Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.
Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response.


Breakfast habit and quality in students from two public primary schools in the city of Santa Fe.
Breakfast provides the necessary energy and nutrients to achieve an optimal physical and mental performance. OBJECTIVE. To find out breakfast frequency, factors that influence breakfast habit and skipping, breakfast quality and snack intake in children from public schools in the city of Santa Fe. POPULATION AND METHODS. Descriptive, cross-sectional study. A total of 637 students were assessed using a closed-ended question survey. RESULTS. Seventy five percent of children had breakfast on a daily basis; only 1.6% had a good quality breakfast. Eating breakfast every day or some days did not depend on having the company of a family member. In the case of first to fifth grade children, the weekly frequency depended on having a family member who made it (p= 0.04). The main cause for skipping breakfast was lack of time. Twenty-three percent of children in sixth and seventh grade indicated feeling unwell when having breakfast. More than 50% of children watched television while having breakfast. Most students in first to third grade had breakfast that could be improved (41%) and which was insufficient (41%). An insufficient quality breakfast was more common among fourth and fifth grade students (50%). A remarkable piece of information is the number of sixth and seventh grade children who had a poor quality breakfast (16%). Very few children had a snack that was appropriate to supplement the final quality of breakfast. CONCLUSIONS. Although a high percentage of school-aged children are used to having breakfast, most have an incomplete breakfast. Very few manage to supplement their breakfast with snacks at mid-morning.


[A new unique HIV-1 recombinant form detected in Belarus].
Republican Research-and-Practical Center for Epidemiology and Microbiology, Ministry of Health of Belarus, Minsk The paper presents data on the molecular genetic characteristics of a new HIV-1 recombinant form. The study has shown that the virus is referred to as HIV-1 subtype B in terms of the gag gene and HIV-1 subtype A in terms of the pol and env genes. At the same time the new isolate is closer, in terms of the gag gene, to the HIV-1 DQ207943 strain isolated in Georgia, in terms of the pol gene, to the HIV-1 AF413987.1 strain isolated in Ukraine and, in terms of the env gene to the HIV-1 AY500393 strain isolated in Russia. Thus, the described new HIV-1 recombinant form has the following structure: BgagApolAenv. The gag, pol, and env gene sequences from the new unique HIV-1 recombinant form have been registered in the international database EMBL/Genbank/DDBJ under accession numbers FR775442.1, FN995656.1, and FR775443.1.


Broad Electronic Modulation of Two-Dimensional Metal-Organic Frameworks over Four Distinct Redox States.
Two-dimensional (2D) inorganic materials have emerged as exciting platforms for (opto)electronic, thermoelectric, magnetic, and energy storage applications. However, electronic redox tuning of these materials can be difficult. Instead, 2D metal-organic frameworks (MOFs) offer the possibility of electronic tuning through stoichiometric redox changes, with several examples featuring one to two redox events per formula unit. Here, we demonstrate that this principle can be extended over a far greater span with the isolation of four discrete redox states in the 2D MOFs LixFe3(THT)2 (x = 0-3, THT = triphenylenehexathiol). This redox modulation results in 10,000-fold greater conductivity, p- to n-type carrier switching, and modulation of antiferromagnetic coupling. Physical characterization suggests that changes in carrier density drive these trends with relatively constant charge transport activation energies and mobilities. This series illustrates that 2D MOFs are uniquely redox flexible, making them an ideal materials platform for tunable and switchable applications.


[The role of hyperuricemia in the development of cognitive changes in the elderly.]
It is known that hyperuricemia is recognized as an independent cardiovascular risk factor. However, uric acid can also perform useful functions due to its antioxidant properties, which may be especially relevant in the context of neurodegenerative diseases. This review examines the currently available data on the relationship between serum uric acid levels and cognitive functions in the elderly, paying special attention to the etiology of cognitive disorders (Alzheimer's disease, Parkinson's dementia and vascular dementia). Despite the high heterogeneity of existing studies due to the different characteristics of the studied populations and methods of assessing cognitive impairment, it was concluded that uric acid can modulate cognitive function in different ways depending on the etiology of dementia. Modern studies demonstrate that uric acid can have a neuroprotective effect in Alzheimer's disease and Parkinson's dementia, while hypouricemia is a risk factor for faster disease progression and is a possible marker of malnutrition. Conversely, a high level of uric acid in the blood serum can negatively affect the course of the disease in vascular dementia. Further studies are needed to clarify the physiopathological role of uric acid in various types of dementia and its clinical and prognostic significance.


Skeletal muscle development and regeneration.
In the late stages of muscle development, a unique cell population emerges that is a key player in postnatal muscle growth and muscle regeneration. The location of these cells next to the muscle fibers triggers their designation as satellite cells. During the healing of injured muscle tissue, satellite cells are capable of forming completely new muscle fibers or restoring damaged muscle fibers. A major problem in muscle healing is the formation of dysfunctional scar tissue, which leads to incomplete functional recovery. Therefore, the identification of factors that improve the process of muscle healing and reduce the formation of scar tissue is of great interest. Because satellite cells possess the capability of self-renewal, a unique feature of stem cells, they play a central role in the search for therapies to improve muscle healing. Growth factor-based and (satellite) cell-based therapies are being investigated to treat minor muscle injuries and intrinsic muscle defects. Major muscle injury that involves the loss of muscle tissue requires the use of scaffolds with or without (satellite) cells. Scaffolds are also being developed to generate muscle tissue in vitro. These approaches aim to restore the structure and function of the injured muscle without dysfunctional scarring.


The Case for a Hubble Constant of 30 km s-1 Mpc-1.
Although recent determinations of the distance to the Virgo cluster based on Cepheid variable stars represent an important step in pinning down the Hubble constant, after 65 years a definitive determination of the Hubble constant still eludes cosmologists. At present, most of the observational determinations place the Hubble constant between 40 and 90 kilometers per second per megaparsec (km s(-1) Mpc(-1)). The case is made here for a Hubble constant that is even smaller than the lower bound of the accepted range on the basis of the great advantages, all theoretical in nature, of a Hubble constant of around 30 kilometers per second per megaparsec. Such a value for the Hubble cures all of the ills of the current theoretical orthodoxy, that is, a spatially flat universe composed predominantly of cold dark matter.


Mobility on discharge from an aged care unit.
Independent mobility is a crucial element of independent living and quality of life. However, little is known about the mobility of older people around the time of discharge from inpatient rehabilitation. The present study aimed to describe mobility on discharge from an aged care rehabilitation unit. The study utilized a descriptive, cross-sectional design. Ninety-five patients (mean age 81 (+/-8) years; 60% female) with diverse chronic conditions (median 5) who were able to walk at least 10m without weight-bearing restrictions were recruited from the aged care rehabilitation wards. Scores on the Barthel Index were obtained on admission and discharge to provide information about their overall level of function. Within the last week of rehabilitation stay, scores on the mobility and locomotion subsections of the Functional Independence Measure, gait velocity, and time and distance parameters of gait were obtained. Gait variables were measured by use of the GAITRite, an instrumented walkway. Medians and interquartile ranges (IQR) were reported for mobility variables. Following inpatient rehabilitation, many patients achieved independence in bed or chair transfers (83%), toilet transfers (81%), shower transfers (60%) and level-surface walking (74%). Only 31% achieved independence in stair climbing. Patients walked slowly at a median (IQR) gait velocity of 45.96 (31.51) cm/s and with markedly diminished cadence and step length. Subjects with a low number of chronic conditions generally performed better on mobility measures than those with a high number of chronic conditions. Although many older people are able to transfer and walk independently around the time of discharge from inpatient rehabilitation their mobility is still often impaired. For example, only 9.5% achieved a walking velocity considered to be adequate for street crossing and few demonstrated the ability to negotiate stairs. This highlights the need for ongoing rehabilitation for many of these older people. The possible cumulative effects of chronic conditions on mobility require further investigation.


Intuition in nursing practice: sharing graduate students' exemplars with undergraduate students.
Failure to acknowledge ways of knowing in nursing education curricula other than linear reasoning hinders the development of the full extent of mental abilities brought to learning situations by nursing students. Nurse educators are challenged to develop creative methods to facilitate nursing students' intuitive thinking. In this article, a teaching strategy is described in which graduate students' exemplars of intuition in clinical practice are shared with undergraduate nursing students. Implications of using this teaching approach to demystify the intuitive process and address its legitimacy are discussed.


HIV-associated anal dysplasia: experience from a multiethnic-HIV clinic in Hawaii.
To assess the proportion as well as predictors of anal dysplasia in HIV-infected Asian/Pacific Islanders. This was a retrospective chart review evaluating the proportion of anal dysplasia among a multiethnic population from an ambulatory university-based HIV clinic in Hawaii. Demographic, clinical, and virologic parameters were examined with respect to abnormal anal Pap smear. Variables included: Pap smear results (outcome variable), cytology results, age, self-reported ethnicity, CD4/ nadir CD4 counts, HIV viral load, antiretroviral therapy use, Hepatitis B and C co-infections, history of sexually transmitted diseases, personal history of cancer, tobacco use, alcohol use, intravenous drug abuse, family history of cancer, and history of genital/anal warts. There were no significant differences in rates of abnormal Pap smear among the ethnic groups. Abnormal Pap smears were associated with history of genital warts (7% normal vs. 18% abnormal, p=.01) and alcohol consumption (16% vs. 27%, p=.05). Hepatitis B infection and current anti-retroviral therapy (ART) were associated with normal Pap cytology (9.7% vs. 0%, p=.03) and (96.8% vs. 86.5%, p=.05) respectively. No differences in the proportion of abnormal Pap smears were seen among ethnic groups followed within an ambulatory HIV clinic.


mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression.
Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.


Should you treat systolic hypertension in elderly patients?
Systolic hypertension is difficult to control in the elderly, but this is not an excuse for denying these patients the benefits of carefully controlled antihypertensive treatment, particularly when target organ disease is present. Although drug therapy may produce alarming symptoms, it is highly doubtful that it increases the incidence of myocardial infarction or permanent neurologic damage. In fact, evidence indicates that antihypertensive therapy may prevent hemorrhagic and thrombotic strokes. Arterial pressure should be reduced slowly and cautiously--to allow control without interfering with cerebral flow stability. Drug therapy should be started in small doses and may be initiated with diuretics. Methyldopa in small or moderate doses has been effective and does not often cause postural hypotension. Drugs that interfere with reflex arteriolar constriction should not be used.


A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism.
Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.


Metal-organic framework derived hybrid Co3O4-carbon porous nanowire arrays as reversible oxygen evolution electrodes.
Hybrid porous nanowire arrays composed of strongly interacting Co3O4 and carbon were prepared by a facile carbonization of the metal-organic framework grown on Cu foil. The resulting material, possessing a high surface area of 251 m(2) g(-1) and a large carbon content of 52.1 wt %, can be directly used as the working electrode for oxygen evolution reaction without employing extra substrates or binders. This novel oxygen evolution electrode can smoothly operate in alkaline solutions (e.g., 0.1 and 1.0 M KOH), affording a low onset potential of 1.47 V (vs reversible hydrogen electrode) and a stable current density of 10.0 mA cm(-2) at 1.52 V in 0.1 M KOH solution for at least 30 h, associated with a high Faradaic efficiency of 99.3%. The achieved ultrahigh oxygen evolution activity and strong durability, with superior performance in comparison to the state-of-the-art noble-metal/transition-metal and nonmetal catalysts, originate from the unique nanowire array electrode configuration and in situ carbon incorporation, which lead to the large active surface area, enhanced mass/charge transport capability, easy release of oxygen gas bubbles, and strong structural stability. Furthermore, the hybrid Co3O4-carbon porous nanowire arrays can also efficiently catalyze oxygen reduction reaction, featuring a desirable four-electron pathway for reversible oxygen evolution and reduction, which is potentially useful for rechargeable metal-air batteries, regenerative fuel cells, and other important clean energy devices.


NOD2/RIG-I Activating Inarigivir Adjuvant Enhances the Efficacy of BCG Vaccine Against Tuberculosis in Mice.
Tuberculosis (TB) caused by Mycobacterium tuberculosis (MTB) kills about 1.5 million people each year and the widely used Bacille Calmette-Guérin (BCG) vaccine provides a partial protection against TB in children and adults. Because BCG vaccine evades lysosomal fusion in antigen presenting cells (APCs), leading to an inefficient production of peptides and antigen presentation required to activate CD4 T cells, we sought to boost its efficacy using novel agonists of RIG-I and NOD2 as adjuvants. We recently reported that the dinucleotide SB 9200 (Inarigivir) derived from our small molecule nucleic acid hybrid (SMNH)® platform, activated RIG-I and NOD2 receptors and exhibited a broad-spectrum antiviral activity against hepatitis B and C, Norovirus, RSV, influenza and parainfluenza. Inarigivir increased the ability of BCG-infected mouse APCs to secrete elevated levels of IL-12, TNF-α, and IFN-β, and Caspase-1 dependent IL-1β cytokine. Inarigivir also increased the ability of macrophages to kill MTB in a Caspase-1-, and autophagy-dependent manner. Furthermore, Inarigivir led to a Capsase-1 and NOD2- dependent increase in the ability of BCG-infected APCs to present an Ag85B-p25 epitope to CD4 T cells in vitro. Consistent with an increase in immunogenicity of adjuvant treated APCs, the Inarigivir-BCG vaccine combination induced robust protection against tuberculosis in a mouse model of MTB infection, decreasing the lung burden of MTB by 1-log10 more than that afforded by BCG vaccine alone. The Inarigivir-BCG combination was also more efficacious than a muramyl-dipeptide-BCG vaccine combination against tuberculosis in mice, generating better memory T cell responses supporting its novel adjuvant potential for the BCG vaccine.


Erratum.
In the letter "Kepone chronology" by Rudolph J. Jaeger (9 July, p. 94, column 3, paragraph 3, line 9), the airborne Kepone concentration in the Life Science Products plant measured by state of Virginia officials in July 1975 was erroneously given as 3 mg/cm(3). The correct concentration was 3 mg/m(3). A portion of a sentence in the preceding paragraph was also erroneously omitted (line 14). The sentence should have read, "A chronicity factor, calculated from these data, is the ratio of the single LD(50) value divided by the LD(50) value in repeatedly dosed animals."


Histological evaluation of combined platelet-rich fibrin membrane and piezo-incision application in orthodontic tooth movement.
The aim of this study was to evaluate the effect of platelet-rich fibrin (PRF) membrane on tooth movement in comparison with shunt control and piezoelectric surgery. Sixteen White Vienna rabbits were included in the study and divided into two groups. Reciprocal forces (20 g) were applied on the maxillary incisors by an orthodontic appliance. In group 1, PRF membrane was placed sub-periosteally on the distal alveolar bone surface of the right central incisors and the left side was kept as control. In group 2, piezo-incisions 3 mm in depth were performed and combined with PRF membrane on the distal alveolar bone surface of the right central incisors, while the left side was kept as control. All rabbits were euthanized on day 21 and bilateral alveolar bone segments from the distal regions were removed for histological evaluation. Isolated PRF membrane application increased the blood vessel (8.3 ± 1.0; P = 0.026), osteoblast (6 ± 0.8; P = 0.027), and osteoclast (2.3 ± 0.8; P = 0.026) counts significantly compared to shunt control. Combined application of PRF membrane + piezo-incision increased the blood vessel (15.3 ± 0.8; P = 0.027), osteoblast (9.8 ± 1.4; P = 0.026), and osteoclast (3.3 ± 0.8; P = 0.024) counts significantly compared to shunt control. The increases in blood vessel count and osteoblast cell count were more evident in the combined application group (both P = 0.002). PRF membrane application significantly increased bone turnover, and the combined application of PRF membrane + piezo-incision was found to be the best method for increasing bone turnover.


[Stent-supported percutaneous therapy of iliac vein stenosis following operative thrombectomy and placement of a shunt].
Among 15 patients with acute thrombotic disease of pelvic veins who had been submitted to operative thrombectomy and creation of arteriovenous fistula in the groin, 12 presented with stenotic lesions 3 months later. These stenoses were submitted to percutaneous angioplasty. If angioplasty failed, percutaneous placement of a vascular stent (wall stent) was performed immediately (n = 7). Stenting in cross-over-technique proved practicable in all cases. Secondary stenotic disease in the exclusively dilated area was observed in 3/5 cases and was also treated with a wall stent. In one patient with recurrent stenoses who refused stenting, extended thrombosis occurred after occlusion of the AV-fistula. At mid-term PTA was successful in only two cases. Intimal hyperplasia was observed in only one wall stent treated patient. Percutaneous treatment of iliacal stenoses in patients with postthrombotic syndrome may be performed safely under the protective effect of the fistula. With the presented technique, patency of pelvic veins could be restored in 11/12 patients with postoperative significant venous stenoses.


A Matter of Fat.
Acute respiratory disease syndrome (ARDS) is a common complication of critical illness, associated with significant morbidity, prolonged intensive care unit (ICU) and hospital stay, and increased mortality. Inflammation plays a central role in ARDS, with inflammatory eicosanoid mediators produced from the ω-6 fatty acid arachidonic acid, such as leukotriene B4, being involved. The ω-3 fatty acids found in fish oil exert anti-inflammatory effects, including decreasing production of inflammatory eicosanoids from arachidonic acid. The ω-3 fatty acids are effective in models relevant to ARDS. Several randomized controlled trials of enteral formulas rich in ω-3 fatty acids, often in combination with other bioactive substances, have been conducted in patients with ARDS. Four of these trials reported marked clinical benefits, 2 reported no effect, and 1 reported a negative impact. A systematic review and meta-analysis of these 7 trials identified no overall effect on ventilator-free days or on ICU-free days. There was a small reduction in ICU length of stay and no overall effect on mortality. However, the authors formally identified that trials that used high fat in both treatment and control groups showed a significant reduction in mortality, while trials that used a high, or higher, fat treatment and a low-fat control group showed a trend toward an increase in mortality. It is concluded that differences in outcome reported among these studies largely relate to the relative fat contents of the treatment and control formulas. Further, it is concluded that high-fat enteral formulas should not be used in this patient group.


Effects of Herbicides on Flowering.
Herbicides have been shown to reduce flower production and to delay flowering, with results varying among herbicides and tested plant species. We investigated the effects of herbicides on flowering in an extensive greenhouse study conducted in Canada and Denmark. The effects of low doses of 5 different herbicides (bromoxynil, ioxynil + bromoxynil, metsulfuron-methyl, clopyralid, and glyphosate), simulating realistic drift scenarios (1 and 5% recommended field rates), on plant flowering were examined using 9 wild plant species exposed at either the seedling (6- to 8-leaf) or flower bud stage. Following herbicide exposure, initial flowering date as well as flower production over time were recorded over the growing period. The effect of herbicides on cumulative flower numbers and flowering time were modeled using Gompertz growth models. Significant delays to peak flowering and/or reductions in flower production were observed in at least one plant species for all tested herbicides, with glyphosate often exhibiting the greatest negative effects, that is, plant death. Except for ioxynil + bromoxynil, there was no clear evidence of either the seedling or the flower bud stage being more sensitive. Overall, 58% of all species × life stage × herbicide treatments resulted in either a statistically significant or a strong decline in flower production with herbicide application rates up to 5% of recommended field rates, whereas significant or strong delays in peak flowering were also detected but were slightly less common. Effects at 1% label rates were minimal. Simultaneous delays to peak flowering and reductions in total flower production occurred in approximately 25% of all cases, indicating that herbicide application rates simulating realistic drift scenarios would likely have negative effects on wild floral communities. Environ Toxicol Chem 2020;39:1244-1256. © 2020 SETAC.


Pelvic actinomycosis: a case report.
Pelvic actinomycosis is rare but can manifest with multiple presentations. A 28-year-old woman, gravida 4, para 2, conceived with a Paraguard intrauterine device (IUD) (FEI Products LLC, North Tonawanda, New York) in place. The IUD had been present for 2 years. The patient presented with an incomplete abortion at 6 weeks' gestation, and the IUD was removed. Two and one-half months later the patient presented with signs and symptoms of pelvic inflammatory disease and underwent hospitalization and exploratory laparotomy. The pathology specimen revealed diffuse actinomycosis involving the tube and ovary, appendix, and bowel mucosa. A Pap smear 3 months earlier had revealed Actinomyces. Actinomyces has been associated with IUD use and may present even after removal of the IUD. Pelvic actinomycosis is rare, and removal of the IUD may not be adequate treatment. If a patient presents with symptoms of infection, early diagnosis and aggressive antibiotics may prevent further complications.


A submersible autonomous sensor for spectrophotometric pH measurements of natural waters.
An autonomous sensor for long-term in situ measurements of the pH of natural waters is described. The system is based upon spectrophotometric measurements of a mixture of sample and sulfonephthalein indicator. A simple plumbing design, using a small, low-power solenoid pump and valve, avoids the need for quantitative addition of indicator. A approximately 50-microL slug of indicator is pulled into the sample stream by the pump, and subsequent pumping and mixing results in a section of indicator and sample where absorbance measurements can be made. The design also permits direct determination of the indicator pH perturbation. Absorbances are recorded at three wavelengths (439, 579, and 735 nm) using a custom-built 1.7-cm path length fiber-optic flow cell. Solution blanks are obtained by periodically flushing the cell with sample. Field tests were performed in a local river over an 8-day period. The in situ accuracy, based on comparison with laboratory spectrophotometric pH measurements, was -0.003 pH unit (n = 16), similar to the measurement precision. No drift was observed during the 8-day period. The absorbance ratio used to calculate pH, in combination with a simple and robust optical design, imparts an inherent stability not achievable with conventional potentiometric methods, making the design feasible for long-term autonomous pH measurements.


Action potential initiation and propagation in layer 5 pyramidal neurons of the rat prefrontal cortex: absence of dopamine modulation.
Somatic and dendritic whole-cell recording was used to examine action potential (AP) initiation and propagation in layer 5 pyramidal neurons of the rat prelimbic prefrontal cortex. APs generated by somatic current injection, or via antidromic stimulation, were reliably recorded at apical dendritic locations as far as 480 microm from the soma. Although the backpropagation of single APs into the apical dendrite was robust, frequency-dependent attenuation was observed during AP trains delivered at 10-100 Hz. APs were usually initiated close to the soma (presumably in the axon); however, strong depolarizing input to the apical dendrite could generate dendritic spikes that preceded somatic APs. AP backpropagation was dependent solely on activation of dendritic voltage-gated sodium channels and did not require activation of dendritic calcium channels. Despite not playing a role in AP backpropagation, calcium-imaging experiments demonstrated that dendritic calcium channels are activated by backpropagating APs, leading to transient increases in intracellular calcium. In addition, calcium imaging revealed that AP backpropagation into the distal apical tuft was frequency dependent. Finally, we tested whether dopamine, a prominent neuromodulator associated with prefrontal activity, could alter AP initiation or backpropagation. Bath-applied dopamine (10 or 100 microm) did not effect AP backpropagation, frequency-dependent depression, local dendritic spike initiation, or AP-induced calcium signaling. These data indicate that AP backpropagation in prefrontal layer 5 pyramidal neurons is robust but frequency dependent in the distal tuft, requires dendritic sodium rather than calcium channel activation, and, unlike other aspects of neuronal excitability, insensitive to modulation by dopamine.


Microvascular adaptations to resistance training are independent of load in resistance-trained young men.
Resistance training promotes microvasculature expansion; however, it remains unknown how different resistance training programs contribute to angiogenesis. Thus, we recruited experienced resistance-trained participants and determined the effect of 12 wk of either high-repetition/low-load or low-repetition/high-load resistance training performed to volitional fatigue on muscle microvasculature. Twenty men performed either a high-repetition [20-25 repetitions, 30-50% of 1-repetition maximum (1RM); n = 10] or a low-repetition (8-12 repetitions, 75-90% of 1RM; n = 10) resistance training program. Muscle biopsies were taken before and after resistance training, and immunohistochemistry was used to assess fiber type (I and II)-specific microvascular variables. High-repetition/low-load and low-repetition/high-load groups were not different in any variable before resistance training. Both protocols resulted in an increase in capillarization. Specifically, after resistance training, the capillary-to-fiber ratio, capillary contacts, and capillary-to-fiber perimeter exchange index were elevated, and sharing factor was reduced. These data demonstrate that resistance training performed to volitional failure, using either high repetition/low load or low repetition/high load, induced similar microvascular adaptations in recreationally resistance-trained young men.


The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer.
Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin's lymphoma, NK-T cell lymphoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-kappaB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.


Producing the "problem" of addiction in drug treatment.
In this article, we argue that the "problem" of addiction emerges as an effect of treatment policy and practice as well as a precursor to it. We draw on the work of Marrati to analyze interviews with policy makers and practitioners in Australia. The interviews suggest that the episode-of-care system governing service activity, outcomes, and funding relies on certain notions of addiction and treatment that compel service providers to designate service users as addicts to receive funding. This has a range of effects, not least that in acquiring the label of "addict," service users enter into bureaucratic and epidemiological systems aimed at quantifying addiction. Rather than treating pre-existing addicts, the system produces "addicts" as an effect of policy imperatives. Because addiction comes to be produced by the very system designed to treat it, the scale of the problem appears to be growing rather than shrinking.


A systems perspective on the effective connectivity of overt speech production.
The aim of this study was to provide a computational system model of effective connectivity in the human brain underlying overt speech production. Meta-analysis of neuroimaging studies and functional magnetic resonance imaging data acquired during a verbal fluency task revealed a core network consisting of Brodmann's area (BA) 44 in Broca's region, anterior insula, basal ganglia, cerebellum, premotor cortex (PMC, BA 6) and primary motor cortex (M1, areas 4a/4p). Dynamic causal modelling (DCM) indicated the highest evidence for a system architecture featuring the insula in a serial position between BA 44 and two parallel nodes (cerebellum/basal ganglia), from which information converges onto the PMC and finally M1. Parameter inference revealed that effective connectivity from the insular relay into the cerebellum/basal ganglia is primarily task driven (preparation) while the output into the cortical motor system strongly depends on the actual word production rate (execution). DCM hence allowed not only a quantitative characterization of the human speech production network, but also the distinction of a preparatory and an executive subsystem within it. The proposed model of physiological integration during speech production may now serve as a reference for investigations into the neurobiology of pathological states such as dysarthria and apraxia of speech.


Refractory or relapsed aggressive B-cell lymphoma failing (R)-CHOP: an analysis of patients treated on the RICOVER-60 trial.
The prognosis of elderly patients with aggressive B-non-Hodgkin's lymphoma after first lymphoma-related treatment failure (TF-L) is not well described. We analysed patient characteristics including the presence of MYC rearrangements and MYC-expression immunohistochemistry (IHC) at diagnosis and modalities of salvage therapy and their impact on the prognosis of patients between 61 and 80 years who had been treated on the RICOVER-60 trial. TF-L occurred in 301 of the 1222 (24.6%) patients; 297 patients could be analysed. Prognosis was extremely poor in patients with primary progressive disease or early relapse (≤12 months) with median survivals of 3.3 and 6.4 months. Survival after TF-L was significantly lower in patients pretreated with R-CHOP compared with CHOP (23.0% versus 36.4% at 2 years, P = 0.016). In patients with MYC translocation at diagnosis Rituximab reduced the risk of TF-L from 58.8% to 26.3%. Survival after TF-L was significant longer for patients after CHOP without MYC translocations (31.8% versus 0% at 2 years, P < 0.001) or negative MYC-IHC (41.0% versus 16.8% at 2 years, P = 0.017) but not after R-CHOP. 224 patients (75.4%) received salvage therapy. Rituximab was part of salvage therapy in 57.4% and improved 2-year survival rate from 20.7% to 46.8% (P < 0.001). The benefit of R was significant after first-line CHOP [2-year overall survival (OS) 49.6% versus 19.1%, P < 0.001] as well as after R-CHOP (2-year OS 33.1% and 22.5%, P = 0.034). For patients pretreated with R-CHOP long-term survival was below 15% regardless of the treatment chosen. MYC rearrangement and IHC are adverse prognostic factors after TF-L for CHOP treated patients, rituximab as part of first-line therapy reduced the effects of MYC-break. Rituximab improves results of any type of salvage therapy; however, survival after progression/relapse of aggressive B-cell lymphoma in elderly patients pretreated with (R)-CHOP is poor regardless of treatment chosen.


A systematic review and meta-analysis of predictors and outcomes of community treatment orders in Australia and New Zealand.
Australia and New Zealand have some of the highest rates of compulsory community treatment order use worldwide. There are also concerns that people from culturally and linguistically diverse backgrounds may have higher rates of community treatment orders. We therefore assessed the health service, clinical and psychosocial outcomes of compulsory community treatment and explored if culturally and linguistically diverse, indigenous status or other factors predicted community treatment orders. We searched the following databases from inception to January 2020: PubMed/Medline, Embase, CINAHL and PsycINFO. We included any study conducted in Australia or New Zealand that compared people on community treatment orders for severe mental illness with controls receiving voluntary psychiatric treatment. Two reviewers independently extracted data, assessing study quality using Joanna Briggs Institute scales. A total of 31 publications from 12 studies met inclusion criteria, of which 24 publications could be included in a meta-analysis. Only one was from New Zealand. People who were male, single and not engaged in work, study or home duties were significantly more likely to be subject to a community treatment order. In addition, those from a culturally and linguistically diverse or migrant background were nearly 40% more likely to be on an order. Indigenous status was not associated with community treatment order use in Australia and there were no New Zealand data. Community treatment orders did not reduce readmission rates or bed-days at 12-month follow-up. There was evidence of increased benefit in the longer-term but only after a minimum of 2 years of use. Finally, people on community treatment orders had a lower mortality rate, possibly related to increased community contacts. People from culturally and linguistically diverse or migrant backgrounds are more likely to be placed on a community treatment order. However, the evidence for effectiveness remains inconclusive and limited to orders of at least 2 years' duration. The restrictive nature of community treatment orders may not be outweighed by the inconclusive evidence for beneficial outcomes.


Regiochemistry and substrate stereoselectivity of O-demethylation of verapamil in the presence of the microsomal fraction from rat and human liver.
The oxidative O-demethylation of verapamil (1), a calcium channel antagonist, in the presence of rat and human liver microsomes was examined. By using GC/MS methodology and synthesized regioisomeric standards, we showed that three of the four possible monophenolic metabolites, alpha-[3-([2-(3,4-dimethoxyphenyl)ethyl]methyl-amino) propyl]-3-methoxy-4-hydroxy-alpha-(1-methylethyl)phenyl-acetonitrile (2), alpha-[3-([2-(3,4-methoxyphenyl)ethyl]methyl-amino) propyl]-3-hydroxy-4-methoxy-alpha-(1-methylethyl)phenylaceto nitrile (3), and alpha-[3-([2-(3-methoxy-4-hydroxyphenyl)ethyl]methylamino) propyl]-3,4-dimethoxy-alpha-(1-methylethyl)phenylacetonitrile (4) were formed. The other possible regioisomeric monophenolic metabolite 5 was not observed. Substrate stereoselectivity for the O-demethylation process was determined when pseudoracemic verapamil [equimolar (S)-(-)-verapamil-d6 and (R)-(+)-verapamil-d0] was used as substrate. In the presence of rat liver microsomes, significant substrate stereoselectivity was observed for formation of 4 (S/R ratio 2.28), whereas marginal substrate stereoselectivity was observed in the formation of both 3 and 2 (S/R ratio approximately 0.8). Substrate stereoselectivity for the O-demethylation process in the presence of human liver microsomes was slight and variable (six samples). Quantitatively, the ratio of O-demethylation products obtained (4:2:3) was similar in the presence of rat and human liver microsomes. In both systems, more than one-half of the total O-demethylation occurred in the aromatic ring of the phenethylamine moiety, and of the total O-demethylation process, more para- than meta-O-demethylation was observed. The similarity of regioselectivity for O-demethylation in the presence of rat and human liver microsomes suggests a similar cytochrome P-450 isozyme or set of isozymes may be responsible for the O-demethylation process.


Tubulovesicular structures (TVS): virus-like particles specific for all subacute spongiform virus encephalopathies--what are they really?
Tubulovesicular structures (TVS) are virus-like particles specific for all the subacute spongiform virus encephalopathies (SSVE). I report here the presence of TVS in the highest range of naturally occurring and experimentally induced SSVE studied so far: natural and experimental Creutzfeld-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, natural bovine spongiform encephalopathy (BSE) and BSE transmitted to pigs and four models of experimental scrapie in hamsters. TVS are spherical particles, approximately 30 nm in diameter. They are observed at both sides of synaptic cleft (i.e. in dendrites and axonal preterminals and terminals). By the ultrastructural criteria, TVS are easily differentiated from other spherical or tubular elements of the nervous system: microtubules, synaptic vesicles, multivesicular bodies and glycogen granules. The number of affected processes roughly correlates with infectivity titre. Their significance is unknown!


Kaposi's sarcoma in the acquired immune deficiency syndrome: a proposal for uniform evaluation, response, and staging criteria. AIDS Clinical Trials Group Oncology Committee.
The availability of uniform and precise criteria for disease evaluation, response to treatment, and clinical staging of Kaposi's sarcoma (KS) in individuals with the acquired immune deficiency syndrome (AIDS) would facilitate therapeutic trials in patients with this neoplasm. Recently, a group of oncologists conducting clinical trials in patients with AIDS-associated KS as part of a cooperative group established by the National Institute of Allergy and Infectious Diseases (NIAID) drafted such criteria. The criteria take into account the unique problems associated with the evaluation of patients with a disseminated cutaneous neoplasm in the setting of a systemic virus infection associated with immune deficiency. The recommendations include a standardized format for documenting the extent of KS on initial and subsequent evaluations, response definitions that include assessments of lesion nodularity and tumor-associated edema in addition to more traditional methods for evaluating tumor response, and a new staging system that includes extent of tumor, immune status, and other AIDS-related disease manifestations, akin to the tumor-node-metastasis (TNM) system used to stage other tumors. The adoption of standardized criteria for the evaluation of KS should prove useful for group trials and for other investigators involved in the treatment of this disease.


Stem cell therapy for the treatment of heart failure.
Congestive heart failure is a complex clinical syndrome resulting from myocardial dysfunction that impairs the cardiovascular system's function. Medical and surgical therapy both still result in a large number of patients with very few options and persistent ventricular dysfunction. The major process to reverse ventricular remodeling would be the enhancement of regeneration of cardiac myocytes, as well as the stimulation of neovascularization within the affected area of the myocardium. This can be achieved by introducing progenitor cells that are capable of differentiating into cardiac myocytes, or that promote neovascularization and restore the normal characteristics of myocardium environment. A number of issues remain as to the type of cells, delivery, timing, and mechanisms involved, however. There have been a number of clinical trials in patients with heart failure that have been based on animal data related to stem cell therapy. Most have utilized whole bone marrow cells or myoblasts. The majority of the studies demonstrate an improvement in ventricular function, reduction in scarring, and improvement in symptoms. Some trials have shown no improvement at all. This review examines the bench-to-bedside developments of stem cell therapy related to congestive heart failure.


Ethnicity and detention: are Black and minority ethnic (BME) groups disproportionately detained under the Mental Health Act 2007?
There is substantial evidence to suggest that Black and minority ethnic (BME) patients are disproportionately detained under the Mental Health Act (MHA). We examined ethnic differences in patients assessed for detention and explored the effect of ethnicity after controlling for confounders. A prospective study of all MHA assessments conducted in 1 year (April 2009-March 2010) within Birmingham and Solihull Mental Health Foundation Trust, UK. Proportion of assessments and detentions within denominator population of service users and regional populations were calculated. Multiple regression analysis was conducted to determine which variables were associated with the outcome of MHA assessment and the role of ethnicity. Of the 1115 assessments, 709 led to detentions (63.58 %). BME ethnic groups were statistically more likely to be assessed and detained under the MHA as compared to Whites, both in the service user and the ethnic population estimates in Birmingham, UK. MHA detention was predicted by having a serious mental illness, the presence of risk, older age and living alone. Ethnicity was not associated with detention under the MHA with age, diagnosis, risk and level of social support accounted for. The BME 'disproportionality' in detention rates seems to be due to higher rates of mental illness, greater risk and poorer levels of social support rather than ethnicity per se.


Cerebral revascularization using latissimus dorsi muscle free flap transfer--technical note.
A method for cerebral revascularization using latissimus dorsi muscle free flap transfer is described. Latissimus dorsi muscle is harvested with thoracodorsal vessels after completion of craniotomy and exposure of superficial temporal vessels. The size of muscle belly which is harvested is dependent on the area where the revascularization is necessary. Microvascular anastomoses of superficial temporal vessels and thoracodorsal vessels are performed in end-to-end fashion. A 31-year-old male patient with moyamoya syndrome was treated by this method. Postoperative angiography demonstrated successful revascularization in the affected hemisphere, with improved perfusion reserve capacity shown by cerebral blood flow study. This type of encephalo-myo-synangiosis (with free muscle flap) is a possible method when vascular reconstruction of an extensive ischemic area which involves anterior and posterior cerebral artery territories is needed in a patient with moyamoya disease or other similar ischemic conditions.


Development and evaluation of a pliable biological valved conduit. Part I: Preparation, biochemical properties, and histological findings.
Different types of external valved conduits have been used for the repair of complex congenital cardiac anomalies that may have otherwise been inoperable. However, an ideal conduit has yet to be found due to complications such as stenosis, thrombosis, calcification of the valve and graft wall, and "peeling" of the neointima. To address those problems, a new extracardiac valved conduit made of bovine jugular vein was developed and evaluated in a preliminary animal study. Harvested bovine vein containing a naturally existing valve was initially incorporated with protamine on the inner surface and then was cross-linked in diglycidyl ether (DE). Fixation with DE allowed the vein and its leaflets to retain a tissue-like elasticity. To provide antithrombogenicity to the graft, heparin was introduced into the lumen to bind ionically to the pre-entrapped protamine. The biological valved conduit of approximately 14 mm diameter was implanted from the right ventricle to pulmonary artery as bypass graft in three dogs. After implantation, the native main pulmonary artery was ligated between the anastomotic sites of the bypass conduit. No anticoagulant or antiplatelet drugs were administered after surgery. One DE-fixed valved conduit was retrieved at 3 months, and the others were removed at 5 months. Only small thrombus areas were found on the white luminal surfaces. The valves and the conduits maintained softness and pliability, similar to before implantation. Additionally, the collagen content, shrink temperature, and tanning index of this newly developed biological valved conduit before and after fixation were measured in the study.(ABSTRACT TRUNCATED AT 250 WORDS)


Glomerular mRNAs in human type 1 diabetes: biochemical evidence for microalbuminuria as a manifestation of diabetic nephropathy.
In patients with type 1 diabetes, some consider microalbuminuria to be a predictor of diabetic nephropathy while others believe it is an early feature of diabetic nephropathy. Levels of mRNAs that are of pathogenetic relevance in diabetic nephropathy were compared in glomeruli isolated from microalbuminuric and overtly proteinuric subjects and in control normoalbuminuric diabetic subjects and living renal transplant donors. In subjects with microalbuminuria and overt proteinuria, glomerular mRNAs were virtually identical and approximately twofold higher for connective tissue growth factor (CTGF; P < 0.01) and collagen alpha2(IV) (P < 0.03) compared to living renal donors and normoalbuminuric patients. Glomerular glyceraldehyde-3-phosphate dehydrogenase (GAPDH) levels were not significantly different among the groups (P = 0.4). Weak but statistically significant correlations were noted between CTGF mRNA and albuminuria (assessed by rank), fractional mesangial surface area, and a composite renal biopsy index. Glomerular CTGF mRNA correlated inversely with creatinine clearance. Glomerular collagen alpha2(IV) mRNA levels correlated with albuminuria (by rank) and less strongly with fractional mesangial area. To our knowledge, these data provide the first biochemical evidence demonstrating that the glomeruli of microalbuminuric patients and those with overt proteinuria do not differ significantly. The data support the concept that microalbuminuria is not "predictive" of diabetic nephropathy, but rather is an earlier point in the spectrum of diabetic nephropathy.


Single and multiple cardiovascular biomarkers in subjects without a previous cardiovascular event.
Aims To assess the incremental value of biomarkers, including N-terminal prohormone of brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), growth differentiation factor 15 (GDF-15), and procollagen type 1 N-terminal propeptide (P1NP), in predicting incident cardiovascular events and mortality among asymptomatic individuals from the general population, beyond traditional risk factors, including fasting glucose and renal function (cystatin C), medication use, and echocardiographic measures. Methods and results Prospective population-based cohort study of 1324 subjects without a previous cardiovascular event, who underwent baseline echocardiography and biomarker assessment between 2002 and 2006. The clinical endpoint was the composite of myocardial infarction, invasively treated stable/unstable ischemic heart disease, heart failure, stroke, or all-cause mortality. Predictive capabilities were evaluated using Cox proportional-hazards regression, Harrell's concordance index (C-index), and net reclassification improvement. Median age was 66 (interquartile range: 60-70) years, and 413 (31%) were female. During median 8.6 (interquartile range: 8.1-9.2) follow-up years, 368 (28%) composite events occurred. NT-proBNP, hs-TnT, GDF-15, and IL-6 were significantly associated with outcome, independently of traditional risk factors, medications, and echocardiography ( p < 0.05 for all). Separate addition of NT-proBNP and GDF-15 to traditional risk factors, medications, and echocardiographic measurements provided significant improvements in discriminative ability (NT-proBNP: C-index 0.714 vs. 0.703, p = 0.03; GDF-15: C-index 0.721 vs. 0.703, p = 0.02). Both biomarkers remained significant predictors of outcome upon inclusion in the same model ( p < 0.05 for both). Conclusions NT-proBNP and GDF-15 each enhance prognostication beyond traditional risk factors, glucose levels, renal function, and echocardiography in individuals without known cardiovascular disease.


Evaluation of the ISO standard 11063 DNA extraction procedure for assessing soil microbial abundance and community structure.
Soil DNA extraction has become a critical step in describing microbial biodiversity. Historically, ascertaining overarching microbial ecological theories has been hindered as independent studies have used numerous custom and commercial DNA extraction procedures. For that reason, a standardized soil DNA extraction method (ISO-11063) was previously published. However, although this ISO method is suited for molecular tools such as quantitative PCR and community fingerprinting techniques, it has only been optimized for examining soil bacteria. Therefore, the aim of this study was to assess an appropriate soil DNA extraction procedure for examining bacterial, archaeal and fungal diversity in soils of contrasting land-use and physico-chemical properties. Three different procedures were tested: the ISO-11063 standard; a custom procedure (GnS-GII); and a modified ISO procedure (ISOm) which includes a different mechanical lysis step (a FastPrep ®-24 lysis step instead of the recommended bead-beating). The efficacy of each method was first assessed by estimating microbial biomass through total DNA quantification. Then, the abundances and community structure of bacteria, archaea and fungi were determined using real-time PCR and terminal restriction fragment length polymorphism approaches. Results showed that DNA yield was improved with the GnS-GII and ISOm procedures, and fungal community patterns were found to be strongly dependent on the extraction method. The main methodological factor responsible for differences between extraction procedure efficiencies was found to be the soil homogenization step. For integrative studies which aim to examine bacteria, archaea and fungi simultaneously, the ISOm procedure results in higher DNA recovery and better represents microbial communities.


Long distance dispersal and connectivity in amphi-Atlantic corals at regional and basin scales.
Among Atlantic scleractinian corals, species diversity is highest in the Caribbean, but low diversity and high endemism are observed in various peripheral populations in central and eastern Atlantic islands and along the coasts of Brazil and West Africa. The degree of connectivity between these distantly separated populations is of interest because it provides insight into processes at both evolutionary and ecological time scales, such as speciation, recruitment dynamics and the persistence of coral populations. To assess connectivity in broadly distributed coral species of the Atlantic, DNA sequence data from two nuclear markers were obtained for six coral species spanning their distributional ranges. At basin-wide scales, significant differentiation was generally observed among populations in the Caribbean, Brazil and West Africa. Concordance of patterns in connectivity among co-distributed taxa indicates that extrinsic barriers, such as the Amazon freshwater plume or long stretches of open ocean, restrict dispersal of coral larvae from region to region. Within regions, dispersal ability appears to be influenced by aspects of reproduction and life history. Two broadcasting species, Siderastrea siderea and Montastraea cavernosa, were able to maintain gene flow among populations separated by as much as 1,200 km along the coast of Brazil. In contrast, brooding species, such as Favia gravida and Siderastrea radians, had more restricted gene flow along the Brazilian coast.


[Percutaneous transhepatic lysis of gallstones].
The present study reports on morphological findings obtained from 15 patients who were submitted to percutaneous transhepatic contact dissolution of gallbladder concrements with methyl-tert.-butyl ether (MTBE) and--in case of slightly calcified gallstones (n = 10)--with ethylene diamine tetraacetic acid (EDTA). At a maximum intracystic catheter placement time of four days complete lysis was obtained in 12 patients. As could be depicted by CT, the solvents induced significant regional or disseminated chemical cholecystitis in the majority of all cases. However, these changes proved to be completely reversible within about five weeks. It is concluded that with certain types of gallstones contact dissolution can be an effective alternative therapeutic technique which, however, requires meticulous morphological controlling in view of the time-consuming treatment of calcified concrements.


A review of biomechanical models.
This paper surveys biomechanical models of the nonimpact type, involving the musculo-skeletal system. Models of bones, joints and body segments, including human gait and motion of the whole body are discussed. In particular, stress analysis of bone, calculation of ligament and muscle forces across joints and the kinetics and kinematics of locomotion are discussed. The models are described in terms of the method of formulation, the method of solution and the realism of the results obtained. There is a need for more data on material properties of various body tissues and more experimental research to develop techniques for validating many of the models. Further work on the selection of appropriate objective functions for indeterminate problems is also required.


Hepatic endosome fractions contain an ATP-driven proton pump.
Endosome fractions were isolated from rat liver homogenates on the basis of the subcellular distribution of circulating ligands, e.g. 125I-asialotransferrin internalized by hepatocytes by a receptor-mediated process. The distribution of endocytosed 125I-asialotransferrin 1-2 min and 15 min after uptake by liver and a monensin-activated Mg2+-dependent ATPase activity coincided on linear gradients of sucrose and Nycodenz. The monensin-activated Mg2+-ATPase was enriched relative to the liver homogenates up to 60-fold in specific activity in the endosome fractions. Contamination of the endosome fractions by lysosomes, endoplasmic reticulum, mitochondria, plasma membranes and Golgi-apparatus components was low. By use of 9-aminoacridine, a probe for pH gradients, the endosome vesicles were shown to acidify on addition of ATP. Acidification was reversed by addition of monensin. The results indicate that endosome fractions contain an ATP-driven proton pump. The ionophore-activated Mg2+-ATPase in combination with the presence of undegraded ligands in the endosome fractions emerge as linked markers for this new subcellular organelle.


Gramicidin structure and disposition in highly curved membranes.
With a view to deciphering aspects of the mechanism of membrane protein crystallization in lipidic mesophases (in meso crystallization), an examination of the structure and disposition of the pore-forming peptide, gramicidin, in the lipidic cubic phase was undertaken. At its simplest, the cubic phase consists of lipid and water in the form of a molecular 'sponge.' The lipid exists as a continuous, highly curved bilayer that divides the aqueous component into two interpenetrating but non-contacting channels. In this study, we show that gramicidin reconstitutes into the lipid bilayer of the cubic phase and that it adopts the channel, or helical dimer, conformation therein. Fluorescence quenching with brominated lipid was used to establish the bilayer location of the peptide. Electronic absorption and emission spectroscopies corroborated this finding. Peptide conformation in the cubic phase membrane was determined by circular dichroism. The identity and microstructure of the mesophases, and their capacity to accommodate gramicidin and other system components (sodium dodecyl sulfate, trifluoroethanol), was established by small-angle X-ray diffraction. Beyond a limiting concentration, gramicidin destabilized the cubic phase in favor of the inverted hexagonal phase. While gramicidin remained bilayer bound as membrane thickness changed, its conformation responded to the degree of bilayer mismatch with the hydrophobic surface of the peptide. These findings support the hypothesis that reconstitution into the lipid bilayer is an integral part of the in meso crystallization process as applied to membrane proteins. They also suggest ways for improving the process of membrane protein crystallogenesis.


Meta-analysis of differences in sleep quality based on actigraphs between day and night shift workers and the moderating effect of age.
This study was to conduct a meta-analysis of studies that used actigraphs to compare the influence of day and night shifts on the sleep quality of workers as well as examine the moderating effect of age. Databases including PubMed, CINAHL, the Cochrane Library, MEDLINE, and EBSCOhost were searched for relevant studies published in English between January 1st, 2000 and April 30st, 2021. Our main targets were studies that used actigraphs to assess the sleep quality of night shift workers. This meta-analysis included 12 papers and was performed using Comprehensive Meta-Analysis (CMA) Version 3.0. Effect sizes were displayed in a forest plot using standardized mean difference (SMD) and 95% confidence intervals (CI). Among the sleep quality indices of the day and night shift workers, no significant difference existed in terms of sleep efficiency (SE) (SMD = 0.27, 95% CI: -0.03-0.57), whereas night shift workers presented longer sleep-onset latency (SOL) (SMD = 0.62, 95% CI: 0.15-1.08), greater wake after sleep onset (WASO) (SMD = 0.41, 95% CI: 0.12-0.70), and longer total sleep time (TST) (SMD = 0.85, 95% CI: 0.32-1.39) than did day shift workers. The differences between the day and night shift workers in SOL, WASO, and TST did not vary with age. Among the sleep quality indices, night shift workers presented longer SOL and greater WASO than did day shift workers. However, night shift workers could regulate their rest time and had adequate TST; thus, their SE was not different from that of day shift workers.


Nasopharyngeal disease in cats: 1. Diagnostic investigation.
Nasal discharge, sneezing and upper respiratory noise are frequent presenting signs in feline practice. The small nasal cavity of the cat can make visualisation of lesions challenging. In addition, investigations may identify only secondary complications of a disease process, rather than the initial aetiological agent. Nasopharyngeal disease is a worldwide problem. However, fungal disease shows regional variations in prevalence. This review, aimed at general practitioners as well as those undertaking more specialist investigations in feline respiratory disease, aims to provide practical guidance on the approach necessary to obtain a diagnosis in cats with nasopharyngeal disease. It should also help to explain why a specific diagnosis may not always be possible. While access to endoscopy and computed tomography is advantageous, extensive information can be gained from equipment readily available in all practices. The information presented in this article is based on peer-reviewed publications and the clinical experience of the authors.


Oral neomycin and bacitracin are effective in preventing surgical site infections in elective colorectal surgery: a multicentre, randomized, parallel, single-blinded trial (COLORAL-1).
Several regimens of oral and intravenous antibiotics (OIVA) have been proposed with contradicting results, and the role of mechanical bowel preparation (MBP) is still controversial. This study aims to assess the effectiveness of oral antibiotic prophylaxis in preventing Surgical Site Infections (SSI) in elective colorectal surgery. In a multicentre trial, we randomized patients undergoing elective colorectal resection surgery, comparing the effectiveness of OIVA versus intravenous antibiotics (IVA) regimens to prevent SSI as the primary outcome (NCT04438655). In addition to intravenous Amoxicillin/Clavulanic, patients in the OIVA group received Oral Neomycin and Bacitracin 24 h before surgery. MBP was administered according to local habits which were not changed for the study. The trial was terminated during the COVID-19 pandemic, as many centers failed to participate as well as the pandemic changed the rules for engaging patients. Two-hundred and four patients were enrolled (100 in the OIVA and 104 in the IVA group); 3 SSIs (3.4%) were registered in the OIVA and 14 (14.4%) in the IVA group (p = 0.010). No difference was observed in terms of anastomotic leak. Multivariable analysis indicated that OIVA reduced the rate of SSI (OR 0.21 / 95% CI 0.06-0.78 / p = 0.019), while BMI is a risk factor of SSI (OR 1.15 / 95% CI 1.01-1.30 p = 0.039). Subgroup analysis indicated that 0/22 patients who underwent OIVA/MBP + vs 13/77 IVA/MBP- experienced an SSI (p = 0.037). The early termination of the study prevents any conclusion regarding the interpretation of the data. Nonetheless, Oral Neomycin/Bacitracin and intravenous beta-lactam/beta-lactamases inhibitors seem to reduce SSI after colorectal resections, although not affecting the anastomotic leak in this trial. The role of MBP requires more investigation.


The σ54 system directly regulates bacterial natural product genes.
Bacterial-derived polyketide and non-ribosomal peptide natural products are crucial sources of therapeutics and yet little is known about the conditions that favor activation of natural product genes or the regulatory machinery controlling their transcription. Recent findings suggest that the σ54 system, which includes σ54-loaded RNA polymerase and transcriptional activators called enhancer binding proteins (EBPs), might be a common regulator of natural product genes. Here, we explored this idea by analyzing a selected group of putative σ54 promoters identified in Myxococcus xanthus natural product gene clusters. We show that mutations in putative σ54-RNA polymerase binding regions and in putative Nla28 EBP binding sites dramatically reduce in vivo promoter activities in growing and developing cells. We also show in vivo promoter activities are reduced in a nla28 mutant, that Nla28 binds to wild-type fragments of these promoters in vitro, and that in vitro binding is lost when the Nla28 binding sites are mutated. Together, our results indicate that M. xanthus uses σ54 promoters for transcription of at least some of its natural product genes. Interestingly, the vast majority of experimentally confirmed and putative σ54 promoters in M. xanthus natural product loci are located within genes and not in intergenic sequences.


Airway management of the critically ill patient: rapid-sequence intubation.
Advances in emergency airway management have allowed intensivists to use intubation techniques that were once the province of anesthesiology and were confined to the operating room. Appropriate rapid-sequence intubation (RSI) with the use of neuromuscular blocking agents, induction drugs, and adjunctive medications in a standardized approach improves clinical outcomes for select patients who require intubation. However, many physicians who work in the ICU have insufficient experience with these techniques to adopt them for routine use. The purpose of this article is to review airway management in the critically ill adult with an emphasis on airway assessment, algorithmic approaches, and RSI.


Long-COVID in children: An exploratory case-control study from a bio-psycho-social perspective.
This study aimed to determine psychosocial differences between children with Long-COVID Syndrome (LCS) and two control groups (i.e., children who did not have COVID-19 and children who had previously had COVID-19 but did not develop LCS) from a bio-psycho-social and psychosomatic perspective. To classify children in these three groups, we examined the percentage of children meeting criteria for LCS, the type, frequency, perceived severity of symptoms, and their prevalence compared with children who never had SARS-CoV-2 infection. Data were collected from 198 Italian mothers of children aged 4 to 13 years using a cross-sectional web-based case-control survey. Of these, 105 were mothers of children who had contracted SARS-CoV-2 and 94 were mothers of children who had previously had COVID-19. Information was collected on the type and frequency of symptoms commonly referred to as "Long-COVID symptoms" and psychosocial dimensions (i.e., maternal and child health anxiety, COVID-19 anxiety, adjustment, and child deprivation). Descriptive analyses, chi-square tests, Student's T-Test, and analyses of variance were performed. 29 children (15% of the total sample) developed LCS, mostly in the neurological/neuropsychiatric domain (59%), and of mild intensity. Regarding psychosocial and psychological dimensions, maternal health anxiety, child deprivation, and fear of SARS-CoV-2 infection differed between groups, with the first two dimensions higher in children with LCS than in controls and the latter lower in children with LCS than in controls. This study sheds light on the need of integrating a psychosocial approach into the medical care of children with LCS and their caregivers.


Patterning and tuning of electrical and optical properties of graphene by laser induced two-photon oxidation.
We demonstrate a simple all-optical patterning method for graphene, based on laser induced two-photon oxidation. By tuning the intensity and dose of irradiation, the level of oxidation is controlled, the band gap is introduced and electrical and optical properties are continuously tuned. Complex patterning is performed for air-suspended monolayer graphene and for graphene on substrates. The presented concept allows development of all-graphene electronic and optoelectronic devices with an all-optical method.


[Prenatal diagnosis of obstructive uropathies - positive predictive value and effect on postnatal therapy].
Prenatal diagnosis of urological anomalies is a standard procedure nowadays. The aim of this study was first to define the frequency of urinary tract anomalies in the selected patients in a level III center for prenatal diagnostics and therapy. The second aim was to show the accuracy of prenatal diagnosis in the special groups of obstructive uropathies. Postnatal diagnoses were used for control of the prenatal findings. In the 12-year retrospective study, we analyzed 21 616 pregnancies scanned for fetal anomalies. In 1 574 fetuses pediatric surgical anomalies were diagnosed. Out of 1 077 follow-ups 618 patients with urinary tract anomalies were found. It could be shown that prenatal ultrasound has a high sensitivity for the diagnosis of obstructive renal tract anomalies. The diagnosis of subpelvine obstruction and muticystic kidney dysplasia can be made with an accuracy of 97 and 98 %. The therapeutic relevance of the diagnosis "isolated hydronephrosis" increases up to 60 % when mild dilatation is neglected. False negative scans for urinary tract anomalies are low at 10 %. Hence, prenatal ultrasound for urinary tract anomalies is a method of high sensitivity. The therapeutic relevance is rather high. The most important question is to find all those patients who need a postnatal therapeutic approach immediately.


Ionic-Liquid-Based Paclitaxel Preparation: A New Potential Formulation for Cancer Treatment.
Paclitaxel (PTX) injection (i.e., Taxol) has been used as an effective chemotherapeutic treatment for various cancers. However, the current Taxol formulation contains Cremophor EL, which causes hypersensitivity reactions during intravenous administration and precipitation by aqueous dilution. This communication reports the preliminary results on the ionic liquid (IL)-based PTX formulations developed to address the aforementioned issues. The formulations were composed of PTX/cholinium amino acid ILs/ethanol/Tween-80/water. A significant enhancement in the solubility of PTX was observed with considerable correlation with the density and viscosity of the ILs, and with the side chain of the amino acids used as anions in the ILs. Moreover, the formulations were stable for up to 3 months. The driving force for the stability of the formulation was hypothesized to be the involvement of different types of interactions between the IL and PTX. In vitro cytotoxicity and antitumor activity of the IL-based formulations were evaluated on HeLa cells. The IL vehicles without PTX were found to be less cytotoxic than Taxol, while both the IL-based PTX formulation and Taxol exhibited similar antitumor activity. Finally, in vitro hypersensitivity reactions were evaluated on THP-1 cells and found to be significantly lower with the IL-based formulation than Taxol. This study demonstrated that specially designed ILs could provide a potentially safer alternative to Cremophor EL as an effective PTX formulation for cancer treatment giving fewer hypersensitivity reactions.


Pharmaceutical company spending on research and development and promotion in Canada, 2013-2016: a cohort analysis.
Competing claims are made about the amount of money that pharmaceutical companies spend on research and development (R&D) versus promotion. This study investigates this question in the Canadian context. Two methods for determining industry-wide figures for spending on promotion were employed. First, total industry spending on detailing and journal advertising for 2013-2016 was abstracted from reports from QuintilesIMS. Second, the mean total promotion spending for the years 2002-2005 was used to estimate total spending for 2013-2016. Total industry spending on R&D came from the Patented Medicine Prices Review Board (PMPRB). R&D to promotion spending using each method of determining the amount spent on promotion was compared for 2013-2016 inclusive. Data on the 50 top promoted drugs, the amounts spent, the companies marketing these products and their overall sales were abstracted from the QuintilesIMS reports. Spending on R&D and promotion as a percent of sales was compared for these companies. Industry wide, the ratio of R&D to promotion spending went from 1.43 to 2.18 when promotion was defined as the amount spent on detailing and journal advertising for the 50 most promoted drugs. Calculating total promotion spending from the mean of the 2002-2005 figures the ratio was 0.88 to 1.32 for the 50 most promoted drugs. For individual companies marketing one or more of the 50 most promoted drugs, mean R&D spending ranged from 3.7% of sales to 4.1% compared to mean promotion spending that went from 1.7 to 1.9%. The ratio of spending on R&D to promotion varied from 2.11 to 2.32. Eight to 10 companies per year spent more on promotion than on R&D. Depending on the method used to determine promotion spending, industry-wide the ratio of R&D spending to promotion ranges from 1.45 to 2.18 (sales representatives and journal advertising only) or from 0.88 to 1.32 (total promotion spending estimated based 2003-2005 data.) For the individual companies promoting one or more of the 50 most promoted drugs, 2.11 to 2.32 times more is spent on R&D compared to promotion. However these results should be interpreted cautiously because of data limitations.


The use of null models and partial least squares approach path modelling (PLS-PM) for investigating risk factors influencing post-weaning mortality in indoor pig farms.
Although post-weaning mortality (PWM) in pig farming is mainly due to the effect of pathogens, farm type or swine management are also directly or indirectly involved. In this work, we used null models and the partial least squares approach (PLS) to structural equation modelling, also known as PLS path modelling (PLS-PM), to explore whether farm type, swine management and pathogens, including porcine circovirus type 2, swine influenza virus, porcine reproductive and respiratory syndrome virus and Aujeszky's disease virus, directly or indirectly influenced PWM in 42 Spanish indoor pig farms. The null model analysis revealed that contact with multiple combinations of viruses could occur by chance. On the other hand, PLS-PM showed that farm characteristics do not influence virus infections, and thus neither farm type nor associated management practices shaped PWM due to pathogens. Accordingly, preventive programmes aimed at controlling PWM in intensive farming should prioritize the control of major pig pathogens.


Carbon Nanotubes and Chronic Granulomatous Disease.
Use of nanomaterials in manufactured consumer products is a rapidly expanding industry and potential toxicities are just beginning to be explored. Combustion-generated multiwall carbon nanotubes (MWCNT) or nanoparticles are ubiquitous in non-manufacturing environments and detectable in vapors from diesel fuel, methane, propane, and natural gas. In experimental animal models, carbon nanotubes have been shown to induce granulomas or other inflammatory changes. Evidence suggesting potential involvement of carbon nanomaterials in human granulomatous disease, has been gathered from analyses of dusts generated in the World Trade Center disaster combined with epidemiological data showing a subsequent increase in granulomatous disease of first responders. In this review we will discuss evidence for similarities in the pathophysiology of carbon nanotube-induced pulmonary disease in experimental animals with that of the human granulomatous disease, sarcoidosis.


One Health Perspectives on Emerging Public Health Threats.
Antimicrobial resistance and emerging infectious diseases, including avian influenza, Ebola virus disease, and Zika virus disease have significantly affected humankind in recent years. In the premodern era, no distinction was made between animal and human medicine. However, as medical science developed, the gap between human and animal science grew deeper. Cooperation among human, animal, and environmental sciences to combat emerging public health threats has become an important issue under the One Health Initiative. Herein, we presented the history of One Health, reviewed current public health threats, and suggested opportunities for the field of public health through better understanding of the One Health paradigm.


Immunotherapy Combinations and Sequences in Urothelial Cancer: Facts and Hopes.
Immune checkpoint inhibitors (ICI) have emerged as a novel therapeutic strategy that achieves significant clinical benefit in several tumor types, including urothelial cancer. Overall, these agents have shown objective response rates of around 20% to 23%, which indicates that a significant proportion of patients do not benefit from immunotherapy when given as monotherapy. Moreover, despite an initial response to therapy and an improvement in the median duration of response compared with chemotherapy, still only half of the patients develop long-term maintained remissions. Active research is ongoing in several fields, aiming to increase the number of patients that benefit from ICI, and this research is largely based on the development of biomarkers for personalized immunotherapy and novel combinations of ICI with other agents. This article will review ongoing efforts to develop combinations of ICI with other therapeutic strategies in patients with urothelial cancer, including chemotherapy, targeted agents, other immunotherapy strategies, and radiotherapy.


Colorimetric and Fluorescent Dual-Mode Immunoassay Based on Plasmon-Enhanced Fluorescence of Polymer Dots for Detection of PSA in Whole Blood.
Although enormous efforts have been devoted to the development of new types of fluorometric immunochromatographic test strip (ICTS) with improved sensitivity over the past years, it still remains a big challenge to design ICTS with colorimetric and fluorescent bimodal signal readout for rapid yet accurate detection of cancer markers in a clinic. Scientists have tried to prepare bimodal reporters by combining fluorescent dyes with metal nanomaterials, but their fluorescence was easily quenched by metal nanomaterials through surface energy transfer, making dual colorimetric and fluorometric ICTS very difficult to be achieved. As compared to conventional fluorescent probes, semiconducting polymer dots (Pdots) exhibit extraordinary fluorescence brightness and facile surface functionalization, which are very suitable to be engineered as bimodal signal reporting reagents. Here, we integrated highly fluorescent Pdots with strongly plasmonic Au nanorods to form Pdot-Au hybrid nanocomposites with dual colorimetric and fluorescent readout abilities. We further utilized these nanohybrids in ICTS for qualitatively fast screening (colorimetry) as well as quantitatively accurate determination (fluorometry) of prostate-specific antigen (PSA) within 10 min. By taking advantage of the plasmon-enhanced fluorescence of Pdots on Au nanorods, this immunoassay possesses much better detection sensitivity of 1.07 pg/mL for PSA, which is at least 2 orders of magnitude lower than that of conventional fluorometric ICTS. Moreover, the direct detection of PSA from human whole blood collected without sample pretreatment makes this Pdot-based ICTS platform promising for on-site point-of-care diagnostics.


Angiography as an index of healing in experimental laparotomy wounds and colonic anastomoses.
The vascular anatomy of healing wounds in rat abdominal wall and obstructed large bowel was examined by sequential angiography, with particular reference to the possibility of tissue necrosis following mass closure of the abdominal wall and of dehiscence after primary anastomosis in obstructed colon. In the abdominal wall, gross distortion of the vascular anatomy one to two weeks after mass closure was accompanied by a central wound zone which had an appearance suggestive of necrosis. By the fourth week after closure vascular anatomy was restored and "necrosis" completely resolved. In left colon that had been acutely obstructed for 72 h an increased risk of anastomotic failure was accompanied by delays in the appearance of new vessels and their growth across the anastomosis, as detected by colonic angiography. Mass closure should not be discarded because of the hypothetical risk of tissue necrosis. Primary anastomosis in acutely obstructed colon is contra-indicated because of risk of delayed healing.


The Effect of Soy Isoflavones on the Menopause Rating Scale Scoring in Perimenopausal and Postmenopausal Women: A Pilot Study.
Menopause is associated with many unpleasant symptoms which vary in different phases of menopausal transition. Although, Hormone Replacement Therapy (HRT) is considered the most effective mode of treatment for these symptoms, its use is associated with increased risk of breast cancer, endometrial cancer and thromboembolic events. Soy isoflavones are being widely used as a safer alternative to HRT, even though scientific evidence of their efficacy is poor or lacking. To study the effect of soy isoflavone supplementation on the menopausal symptoms in perimenopausal and postmenopausal women. An observational pilot study was done involving 29 perimenopausal and 21 postmenopausal women prescribed 100 mg soy isoflavones for 12 weeks. Menopause Rating Scale (MRS) questionnaire was administered to the patients before starting soy isoflavone therapy and at the end of treatment. Responses were analysed using Statistical Package for Social Sciences (SPSS) software 23.0. Total score of both the groups were comparable at baseline. Among perimenopausal women highest score was given to symptoms of psychological domain. Urogenital symptoms were the worst among postmenopausal women. After 12 weeks of treatment, total scores improved significantly by 19.55% and 12.62% in the perimenopausal and postmenopausal women respectively. The greatest improvement was seen in scores of hot flashes for both the groups and the least improvement was shown by symptoms of urogenital subscale. Soy isoflavone improves the MRS score among both the perimenopausal and postmenopausal women. As they are most effective for somatic and psychological symptoms, their use could be beneficial during perimenopause.


Choice of contracts in the British National Health Service: an empirical study.
Following major reforms of the British National Health Service (NHS) in 1990, the roles of purchasing and providing health services were separated, with the relationship between purchasers and providers governed by contracts. Using a mixed multinomial logit analysis, we show how this policy shift led to a selection of contracts that is consistent with the predictions of a simple model, based on contract theory, in which the characteristics of the health services being purchased and of the contracting parties influence the choice of contract form. The paper thus provides evidence in support of the practical relevance of theory in understanding health care market reform.


The importance of hydration and DNA conformation in interpreting infrared spectra of cells and tissues.
Since Watson and Crick's historical papers on the structure and function of DNA based on Rosalind Franklin's and Maurice Wilkin's X-ray diffraction patterns tremendous scientific curiosity has been aroused by the unique and dynamic structure of the molecule of life. A-DNA and B-DNA represent different conformations of the DNA molecule, which is stabilised by hydrogen interactions between base pairs, stacking interactions between neighboring bases and long-range intra- and inter-backbone forces. This review highlights the contribution Fourier transform infrared (FTIR) spectroscopy has made to the understanding of DNA conformation in relation to hydration and its potential role in clinical diagnostics. The review will first begin by elucidating the main forms of DNA conformation found in nature and the general structures of the A, B and Z forms. This is followed by a detailed critique on infrared spectroscopy applied to DNA conformation highlighting pivotal studies on isolated DNA, polynucleotides, nucleoprotein and nucleohistone complexes. A discussion on the potential of diagnosing cancer using FTIR spectroscopy based on the detection of DNA bands in cells and tissues will ensue, highlighting the recent studies investigating the conformation of DNA in hydrated and dehydrated cells. The method of hydration as a way to facilitate DNA conformational band assignment will be discussed and the conformational change to the A-form upon dehydration will be used to explain the reason for the apparent lack of FTIR DNA signals observed in fixed or air-dried cells and tissues. The advantages of investigating B-DNA in the hydrated state, as opposed to A-DNA in the dehydrated state, are exemplified in a series of studies that show: (1) improved quantification of DNA in cells; (2) improved discrimination and reproducibility of FTIR spectra recorded of cells progressing through the cell cycle; (3) insights into the biological significance of A-DNA as evidenced by an interesting study on bacteria, which can survive desiccation and at the same time undergo the B-A-B transition. Finally, the importance of preserving the B-DNA conformation for the diagnosis of cancer is put forward as way to improve the sensitivity of this powerful technique.


Reducing Hepatocyte Injury and Necrosis in Response to Paracetamol Using Noncoding RNAs.
The liver performs multiple functions within the human body. It is composed of numerous cell types, which play important roles in organ physiology. Our study centers on the major metabolic cell type of the liver, the hepatocyte, and its susceptibility to damage during drug overdose. In these studies, hepatocytes were generated from a renewable and genetically defined resource. In vitro-derived hepatocytes were extensively profiled and exposed to varying levels of paracetamol and plasma isolated from liver-failure patients, with a view to identifying noncoding microRNAs that could reduce drug- or serum-induced hepatotoxicity. We identified a novel anti-microRNA, which reduced paracetamol-induced hepatotoxicity and glutathione depletion. Additionally, we identified a prosurvival role for anti-microRNA-324 following exposure to plasma collected from liver failure patients. We believe that these studies represent an important advance for the field, demonstrating the power of stem cell-derived systems to model human biology "in a dish" and identify novel noncoding microRNAs, which could be translated to the clinic in the future. The liver performs vital functions within the human body and is composed of numerous cell types. The major metabolic cell type of the liver, the hepatocyte, is susceptible to damage during drug overdose. In these studies, hepatocytes were generated from a renewable resource and exposed to varying levels of paracetamol, with a view to identifying interventions that could reduce or attenuate drug-induced liver toxicity. A novel noncoding RNA that reduced paracetamol-induced hepatocyte toxicity was identified. These findings may represent an important advance for the field.


A novel GTP-binding protein gamma-subunit, G gamma 8, is expressed during neurogenesis in the olfactory and vomeronasal neuroepithelia.
A novel heterotrimeric G-protein gamma-subunit has been cloned, and its function has been confirmed by expression and purification. This gamma-subunit is only detected in the olfactory epithelium, the vomeronasal epithelium and, to a lesser extent, the olfactory bulb. It is absent from all other tissues studied including the nasal respiratory epithelium. During development, expression of G gamma 8 in the olfactory epithelium parallels neurogenesis, peaking shortly after birth and declining in the adult. In situ hybridization studies localize expression of this novel gamma-subunit to the sensory neurons; hybridization is strongest in the region of the epithelium that contains immature neurons. Unlike proteins that are expressed only in mature olfactory neurons (e.g. olfactory marker protein or Golf alpha), expression of G gamma 8 in the olfactory epithelium is relatively unaffected by olfactory bulbectomy. In the vomeronasal epithelium expression of G gamma 8 is also highest in the developing neurons. Taken together, these findings are consistent with a very specific role for G gamma 8 in the development and turnover of olfactory and vomeronasal neurons.


Harmonic generation of an obliquely incident ultrasonic wave in solid-solid contact interfaces.
The conventional acoustic nonlinear technique to evaluate the contact acoustic nonlinearity (CAN) at solid-solid contact interfaces (e.g., closed cracks), which uses the through-transmission of normally incident bulk waves, is limited in that access to both the inner and outer surfaces of structures for attaching pulsing and receiving transducers is difficult. The angle beam incidence and reflection technique, where both the pulsing and receiving transducers are located on the same side of the target, may allow the above problem to be overcome. However, in the angle incidence technique, mode-conversion at the contact interfaces as well as the normal and tangential interface stiffness should be taken into account. Based on the linear and nonlinear contact stiffness, we propose a theoretical model for the reflection of an ultrasonic wave angularly incident on contact interfaces. In addition, the magnitude of the CAN-induced second harmonic wave in the reflected ultrasonic wave is predicted. Experimental results obtained for the contact interfaces of A16061-T6 alloy specimens at various loading pressures showed good agreement with theoretical predictions. Such agreement proves the validity of the suggested oblique incidence model.


[Portal hypertension as a clinical manifestation of hepatic lesions in sarcoidosis].
The paper is devoted to differential diagnostics of portal hypertension (PH) in view of frequent diagnostic mistakes (10-15%) associated with this pathology. PH syndrome is usually interpreted by practitioners as a clinical manifestation of liver cirrhosis even if it is not necessarily related to the involvement of this organ. In patients with hepatic pathology, PH is likely to develop not only in case of fibrotic transformation and false lobule formation but also in case of disturbed blood flow in the portal vein, e.g. when granulomatous lesion of parenchyma takes place. Pathophysiological mechanisms and clinical peculiarities of intra-, sub-, suprahepatic and mixed forms of this condition are discussed. Etiological factors leading to the development of PH syndrome are considered. An original observation is presented of a patient with generalized sarcoidosis and histologically confirmed thoracic lymph nodes, spleen, lungs, liver; moderate granulomatous hepatitis, septal fibrosis (Knodel histology activity index 1-1-3-3- (8 scores)), PH, grade 1 oesophageal varicosis, splenomegaly, splenorenal anastomoses. The involvement of liver in the pathological process did not exceed 20%. Clinical, laboratory and instrumental studies rarely reveal manifestations of these changes. The diagnosis is verified histologically (discovery of granulomas formed by epithelial and giant multinuclear cells without signs of caseous necrosis. The reported case is distinctive for the development of PH in association of multiple giant heatic granulomas preventing the normal blood flow.