. The key to such successful management is continuous monitoring by either subarachnoid bolt or ventricular cannula. Indications and techniques for monitoring are outlined, as is a ventricular cannula. Indications and techniques for monitoring are outlined, as is a step-by-step approach to management of intracranial hypertension as it develops.


Using the healthcare matrix with interns and medical students as a tool to effect change.
The Healthcare Matrix is a tool developed at Vanderbilt University Medical Center which assesses the care of patients using the Accreditation Council for Graduate Medical Education (ACGME) competencies and the Institute of Medicine (IOM) Aims for Improvement. House staff have been using this tool since 2004 as a means of learning the competencies in the daily care of patients. As the residents fill in the cells of the Matrix, the opportunities for improvement become evident. Anesthesia interns were introduced to the Matrix at bimonthly meetings to analyze a real case of complex and/or flawed patient management. Each resident completed his/her own Matrix and then the group selected one Matrix as their improvement project. This article will present one Matrix case, how quality improvement (QI) tools and methods were utilized and what resulting improvements were made. The analyzed case revealed numerous flaws with nonstandardized handoffs, incorrect and insufficient documentation, and unclear roles/responsibilities. An ideal process flowchart was developed highlighting improved handoffs and the need for a new admitting policy to the intensive care unit (ICU). The Healthcare Matrix is an effective tool for teaching the ACGME competencies in patient care. The resequencing of the competencies in the Matrix makes it easy to identify where improvements are needed. When taught the tools and methods of quality improvement, even interns can make a significant contribution to the improvement of patient care.


Plasmonic vesicles of amphiphilic gold nanocrystals: self-assembly and external-stimuli-triggered destruction.
We have developed a new class of plasmonic vesicular nanostructures assembled from amphiphilic gold nanocrystals with mixed polymer brush coatings. One major finding is that the integration of gold nanocrystals (nanoparticles and nanorods) with two types of chemically distinct polymer grafts, which are analogous to block copolymers as a whole, creates a new type of hybrid building block inheriting the amphiphilicity-driven self-assembly of block copolymers to form vesicular structures and the plasmonic properties of the nanocrystals. In contrast to other vesicular structures, the disruption of the plasmonic vesicles can be triggered by stimulus mechanisms inherent to either the polymer or the nanocrystal. Recent advances in nanocrystal synthesis and controlled surface-initiated polymerization have opened a wealth of possibilities for expanding this concept to other types of nanocrystals and integrating different types of nanocrystals into multifunctional vesicles. The development of multifunctional vesicles containing stimuli-responsive polymers could enable their broader applications in biosensing, multimodality imaging, and theragnostic nanomedicine.


Selective Preliminary Incubation for Gram-Negative Psychrotrophic Bacteria in Milk.
Milk samples containing crystal violet, benzalkonium chloride, crystal violet: benzalkonium chloride, or alkylaryl sulfonate were inoculated with each of Pseudomonas fluorescens , Pseudomonas fragi , Pseudomonas putida , Pseudomonas aeruginosa , Escherichia coli , Bacillus cereus , Staphylococcus aureus , and Streptococcus sp. Samples were incubated at 21°C for 18 h, and growth of the bacteria monitored to evaluate the inhibitory effects of the added reagents. Benzalkonium chloride proved to be the preferred inhibitor for selective incubation. It inhibited growth of Bacillus cereus , Staphylococcus aureus , and Streptococcus sp. at initial cell concentrations of 101, 102, and 104 per ml, while allowing uninhibited growth of all Pseudomonas species tested with an average increase of 3 logs. This finding is most important for the selective preliminary incubation necessary prior to milk quality assessment by plating and rapid instrumentation methods.


[Cutaneous side-effects in drug assessment].
Drug-induced cutaneous side-effects are very frequent. All dermatitis may be induced by drugs. It is difficult to identify the drug responsible because patients take many drugs (prescriptions, self medication). For each pathology, physicians may use assessment methods based on specific chronological criteria (challenge, dechallenge, rechallenge) and specific semeiological criteria (promoting factors, alternate non-drug related explications, specific laboratory tests) to identify the drug responsible.


Validation of the antifactor Xa and antifactor IIa assays for the potency assessment of nadroparin in pharmaceutical formulations.
The low-molecular weight heparin nadroparin calcium is used clinically for the prevention and treatment of venous and arterial thrombosis. The antifactor Xa and antifactor IIa assays were validated by investigating the parameters of range, linearity (r2 = 0.9905 and r2 = 0.9914, respectively) precision, accuracy, and robustness. The 2 methods incorporated a chromogenic endpoint and detection at 405 nm, yielding good results with detection limits of 0.004 and 0.01 IU/mL and quantitation limits of 0.01 and 0.03 IU/mL, respectively, for the antifactor Xa and antifactor IIa assays. Nadroparin calcium pharmaceutical products were evaluated by the antifactor Xa assay and the antifactor IIa assay, giving potencies between 93.86 and 109.88%, with an antifactor Xa/antifactor IIa ratio between 3.2 and 3.7. The results demonstrated the validity of the assays that are useful methodologies for the routine quality control of nadroparin in pharmaceutical formulations.


Colony-stimulating factor 1 expression is down-regulated during the adipocyte differentiation of H-1/A marrow stromal cells and induced by cachectin/tumor necrosis factor.
We isolated clonal sublines of the established mouse marrow stromal cell line, H-1. These clonal sublines underwent differentiation into adipocytes in various degrees. One subline, H-1/A, underwent adipocyte differentiation after confluence, while another subline, H-1/D, did not differentiate. In H-1/A cells, the 4.5- and 2.5-kb major mRNA species of colony-stimulating factor 1 (CSF-1) were expressed before differentiation and were down-regulated at a posttranscriptional level during the differentiation of H-1/A cells. The down-regulation of the CSF-1 gene was not a result of arrested cellular growth, because no down-regulation was detected in the nondifferentiating sister line, H-1/D. This down-regulation appeared to be an early event in differentiation. Cachectin/tumor necrosis factor transiently induced the expression of CSF-1 and inhibited the differentiation of H-1/A cells into adipocytes. This induced expression of CSF-1 was due to an increased rate of transcription.


Subclinical peritubular capillaritis in serial graft biopsies in cadaveric kidney transplant recipient with pre-transplant anti-HLA antibodies.
National Fukuoka-Higashi Medical Center, Koga, Japan A 63-yr-old Japanese woman on 18-yr hemodialysis (HD) program underwent cadaveric kidney transplantation from non-heart beating donor. Pre-transplant lymphocytotoxicity test was negative, but flow cytometric cross-match and flow-cytometric panel reactive antibody (PRA) screening tests were positive. Flow-PRA single-antigen test revealed several anti-HLA antibodies including donor-specific antibody (DSA). She was treated with plasma exchange (PEX) and rituximab to prevent antibody-mediated rejection (AMR). Urinary output increased from post-operative day (POD) 5 and HD was discontinued from POD8. Graft biopsy performed on POD11 showed severe peritubular capillaritis (PTCitis), numerous polymorphonuclear neutrophils (PMNs), and moderate glomerulitis. Although C4d immunostaining on PTC was negative, the case was diagnosed as subclinical AMR based on the presence of pre-transplant DSA and PTCitis with predominant PMNs. The patient was treated with additional PEX and rituximab, which increased urinary output and reduced serum creatinine (sCr). Graft biopsy repeated on POD39 showed persistent severe PTCitis, moderate interstitial infiltration, and mild tubulitis. C4d on PTC was negative again. The patient was discharged from the hospital on POD40. During the seven months follow-up at the outpatient clinic, the sCr level has shown a slight increase. In this case, the patient had DSA, which can be detected only by flow-PRA. In both graft biopsies, C4d on PTC was negative despite the presence of severe PTCitis, and thus the diagnosis of AMR could not be established. However, the significance of subclinical PTCitis is reported perhaps as an early marker for chronic AMR and to emphasize the importance of close follow-up.


Two-stage design of sequencing studies for testing association with rare variants.
Multiple rare variants have been suggested as accounting for some of the associations with common single nucleotide polymorphisms identified in genome-wide association studies or possibly some of the as yet undiscovered heritability. We consider the power of various approaches to designing substudies aimed at using next-generation sequencing technologies to discover novel variants and to select some subsets that are possibly causal for genotyping in the original case-control study and testing for association using various weighted sum indices. We find that the selection of variants based on the statistical significance of the case-control difference in the subsample yields good power for testing rare variant indices in the main study, and that multivariate models including both the summary index of rare variants and the associated common single nucleotide polymorphisms can distinguish which is the causal factor. By simulation, we explore the effects of varying the size of the discovery subsample, choice of index, and true causal model.


The effect of a graphical interpretation of a statistic trend indicator (Trigg's Tracking Variable) on the detection of simulated changes.
Anaesthesia involves processing large amounts of information over time. One task of the anaesthetist is to detect substantive changes in physiological variables promptly and reliably. It has been previously demonstrated that a graphical trend display of historical data leads to more rapid detection of such changes. We examined the effect of a graphical indication of the magnitude of Trigg's Tracking Variable, a simple statistically based trend detection algorithm, on the accuracy and latency of the detection of changes in a micro-simulation. Ten anaesthetists each viewed 20 simulations with four variables displayed as the current value with a simple graphical trend display. Values for these variables were generated by a computer model, and updated every second; after a period of stability a change occurred to a new random value at least 10 units from baseline. In 50% of the simulations an indication of the rate of change was given by a five level graphical representation of the value of Trigg's Tracking Variable. Participants were asked to indicate when they thought a change was occurring. Changes were detected 10.9% faster with the trend indicator present (mean 13.1 [SD 3.1] cycles vs 14.6 [SD 3.4] cycles, 95% confidence interval 0.4 to 2.5 cycles, P = 0.013. There was no difference in accuracy of detection (median with trend detection 97% [interquartile range 95 to 100%], without trend detection 100% [98 to 100%]), P = 0.8. We conclude that simple statistical trend detection may speed detection of changes during routine anaesthesia, even when a graphical trend display is present.


[A special form of epileptic signs in childhood (author's transl)].
It is known that some children produce parietal spikes, evoked by tactile stimulation to their feet or other parts of their bodies. This paper investigates whether this curious phenomenon remains with the children unchanged for several years and then disappears or whether it has an evolution towards epilepsy. It has been found that 36% of the subjects, who showed a normal EEG in the first examination, developed a spontaneous focus of spikes during their sleep or waking period; during a period of up to 3 years 16% of the children present a clinical state represented by seizures. In conclusion, it is felt that the cause of this condition may be due to hyperexcitability of a small cortical parietal area.


Interleukin 6 (rs1800795) gene polymorphism is associated with cardiovascular diseases: a meta-analysis of 74 studies with 86,229 subjects.
Cardiovascular diseases (CVD) are group of complex and multifactorial pathologies, in which interleukin-6 (IL-6) gene polymorphisms have been associated with several components of the CVD. Thus, in this study, we thoroughly reviewed and meta-analyzed evidence on the association between the IL-6 (rs1800795) gene polymorphism and CVD. We systematically searched in the PubMed, Web of Sciences, and Scopus databases. The analyses were performed using five study groups based on (1) a combined pool of the overall populations, (2) the country of birth, (3) the continent of birth, (4) the diagnosis and (5) both location (country or continent) and diagnosis. The analysis included the allelic, homozygote, heterozygote, dominant and recessive models. The meta-analysis showed that -174G>C (rs1800795) is a risk factor for CVD (allelic: OR=1.06, CI 95%=1.02-1.10. Z p value <0.0001; homozygous: OR=1.11, CI 95%=1.03-1.19, Z p value= 0.002; heterozygous: OR=1.08, CI 95%=1.03-1.21, Z p value= 0.003; dominant: OR= 1.12, CI 95%= 1.07-1.18, Z p value= 0.001) and that this risk increases in the Chinese population. Additionally, we found that carriers of the C allele of 174G>C (rs1800795) polymorphism have an increase in the risk of coronary artery disease under the hereditary models assessed in the study. Using robust data, we found that IL-6 (rs1800795) -174G>C gene polymorphism is associated with CVD risk.


CCR3 deficiency is associated with increased osteoclast activity and reduced cortical bone volume in adult male mice.
Increasing evidence emphasizes the importance of chemokines and chemokine receptors as regulators of bone remodeling. The C-C chemokine receptor 3 (CCR3) is dramatically upregulated during osteoclastogenesis, but the role of CCR3 in osteoclast formation and bone remodeling in adult mice is unknown. Herein, we used bone marrow macrophages derived from adult male CCR3-proficient and CCR3-deficient mice to study the role of CCR3 in osteoclast formation and activity. CCR3 deficiency was associated with formation of giant hypernucleated osteoclasts, enhanced bone resorption when cultured on bone slices, and altered mRNA expression of related chemokine receptors and ligands. In addition, primary mouse calvarial osteoblasts isolated from CCR3-deficient mice showed increased mRNA expression of the osteoclast activator-related gene, receptor activator of nuclear factor kappa-B ligand, and osteoblast differentiation-associated genes. Microcomputed tomography analyses of femurs from CCR3-deficient mice revealed a bone phenotype that entailed less cortical thickness and volume. Consistent with our in vitro studies, the total number of osteoclasts did not differ between the genotypes in vivo. Moreover, an increased endocortical osteoid mineralization rate and higher trabecular and cortical bone formation rate was displayed in CCR3-deficient mice. Collectively, our data show that CCR3 deficiency influences osteoblast and osteoclast differentiation and that it is associated with thinner cortical bone in adult male mice.


Long-term outcomes in patients with acute pulmonary embolism after in-hospital treatment: study protocol of the prospective Lungenembolie Augsburg Studie (LEA study).
Acute pulmonary embolism (PE) is a frequent life-threatening event and an important cause of hospitalisation, morbidity and mortality worldwide. Limited information on the long-term course of PE patients is available so far. The Lungenembolie Augsburg study will provide a view on the predisposing and PE-provoking factors, diagnostic procedures and short as well as long-term treatment options. Especially, the data on the long-term course of the disease-in combination with omics data obtained in biospecimens-will generate new knowledge regarding triggers, disease progression, treatment, long-term sequelae, prognosis and prevention of disease recurrence. In this prospective study, we will include about 1000 patients admitted to the university hospital of Augsburg, aged 18 years and older with a confirmed diagnosis of acute PE. At baseline, demographic information, symptoms on presentation, delay in diagnosis, predisposing and PE-provoking factors, comorbidity, quality of life, symptoms of anxiety and depression, information on invasive and non-invasive treatment procedures, complications and laboratory parameters will be collected. During the hospital stay, 30 mL blood will be collected from the patients, processed, aliquoted and frozen at -80°C. In a subgroup of patients, an eight-channel polygraphy will be carried out to assess sleep-disordered breathing. All study participants will be followed up for 60 months via postal questionnaires or telephone interviews after hospital discharge. Long-term survival, bleeding complications and PE recurrence during the follow-up are the primary study outcomes. To identify risk factors and determinants associated with these outcomes, confounder-adjusted Cox-regressions will be used for modelling and to estimate relative risks. Effect modification by age and sex will be examined. The study protocol was approved by the Ethics Committee of the Ludwig-Maximilians-Universität München (Date of approval: 1 August 2017, Reference number: 17-378). Study results will be presented at national and international conferences and published in peer-reviewed scientific journals.


Matrix metalloproteinase-9 is associated with acute inflammation after olfactory injury.
We previously reported an increase in matrix metalloproteinase-9 (MMP-9) levels in the olfactory bulb immediately after nerve transection; however, its role remains unknown. In this study, we determined the source of MMP-9 by monitoring the infiltration of inflammatory leukocytes in the olfactory bulb after nerve transection. We used myeloperoxidase to identify neutrophils and CD68 to identify macrophages at days 1, 7, and 10. MMP-9 colocalized with neutrophils at all three time points but was not contained in macrophages. This is the first study to demonstrate that MMP-9 is associated with early inflammatory response after olfactory injury, and provides insight into mechanisms underlying olfactory injury and recovery processes.


Bithalamic Infarction (Artery of Percheron Occlusion) after Anterior Cervical Discectomy and Fusion.
Bithalamic infarction resulting from occlusion of the artery of Percheron after cervical spine surgery is a rare pathological entity. Diagnosis and early detection are challenging. Prompt management may help to improve the outcome. We present a case of a 39-year-old male patient, smoker, diagnosed with multiple cervical disc herniations, who underwent Anterior Cervical Discectomy and Fusion (ACDF) for C3-C4, C4-C5, and C5-C6. During the 2-hour and 50-minute surgery, the patient was lying supine with his neck hyperextended. The intraoperative procedure was uneventful. During surgery, blood pressure ranged around 110 mmHg∖50 mmHg. At the end of surgery, the patient's recovery from general anesthesia was normal with no delaying or complication; on next the day, patient developed a sudden loss of consciousness. Urgent brain computed tomography (CT) was normal; two days later, follow-up CT and CT Angiography (CTA) revealed bilateral thalamic infarction with right vertebral artery occlusion from its origin. Intraoperative surgical manipulation, hypotensive anesthesia, and prolonged neck hyperextension might have contributed to stroke in this patient. ACDF carries a potential risk for posterior circulation stroke. Artery of Percheron infarction should be considered in the differential diagnosis of patients developing a sudden loss of consciousness after ACDF. Vertebral artery thrombosis should be taken into account as an important possible cause of embolism.


Exposure to the immunosuppressant, perfluorooctanoic acid, enhances the murine IgE and airway hyperreactivity response to ovalbumin.
These studies were conducted to investigate the role of dermal exposure to perfluorooctanoic acid (PFOA), a known immunosuppressant, on the hypersensitivity response to ovalbumin (OVA) in a murine model of asthma. PFOA has had widespread use as a carpet and fabric protectant. BALB/c mice were exposed dermally, on the dorsal surface of each ear, to concentrations of PFOA ranging from 0.01 to 1.5% (applied dose 0.25-50 mg/kg) for 4 days. In hypersensitivity studies, mice were also ip injected with 7.5 microg OVA and 2 mg alum on days 1 and 10 and in some studies challenged with 250 microg OVA by pharyngeal aspiration on days 17 and 26. Following exposure to PFOA, an increase in liver weights and a decrease in thymus and spleen weights and cellularities were observed. Similar immunomodulatory trends were demonstrated in mice coadministered PFOA and OVA. Compared to the OVA alone-exposed animals, an increase in total IgE was demonstrated when mice were coexposed to OVA and concentrations of PFOA ranging from 0.75 to 1.5%, while the OVA-specific IgE response peaked with 0.75% PFOA coexposure (p < or = 0.05). OVA-specific airway hyperreactivity was increased in the 1.0% PFOA coexposed group (p < or = 0.05), with an increased pleiotropic cell response characterized by eosinophilia and mucin production, in animals coexposed to concentrations of PFOA up to 1.0%, as compared to the OVA alone-exposed animals. In a murine model, PFOA was demonstrated to be immunotoxic following dermal exposure, with an enhancement of the hypersensitivity response to OVA, suggesting that PFOA exposure may augment the IgE response to environmental allergens.


Acute septic arthritis caused by Neisseria meningitidis serogroup W-135.
Neisseria meningitidis, serogroup W-135 was isolated from blood cultures of a 22-month-old child with acute septic arthritis of the left knee. Recovery was complete after treatment with penicillin G. Acute septic arthritis may be the initial presentation of disease caused by Neisseria meningitidis serogroup W-135.


An application of the patient rule-induction method for evaluating the contribution of the Apolipoprotein E and Lipoprotein Lipase genes to predicting ischemic heart disease.
Different combinations of genetic and environmental risk factors are known to contribute to the complex etiology of ischemic heart disease (IHD) in different subsets of individuals. We employed the Patient Rule-Induction Method (PRIM) to select the combination of risk factors and risk factor values that identified each of 16 mutually exclusive partitions of individuals having significantly different levels of risk of IHD. PRIM balances two competing objectives: (1) finding partitions where the risk of IHD is high and (2) maximizing the number of IHD cases explained by the partitions. A sequential PRIM analysis was applied to data on the incidence of IHD collected over 8 years for a sample of 5,455 unrelated individuals from the Copenhagen City Heart Study (CCHS) to assess the added value of variation in two candidate susceptibility genes beyond the traditional, lipid and body mass index risk factors for IHD. An independent sample of 362 unrelated individuals also from the city of Copenhagen was used to test the model obtained for each of the hypothesized partitions.


Global health, national development, and the role of government.
In spite of extreme differences in health status between the more developed and less developed countries, trends of infant mortality and life expectancy show substantial improvements in both types of country between 1950 and 1980. These improvements may be attributed to three types of change: 1) socio-economic development with decolonization, increased industrialization, growth of gross domestic product, urbanization, the gains of women, and enhanced education; 2) cross-national influences due to greater international trade, the spread of technology, and widespread affirmation of human rights; and 3) national health system development through expanded governmental health programs. Further improvements will depend on greater strength in public sector health services rather than private sector services which aggravate inequities.


Parent of origin differences in psychosocial burden and approach to BRCA risk management.
We conducted a mixed-method study to examine coping response in BRCA+ women based on parent of origin (maternally vs paternally inherited BRCA mutation). Quantitative findings (n = 408) revealed paternally inherited cases had genetic testing later and were more likely to have a cancer diagnosis. Having a maternally inherited mutation was the strongest predictor of proactive risk management response. Qualitative interviews (n = 56) identified proactive responses among maternally inherited cases compared to reactive responses in paternally inherited cases. Findings underscore the importance of unbiased pedigree analysis to determine cancer risk. Women with paternally inherited BRCA mutations may benefit from additional psychosocial support.


Single-Nucleotide Polymorphisms Reveal Spatial Diversity Among Clones of Yersinia pestis During Plague Outbreaks in Colorado and the Western United States.
In western North America, plague epizootics caused by Yersinia pestis appear to sweep across landscapes, primarily infecting and killing rodents, especially ground squirrels and prairie dogs. During these epizootics, the risk of Y. pestis transmission to humans is highest. While empirical models that include climatic conditions and densities of rodent hosts and fleas can predict when epizootics are triggered, bacterial transmission patterns across landscapes, and the scale at which Y. pestis is maintained in nature during inter-epizootic periods, are poorly defined. Elucidating the spatial extent of Y. pestis clones during epizootics can determine whether bacteria are propagated across landscapes or arise independently from local inter-epizootic maintenance reservoirs. We used DNA microarray technology to identify single-nucleotide polymorphisms (SNPs) in 34 Y. pestis isolates collected in the western United States from 1980 to 2006, 21 of which were collected during plague epizootics in Colorado. Phylogenetic comparisons were used to elucidate the hypothesized spread of Y. pestis between the mountainous Front Range and the eastern plains of northern Colorado during epizootics. Isolates collected from across the western United States were included for regional comparisons. By identifying SNPs that mark individual clones, our results strongly suggest that Y. pestis is maintained locally and that widespread epizootic activity is caused by multiple clones arising independently at small geographic scales. This is in contrast to propagation of individual clones being transported widely across landscapes. Regionally, our data are consistent with the notion that Y. pestis diversifies at relatively local scales following long-range translocation events. We recommend that surveillance and prediction by public health and wildlife management professionals focus more on models of local or regional weather patterns and ecological factors that may increase risk of widespread epizootics, rather than predicting or attempting to explain epizootics on the basis of movement of host species that may transport plague.


Regulatory properties of acetylcholine receptor: evidence for two different inhibitory sites, one for acetylcholine and the other for a noncompetitive inhibitor of receptor function (procaine).
Does the acetylcholine receptor have a specific regulatory (inhibitory) site for the natural receptor ligand acetylcholine? This paper deals with this question. The inhibition of acetylcholine-receptor function by diverse organic cations including local anesthetics such as procaine has been well documented. Evidence indicates that these compounds are noncompetitive inhibitors, enter the open-channel form of the receptor, and block it and that the extent of this blockage depends on the transmembrane voltage of the cell. Recently we reported that in the electroplax of Electrophorus electricus the receptor-controlled transmembrane ion flux is inhibited by acetylcholine in a voltage-dependent, noncompetitive manner. We report here that the Torpedo californica receptor also has an inhibitory site for acetylcholine. The question of whether acetylcholine, which is an organic cation, binds to the same site as other organic cations such as the noncompetitive inhibitor procaine is important and is addressed. The results reported here of chemical kinetic investigations, with receptor-rich E. electricus and T. californica membrane vesicles, indicate that the inhibition of receptor function by acetylcholine and by a local anesthetic, procaine, involves two different receptor sites. The existence of a specific inhibitory site for the natural receptor-ligand acetylcholine suggests that this site can play an important role in the modulation of receptor function and in the regulation of transmission of signals between cells.


Drawing lines and circles in Parkinson's Disease: The lateralized symptoms interfere with the movements of the unaffected hand.
Evidence about altered bimanual coordination has been reported in Parkinson's Disease. However, no previous study has explored such an alteration quantifying the interference effect that the trajectory of each hand might impose on the other one. Thus, in the present research, we applied the traditional Circles-Lines Coupling Task, which allowed assessing the motor coordination of the two hands, in the context of Parkinson's Disease. Thirty-six individuals affected by Parkinson's Disease were consecutively recruited and assigned to two groups according to their symptoms' lateralization. Moreover, eighteen age-matched healthy controls participated in the study. We capitalized on the Circles-Lines Coupling Task, in which the performance during incongruent movements (drawing lines with one hand and circles with the other hand) was compared with the performance during congruent movements (drawing lines with both hands). A bimanual coupling index was computed to compare the interference effect of each hand on the other one. In healthy controls, the bimanual coupling index did not differ between the two hands. Crucially, in both groups of individuals affected by Parkinson's Disease, the less affected hand showed a significantly higher bimanual coupling index, due to the abnormal interference exerted by the most affected one, than vice versa. Our results highlighted an altered spatial bimanual coupling in Parkinson's disease, depending on the symptoms' lateralization. We offered different explanations of our results according to the theoretical frameworks about the mechanisms subserving bimanual coordination.


Scopolamine for uterine involution of dairy cows.
The objective of this study was to evaluate the effect of administration of scopolamine (a parasympatholytic drug) immediately after delivery, on uterine involution in dairy cows. The cows were divided into two groups: group T (treated with scopolamine butylbromide 40 mg/100 kg P.V., within 24 h of delivery) and group C (treated with 2 ml/q of saline solution). The cows were monitored at T0, within 24 h of delivery, T7, T14, T28 and T40 respectively 7th, 14th, 28th and 40th day postpartum, by measuring the levels of hydroxyproline (HYP), an important marker of uterine involution; by ultrasound examination for the measurement of the diameter of uterine horns and of blood flow in the middle uterine artery; and by evaluation of reproductive indices. HYP showed higher concentrations in the T group than in the C group at all times, but the difference was significant at T7 and T40. Uterine diameters were reduced from T7 to T40, with lower values in the T group, as compared to the C group; the pulsatility index (PI) of the middle uterine artery increased in the T group compared to the C group, with a statistically significant difference at T7. There was a better conception-delivery interval and higher pregnancy rate in the T group compared to the C group. It is likely that scopolamine blocked the uterine contractions in postpartum, for the duration of its half-life. After cessation of its pharmacological effect, the uterus may have started to contract more effectively. These results suggested that scopolamine could be useful as a pharmacological approach to postpartum management.


"Babysitting" the flap: a novel approach to chimeric flap transfer.
Previous studies have described compound flaps based on the subscapular system for a variety of reconstructive needs. Most commonly, the combination includes the fasciocutaneous parascapular flap with the latissimus dorsi muscle flap used in the reconstruction of extensive lower extremity wounds. Indications for combined flaps are typically restricted to selective and complex reconstructions. Our experience with a novel approach to compound flap transfer in an elderly patient with multiple comorbidities is described.


The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer.
Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p=0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p=0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p=0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p=0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p=0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p=0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients.