An open-label phase 2 study of twice-weekly bortezomib and intermittent pegylated liposomal doxorubicin in patients with ovarian cancer failing platinum-containing regimens.
Pegylated liposomal doxorubicin (PLD) is an established treatment for relapsed ovarian cancer. Preclinical and clinical evidences in other tumor types suggest that the proteasome inhibitor bortezomib can act synergistically with PLD. Patients with relapsed ovarian cancer (N = 58), previously treated with platinum (100%) and taxane (95%), received bortezomib, 1.3 mg/m intravenous (days 1, 4, 8, and 11), and PLD, 30 mg/m intravenous (day 1), every 3 weeks. Tumor responses were assessed using Response Evaluation Criteria In Solid Tumors and Gynecologic Cancer Intergroup criteria. An optimal 2-stage design was implemented. Gene expression profiling in peripheral blood was characterized before and during treatment in 10 platinum-sensitive patients enrolled in stage 2 of the study. Median number of bortezomib-PLD cycles was 3.5. Of 38 patients in the platinum-sensitive group, 9 responses were observed (median duration, 4.8 months). The platinum-resistant group was closed at stage 1 owing to lack of response. Toxicity was moderate and mainly consisted of hematologic, gastrointestinal, and mucositis events. Of the total 58 patients, peripheral neuropathy was reported in 9 patients (none were grade 3). Transcription profiling identified the prevalence of genes associated with ribonucleoprotein complexes, RNA processing, and protein translation. The gene expression changes were more robust in patients who responded or had stable disease compared with patients who had progressive disease. The combination of bortezomib and PLD was well tolerated, but the antitumor activity is insufficient to warrant further investigation in ovarian cancer.


Caffeine intake and its influences on heart rate variability recovery in healthy active adults after exercise: A systematic review and meta-analysis.
Results regarding the effects of caffeine (CAF) intake on the autonomic control of heart rate recovery exercise remain inconclusive. Thus far, no study has used effect measures to pool the results of different experiments. We aim to assess the acute effect of CAF intake before exercise on the recovery of heart rate variability (HRV) after exercise through a systematic review and meta-analysis. Randomized controlled clinical trials were included; sample composed of physically active or trained adults; CAF should be offered/ingested before exercise, with dosage between 100 and 400 mg or between 2 and 6 mg/kg and administration/ingestion route analogous in the protocols; studies required to present results of HRV indices before and after exercise. Bias risk analysis and meta-analysis were performed. Twelve studies were included in the qualitative synthesis and five studies were encompassed in the quantitative synthesis (meta-analysis). For the Root-mean-square standard deviation (RMSSD) index we revealed p = 0.67, Total 95% confidence interval (95% CI) ranged from -0.45 to 0.29, and 66.7% for heterogeneity between groups were reported. Concerning the High Frequency (HF) index, we observed p = 0.22, Total 95% CI that ranged from -0.34 to 0.30, and 44% for heterogeneity between groups. CAF intake did not affect heart rate variability recovery after exercise.


Familial auriculotemporal nerve (Frey) syndrome.
Auriculotemporal nerve (Frey) syndrome in children is rare, and may be misdiagnosed as food allergy. Trauma to the auriculotemporal nerve during forceps-assisted delivery has been implicated in about half of the reported childhood Frey syndrome cases and most patients present with unilateral involvement. We describe two Caucasian sisters with bilateral Frey syndrome, neither of whom was delivered with forceps assistance, and highlight its distinction from food allergy. Frey syndrome may occur in a familial pattern, and in the absence of a history of perinatal trauma.


Fine structure of the receptors at the myotendinous junction of human extraocular muscles.
The myotendinous junction of the human extraocular muscles was studied by electron microscopy. Some peculiar receptorial structures have been found in the majority of the samples examined. These structures are very small and consist of 1) the terminal portion of one muscle fibre, 2) the tendon into which it inserts and 3), within the tendon, a rich nerve arborization, whose branches are always very close to the muscle component. Only one discontinuous layer, made up of flat cells, which lack a basal lamina and often show pinocytotic vesicles, encapsules every musculo-tendinous complex. The tendinous component consists of amorphous ground substance of different electron density, of collagen and elastic fibres and is divided in compartments by ramified cells, which make an inner capsular-like covering to the nerve fibres. Three types of afferent nerve endings can be identified. One type is usually more frequent than the others, possesses a large number of neurotubules and neurofilaments and few mitochondria and is always surrounded by a Schwann cell which forms finger-like processes penetrating into the axoplasm. The second type is only partially enveloped by the Schwann cell. The axoplasm is devoid of neurotubules and contains few neurofilaments, several mitochondria and groups of small clear vesicles placed in the areas uncovered by the glial sheath. The third one is completely surrounded by the Schwann cell, but is devoid of neurotubules and neurofilaments and full of mitochondria. These morphological features correspond well with the probable role of these receptorial structures, which is to ensure very exact and precise ocular movements.


The founder mutation MSH2*1906G-->C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population.
Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by mutations in the mismatch-repair genes. We report here the identification and characterization of a founder mutation in MSH2 in the Ashkenazi Jewish population. We identified a nucleotide substitution, MSH2*1906G-->C, which results in a substitution of proline for alanine at codon 636 in the MSH2 protein. This allele was identified in 15 unrelated Ashkenazi Jewish families with HNPCC, most of which meet the Amsterdam criteria. Genotype analysis of 18 polymorphic loci within and flanking MSH2 suggested a single origin for the mutation. All colorectal cancers tested showed microsatellite instability and absence of MSH2 protein, by immunohistochemical analysis. In an analysis of a population-based incident series of 686 Ashkenazi Jews from Israel who have colorectal cancer, we identified 3 (0.44%) mutation carriers. Persons with a family history of colorectal or endometrial cancer were more likely to carry the mutation than were those without such a family history (P=.042), and those with colorectal cancer who carried the mutation were, on average, younger than affected individuals who did not carry it (P=.033). The mutation was not detected in either 566 unaffected Ashkenazi Jews from Israel or 1,022 control individuals from New York. In hospital-based series, the 1906C allele was identified in 5/463 Ashkenazi Jews with colorectal cancer, in 2/197 with endometrial cancer, and in 0/83 with ovarian cancer. When families identified by family history and in case series are included, 25 apparently unrelated Ashkenazi Jewish families have been found to harbor this mutation. Although this pathogenic mutation is not frequent in the Ashkenazi Jewish population (accounting for 2%-3% of colorectal cancer in those whose age at diagnosis is <60 years), it is highly penetrant and accounts for approximately one-third of HNPCC in Ashkenazi Jewish families that fulfill the Amsterdam criteria.


Without a license, or accidents waiting to happen.
This is a memoir of circumstances that have shaped my life as a scientist, some of the questions that have excited my interest, and some of the people with whom I have shared that pursuit. I was introduced to transcription soon after the discovery of RNA polymerase and have been fascinated by questions relating to gene regulation since that time. My account touches on early experiments dealing with the ability of RNA polymerase to selectively transcribe its DNA template. Temporal programs of transcription that control the multiplication cycles of viruses (phages) and the precise mechanisms generating this regulation have been a continuing source of fascination and new challenges. A longtime interest in eukaryotic RNA polymerase III has centered on yeast and on the enumeration and properties of its transcription initiation factors, the architecture of its promoter complexes, and the mechanism of transcriptional initiation. These areas of research are widely regarded as separate, but to my thinking they have posed similar questions, and I have been unwilling or unable to abandon either one for the other. An additional interest in archaeal transcription can be seen as stemming naturally from this point of view.


Parasitic infection among children living in two orphanages in Cairo.
Children living in institutions as orphanages are more exposed to intestinal parasitism, since crowding and behavioral pattern contribute greatly to the spread of parasitic infection. The present study was conducted on 100 children living in Ain-Shams and El-Mowassa orphanages, Cairo. Twenty children living under appropriate health conditions were studied as controls. Ages of both groups ranged from 6-12 years. The results of this study revealed that 69/100 (69%) orphanage children were positive for parasitic infection, while 8/20 (40%) control subjects were positive for parasitic infection; the difference was statistically significant. Enterobius vermicularis was the commonest parasite among both groups. Other parasitic infections detected were; Giardia lamblia, Entamoeba histolytica, Hymenolepis nana and Entamoeba coli with a prevalence of 10%, 9%, 2% and 9% respectively in the study group compared to 15%, 10%, 0% and 5% in the control group; the differences were statistically not significant. Cryptosporidium oocysts were not detected in both groups.


Depression, survival, and epidermal growth factor receptor genotypes in patients with metastatic non-small cell lung cancer.
Although depression appears to be associated with worse survival from cancer, the underlying mechanisms of this association are unknown. Tumor epidermal growth factor receptor (EGFR) genotype is a known predictor of survival in metastatic non-small cell lung cancer (NSCLC) and appears to be associated with depression. We hypothesized that tumor EGFR genotype may account for a relationship between depression and survival in this population. We investigated this possible relationship in a cohort of patients with metastatic NSCLC, in which we had previously demonstrated an association between depression and worse survival. A cohort of 151 patients with newly diagnosed metastatic NSCLC were enrolled and followed in a randomized controlled trial of early palliative care. At enrollment, 150 had depression assessed with the Patient Health Questionnaire-9 (PHQ-9), and categorical scoring for major depressive syndrome (MDS) was used for analyses. Patients with tumor tissue available underwent EGFR genotyping. Associations with survival were tested using Cox proportional hazards models, adjusting for potential confounders. Twenty-one patients (14.0%) met criteria for MDS. Forty-four patients (29.3%) had EGFR genotyping, and 17 (38.6%) of these harbored EGFR mutations. Patients with EGFR mutations had significantly lower PHQ-9 scores (p = 0.03), and none met criteria for depression. EGFR mutations were significantly associated with superior survival (p = 0.02). When both depression and EGFR genotype were simultaneously entered into the model, only EGFR mutations remained significantly associated with survival (p = 0.02), and the effect of depression was attenuated. Depression is associated with worse survival in metastatic NSCLC, and this relationship may be at least partially explained by tumor EGFR genotype. Further study into whether depression could be associated with specific biologic properties of cancer that vary by genotype is warranted.


Decrease of natural killer cell activity and monokine production in peripheral blood of patients treated with recombinant tumor necrosis factor.
Tumor necrosis factor (TNF), a protein predominantly produced by activated macrophages/monocytes, is presently available in recombinant, purified form for clinical trials. Intensive studies in many laboratories have shown that besides the tumorcytotoxic effects, TNF acts on a large array of different cells and has potent immunomodulatory activities. In a clinical phase I study, some immunologic functional parameters of blood cells from patients who received 24-hour infusions of recombinant human TNF (rhTNF) were analyzed. Natural killer (NK) cell activity, TNF production, interleukin-1 (IL-1) production and mitogen-induced proliferation were measured either in whole blood samples or in cultures of peripheral mononuclear leukocytes of the patients directly before and after rhTNF infusion. NK cell activity, TNF and IL-1 production capacity and proliferative responses to concanavalin A (Con A) were significantly reduced after rhTNF application. We conclude from these observations that rhTNF in vivo acts directly or indirectly on NK cells and monocytes by either inactivating their functional capacity or by absorbing the relevant cells to the endothelial cell layer, thus removing them from circulation.


The impact of health insurance in Africa and Asia: a systematic review.
To evaluate the impact of health insurance on resource mobilization, financial protection, service utilization, quality of care, social inclusion and community empowerment in low- and lower-middle-income countries in Africa and Asia. A systematic search for randomized controlled trials, quasi-experimental and observational studies published before the end of 2011 was conducted in 20 literature databases, reference lists of relevant studies, web sites and the grey literature. Study quality was assessed with a quality grading protocol. Inclusion criteria were met by 159 studies - 68 in Africa and 91 in Asia. Most African studies reported on community-based health insurance (CBHI) and were of relatively high quality; social health insurance (SHI) studies were mostly Asian and of medium quality. Only one Asian study dealt with private health insurance (PHI). Most studies were observational; four had randomized controls and 20 had a quasi-experimental design. Financial protection, utilization and social inclusion were far more common subjects than resource mobilization, quality of care or community empowerment. Strong evidence shows that CBHI and SHI improve service utilization and protect members financially by reducing their out-of-pocket expenditure, and that CBHI improves resource mobilization too. Weak evidence points to a positive effect of both SHI and CBHI on quality of care and social inclusion. The effect of SHI and CBHI on community empowerment is inconclusive. Findings for PHI are inconclusive in all domains because of insufficient studies. Health insurance offers some protection against the detrimental effects of user fees and a promising avenue towards universal health-care coverage.


SULT1A1 Arg213His polymorphism is associated with bladder cancer risk: a meta-analysis.
The evidence of an association between the Sulfotransferase 1A1 (SULT1A1) Arg213His polymorphism (rs9282861) and bladder cancer risk is still conflicting. We conducted a meta-analysis to assess the association between this polymorphism and bladder cancer risk. PubMed, EMBASE, HuGE Navigator, and Web of Science databases were searched for correlative articles. The risk (odds ratio, OR) was used to estimate the association between SULT1A1 Arg213His polymorphism and bladder cancer risk. All of the studies used either fixed-effects or random-effects models. For assessing the credibility of an association, we applied the Venice criteria. Seven published case-control studies with 1688 cases and 2842 controls were included in this meta-analysis. There were 5 studies of Caucasians and 2 studies of Asians. Four studies reported data on smoking behavior. The percentage of Arg/Arg was higher in Asians and non-smokers than that in Caucasians and smokers, respectively. A significant association of this polymorphism with bladder cancer was found (OR=1.45, 95% CI 1.18-1.78, P=0.0004). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR=1.43, 95% CI 1.16-1.77, P=0.0008) but not among Asians (OR=1.89, 95% CI 0.68-5.26, P=0.22). In the subgroup analysis by smoking behavior, increased bladder cancer risk was found in the smokers (OR=1.39, 95% CI 1.01-1.91, P=0.04) and non-smokers (OR=1.74, 95% CI 1.24-2.43, P=0.001). In conclusion, this meta-analysis indicated that SULT1A1 Arg213His polymorphism is associated with bladder cancer risk.


Impairment of T-cell regulation of the humoral immune response to type III pneumococcal polysaccharide in diabetic mice.
The peak plaque-forming-cell (PFC) and serum antibody responses of diabetic mice to type III pneumococcal capsular polysaccharide (S3) were delayed compared with normals. Proliferation of PFC precursors was not inhibited in an insulin-deficient environment. The delay in the PFC response to S3 did not occur in diabetic nude mice but was demonstrable in their thymus-bearing heterozygote littermates. Therefore, T-cells appear to mediate the delay in the response of diabetic mice to S3 probably by delaying their differentiation into PFC. Diabetic mice responded normally to the induction of low-dose tolerance to S3, indicating the presence of active suppressor T-cells (Ts) in these mice. However, inactivation of Ts by anti-lymphocyte serum (ALS) required a higher dose in the diabetic mice. Furthermore, inactivation of Ts by ALS totally abolished the delay in peak PFC response. These findings suggest that the delayed PFC response to S3 in diabetic mice was the result of excessive splenic Ts activity. In peripheral blood, diabetic mice appeared to have more amplifier T-cell activity or less suppressor T-cell activity than normals. This response was normalized by insulin treatment. DIABETES 32:156-164, February 1983.


Subcutaneous phycomycosis.
Subcutaneous phycomycosis, a uncommon fungal infection of the human skin, is discussed and a representative case is described. Subcutaneous phycomycosis is a chronic, progressive fungal infection of the deeper layers of the human skin that causes localized, mobile, firm and non-tender swellings. The causative organism is the Basidiobolus haptosporus, a fungus commonly found in rotting vegetation in the soil.


Seasonal fluctuations attenuate stimulatory or inhibitory impacts of colonial birds on abundance, structure and diversity of soil biota.
Soil microorganisms and free-living nematodes were investigated in association with the nesting and roosting habitats of the following piscivorous and omnivorous colonial birds: black kite (Milvus migrans), great cormorant (Phalacrocorax carbo), black-crowned night heron (Nycticorax nycticorax) and little egret (Egretta garzetta), in Israel's Mediterranean region. Abiotic variables, abundance, trophic structure, sex ratio and genus diversity of soil free-living nematodes, and total abundance of bacteria and fungi, were measured during the wet season, following our previous study conducted during the dry season. The observed soil properties were important drivers of soil biota structure. Presence of the most efficient elements for soil organisms, such as phosphorus and nitrogen, was strongly dependent on the diet of the compared piscivorous and omnivorous bird colonies; levels of these nutrients were notably higher in the bird habitats than in their respective control sites during the study period. Ecological indices showed that the different species of colonial birds can have different (stimulatory or inhibitory) impacts on abundance and diversity of the soil biota, affecting the structure of the soil free-living nematode population at the generic, trophic and sexual levels during the wet season. A comparison with results from the dry season illustrated that seasonal fluctuations can change, and even attenuate the effect of bird activity on the abundance, structure and diversity of the soil communities.


Giant room temperature compression and bending in ferroelectric oxide pillars.
Plastic deformation in ceramic materials is normally only observed in nanometre-sized samples. However, we have observed high levels of plasticity (>50% plastic strain) and excellent elasticity (6% elastic strain) in perovskite oxide Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3, under compression along <100>pc pillars up to 2.1 μm in diameter. The extent of this deformation is much higher than has previously been reported for ceramic materials, and the sample size at which plasticity is observed is almost an order of magnitude larger. Bending tests also revealed over 8% flexural strain. Plastic deformation occurred by slip along {110} <1[Formula: see text]0 > . Calculations indicate that the resulting strain gradients will give rise to giant flexoelectric polarization. First principles models predict that a high concentration of oxygen vacancies weaken the covalent/ionic bonds, giving rise to the unexpected plasticity. Mechanical testing on oxygen vacancies-rich Mn-doped Pb(In1/2Nb1/2)O3-Pb(Mg1/3Nb2/3)O3-PbTiO3 confirmed this prediction. These findings will facilitate the design of plastic ceramic materials and the development of flexoelectric-based nano-electromechanical systems.


[The urological screening of children with myelodysplasia].
All children with myelodysplasia have urological diseases. Nevertheless, errors in urological policy and diagnosis are made just at the first stage of a study, by leading to inadequate treatment, progressive obstructive complications, chronic renal failure. The authors propose a urological screening, simple, accessible, and safe tests, which may evaluate the urinary system, determine the expediency and urgency of further examination during early management of children with myelodysplasia.


Microrheology and Spatial Heterogeneity of Staphylococcus aureus Biofilms Modulated by Hydrodynamic Shear and Biofilm-Degrading Enzymes.
Particle tracking microrheology was used to investigate the viscoelasticity of Staphylococcus aureus biofilms grown in microfluidic cells at various flow rates and when subjected to biofilm-degrading enzymes. Biofilm viscoelasticity was found to harden as a function of shear rate but soften with increasing height away from the attachment surface in good agreement with previous bulk results. Ripley's K-function was used to quantify the spatial distribution of the bacteria within the biofilm. For all conditions, biofilms would cluster as a function of height during growth. The effects of proteinase K and DNase-1 on the viscoelasticity of biofilms were also investigated. Proteinase K caused an order of magnitude change in the compliances, softening the biofilms. However, DNase-1 was found to have no significant effects over the first 6 h of development, indicating that DNA is less important in biofilm maintenance during the initial stages of growth. Our results demonstrate that during the preliminary stages of Staphylococcus aureus biofilm development, column-like structures with a vertical gradient of viscoelasticity are established and modulated by the hydrodynamic shear caused by fluid flow in the surrounding environment. An understanding of these mechanical properties will provide more accurate insights for removal strategies of early-stage biofilms.


In vivo kinetics of Wolbachia depletion by ABBV-4083 in L. sigmodontis adult worms and microfilariae.
Depletion of Wolbachia endosymbionts of human pathogenic filariae using 4-6 weeks of doxycycline treatment can lead to permanent sterilization and adult filarial death. We investigated the anti-Wolbachia drug candidate ABBV-4083 in the Litomosoides sigmodontis rodent model to determine Wolbachia depletion kinetics with different regimens. Wolbachia reduction occurred in mice as early as 3 days after the initiation of ABBV-4083 treatment and continued throughout a 10-day treatment period. Importantly, Wolbachia levels continued to decline after a 5-day-treatment from 91.5% to 99.9% during a 3-week washout period. In jirds, two weeks of ABBV-4083 treatment (100mg/kg once-per-day) caused a >99.9% Wolbachia depletion in female adult worms, and the kinetics of Wolbachia depletion were recapitulated in peripheral blood microfilariae. Similar to Wolbachia depletion, inhibition of embryogenesis was time-dependent in ABBV-4083-treated jirds, leading to a complete lack of late embryonic stages (stretched microfilariae) and lack of peripheral microfilariae in 5/6 ABBV-4083-treated jirds by 14 weeks after treatment. Twice daily treatment in comparison to once daily treatment with ABBV-4083 did not significantly improve Wolbachia depletion. Moreover, up to 4 nonconsecutive daily treatments within a 14-dose regimen did not significantly erode Wolbachia depletion. Within the limitations of an animal model that does not fully recapitulate human filarial disease, our studies suggest that Wolbachia depletion should be assessed clinically no earlier than 3-4 weeks after the end of treatment, and that Wolbachia depletion in microfilariae may be a viable surrogate marker for the depletion within adult worms. Furthermore, strict daily adherence to the dosing regimen with anti-Wolbachia candidates may not be required, provided that the full regimen is subsequently completed.


Domain-specific control of neurogenesis achieved through patterned regulation of Notch ligand expression.
Homeodomain (HD) transcription factors and components of the Notch pathway [Delta1 (Dll1), Jagged1 (Jag1) and the Fringe (Fng) proteins] are expressed in distinct progenitor domains along the dorsoventral (DV) axis of the developing spinal cord. However, the internal relationship between these two regulatory pathways has not been established. In this report we show that HD proteins act upstream of Notch signalling. Thus, HD proteins control the spatial distribution of Notch ligands and Fng proteins, whereas perturbation of the Notch pathway does not affect the regional expression of HD proteins. Loss of Dll1 or Jag1 leads to a domain-specific increase of neuronal differentiation but does not affect the establishment of progenitor domain boundaries. Moreover, gain-of-function experiments indicate that the ability of Dll1 and Jag1 to activate Notch is limited to progenitors endogenously expressing the respective ligand. Fng proteins enhance Dll1-activated Notch signalling and block Notch activation mediated by Jag1. This finding, combined with the overlapping expression of Fng with Dll1 but not with Jag1, is likely to explain the domain-specific activity of the Notch ligands. This outcome is opposite to the local regulation of Notch activity in most other systems, including the Drosophila wing, where Fng co-localizes with Jagged/Serrate rather than Dll/Delta, which facilitates Notch signalling at regional boundaries instead of within domains. The regulation of Notch activation in the spinal cord therefore appears to endow specific progenitor populations with a domain-wide autonomy in the control of neurogenesis and prevents any inadequate activation of Notch across progenitor domain boundaries.


Normal values of proximal aorta diameters in healthy Sub Saharan Africans: The TAHES study.
Reported ranges of normal values are mostly issued from studies performed with Caucasians. This study is a part of TAHES, a population-based prospective cohort study in Benin and aims to establish normal reference values for echocardiographic diameters of the proximal aorta in Africans. Transthoracic echocardiography (TTE) examinations were performed by four cardiologists following pre-defined protocols, and analyzed off-line by a single observer. Aortic root diameters were measured during diastole for sinuses of Vasalva (SV), sinotubular junction (STJ) and proximal ascending aorta (AA), and during systole for annulus. Upper limits were defined as the 95th percentiles. We included 513 normotensive, non-diabetic, and cardiovascular disease-free individuals (206 men, 307 women, age 40 ± 14 years). The diameters of the proximal aorta were significantly greater in men. The inner-edge-to-inner-edge non-indexed upper values for the annulus, SV, STJ and AA were respectively 25, 34, 28.5, 32 mm in men and 22, 30, 26, 30 mm in women. The leading-edge-to-leading-edge upper values were respectively 38, 35, 36 for men and 34, 33, 32 mm for women. No significant differences between sexes were recorded for body surface area (BSA)-indexed diameters of the annulus, STJ and AA. BSA-indexed SV dimension was greater in men than women were. SV, STJ, AA indexed-diameters correlated with age in both sexes but not for annulus indexed-diameter. Normal values from a general population in West Africa could to differ from those established in Caucasian populations. Ethnic-specific reference diameters are here proposed for appropriate diagnosis of proximal aortic diseases in sub-Saharan Africa.


Relationship between gluteal muscle strength, corticospinal excitability, and jump-landing biomechanics in healthy women.
Components of gluteal neuromuscular function, such as strength and corticospinal excitability, could potentially influence alterations in lower extremity biomechanics during jump landing. To determine the relationship between gluteal muscle strength, gluteal corticospinal excitability, and jump-landing biomechanics in healthy women. University laboratory. Descriptive laboratory study. 37 healthy women (21.08 ± 2.15 y, 164.8 ± 5.9 cm, 65.4 ± 12.0 kg). Bilateral gluteal strength was assessed through maximal voluntary isometric contractions (MVIC) using an isokinetic dynamometer. Strength was tested in the open chain in prone and side-lying positions for the gluteus maximus and gluteus medius muscles, respectively. Transcranial magnetic stimulation was used to elicit measures of corticospinal excitability. Participants then performed 3 trials of jump landing from a 30-cm box to a distance of 50% of their height, with an immediate rebound to a maximal vertical jump. Each jump-landing trial was video recorded (2-D) and later scored for errors. MVICs normalized to body mass were used to assess strength in the gluteal muscles of the dominant and nondominant limbs. Corticospinal excitability was assessed by means of active motor threshold (AMT) and motor-evoked potentials (MEP) elicited at 120% of AMT. The Landing Error Scoring System (LESS) was used to evaluate jump-landing biomechanics. A moderate, positive correlation was found between dominant gluteus maximus MEP and LESS scores (r = .562, P = .029). No other significant correlations were observed for MVIC, AMT, or MEP for the gluteus maximus and gluteus medius, regardless of limb. The findings suggest a moderate relationship between dominant gluteus maximus corticospinal excitability and a clinical measure of jump-landing biomechanics. Further research is required to substantiate the findings and expand our understanding of the central nervous system's role in athletic movement.


Triadin regulates cardiac muscle couplon structure and microdomain Ca(2+) signalling: a path towards ventricular arrhythmias.
Since the discovery of triadin >20 years ago as one of the major proteins located in the junctional sarcoplasmic reticulum, the field has come a long way in understanding the pivotal role of triadin in orchestrating sarcoplasmic reticulum Ca(2+)-release and hence excitation-contraction (EC) coupling. Building on the information gathered from earlier lipid bilayer and myocyte overexpression studies, the gene-targeted ablation of Trdn demonstrated triadin's indispensable role for maintaining the structural integrity of the couplon. More recently, the discovery of inherited and acquired diseases displaying altered expression and function of triadin has further emphasized the role of triadin in health and disease. Novel therapeutic approaches could be aimed at correcting the loss of triadin in diseased hearts, and thereby correcting the sub-cellular EC coupling defect. This review summarizes current concepts of the impact of triadin on cardiac EC coupling with a focus towards triadin's role for ventricular arrhythmia.


High Exposure to Perfluoroalkyl Substances and Antibody Responses to SARS-CoV-2 mRNA Vaccine-an Observational Study in Adults from Ronneby, Sweden.
Per- and polyfluoroalkyl substances (PFAS) are widely used, environmentally ubiquitous, and stable chemicals that have been associated with lower vaccine-induced antibody responses in children; however, data on adults are limited. The drinking water from one of the two waterworks in Ronneby, Sweden, was heavily contaminated for decades with PFAS from firefighting foams, primarily perfluorohexane sulfonic acid and perfluorooctanesulfonic acid (PFOS). Vaccination against SARS-CoV-2 offered a unique opportunity to investigate antibody responses to primary vaccination in adults who had been exposed to PFAS. Our objective was to evaluate associations between PFAS, across a wide range of exposure levels, and antibody responses in adults 5 wk and 6 months after a two-dose vaccination regime against SARS-CoV-2. Adults age 20-60 y from Ronneby (n=309, median PFOS serum level 47 ng/mL, fifth to 95th percentile 4-213 ng/mL) and a group with background exposure (n=47, median PFOS serum level 4 ng/mL) received two doses of the Spikevax (Moderna) mRNA vaccine. The levels of seven PFAS were measured in serum before vaccination. Serum immunoglobulin G antibodies against the SARS-CoV-2 spike antigen (S-Abs) were measured before vaccination and at 5 wk (n=350) and 6 months (n=329) after the second vaccine dose. Linear regression analyses were fitted against current, historical, and prenatal exposure to PFAS, adjusting for sex, age, and smoking, excluding individuals with previous SARS-CoV-2-infection. PFAS exposure, regardless of how it was estimated, was not negatively associated with antibody levels 5 wk [current PFOS: -0.5% S-Abs/PFOS interquartile range (IQR); 95% confidence interval (CI): -8, 7] or 6 months (current PFOS: 3% S-Abs/PFOS IQR; 95% CI: -6, 12) after COVID-19 vaccination. Following a strict study protocol, rigorous study design, and few dropouts, we found no indication that PFAS exposure negatively affected antibody responses to COVID-19 mRNA vaccination for up to 6 months after vaccination. https://doi.org/10.1289/EHP11847.


HIV-Mycobacterium tuberculosis co-infection: a 'danger-couple model' of disease pathogenesis.
Tuberculosis (TB) and human immunodeficiency virus (HIV) infection interfere and impact the pathogenesis phenomena of each other. Owing to atypical clinical presentations and diagnostic complications, HIV/TB co-infection continues to be a menace for healthcare providers. Although the increased access to highly active antiretroviral therapy (HAART) has led to a reduction in HIV-associated opportunistic infections and mortality, the concurrent management of HIV/TB co-infection remains a challenge owing to adverse effects, complex drug interactions, overlapping toxicities and tuberculosis -associated immune reconstitution inflammatory syndrome. Several hypotheses have been put forward for the exacerbation of tuberculosis by HIV and vice versa supported by immunological studies. Discussion on the mechanisms produced by infectious cofactors with impact on disease pathology could shed light on how to design potential interventions that could decelerate disease progression. With no vaccine for HIV and lack of an effective vaccine for tuberculosis, it is essential to design strategies against HIV-TB co-infection.


Dose-response relationships of the sigmoid for urgency syndrome after gynecological radiotherapy.
To find out what organs and doses are most relevant for 'radiation-induced urgency syndrome' in order to derive the corresponding dose-response relationships as an aid for avoiding the syndrome in the future. From a larger group of gynecological cancer survivors followed-up 2-14 years, we identified 98 whom had undergone external beam radiation therapy but not brachytherapy and not having a stoma. Of those survivors, 24 developed urgency syndrome. Based on the loading factor from a factor analysis, and symptom frequency, 15 symptoms were weighted together to a score interpreted as the intensity of radiation-induced urgency symptom. On reactivated dose plans, we contoured the small intestine, sigmoid colon and the rectum (separate from the anal-sphincter region) and we exported the dose-volume histograms for each survivor. Dose-response relationships from respective risk organ and urgency syndrome were estimated by fitting the data to the Probit, RS, LKB and gEUD models. The rectum and sigmoid colon have steep dose-response relationships for urgency syndrome for Probit, RS and LKB. The dose-response parameters for the rectum were D50: 51.3, 51.4, and 51.3 Gy, γ50 = 1.19 for all models, s was 7.0e-09 for RS and n was 9.9 × 107 for LKB. For Sigmoid colon, D50 were 51.6, 51.6, and 51.5 Gy, γ50 were 1.20, 1.25, and 1.27, s was 2.8 for RS and n was 0.079 for LKB. Primarily the dose to sigmoid colon as well as the rectum is related to urgency syndrome among gynecological cancer survivors. Separate delineation of the rectum and sigmoid colon in order to incorporate the dose-response results may aid in reduction of the incidence of the urgency syndrome.


Tumor-derived TGF-beta mediates conversion of CD4+Foxp3+ regulatory T cells in a murine model of pancreas cancer.
CD4+25+Foxp3+ regulatory T cells (Treg) play a critical role in the induction of tolerance to tumor-associated antigens and suppression of antitumor immunity. How Treg are induced in cancer is poorly understood. We reported previously that Treg are significantly elevated in the peripheral blood of patients with pancreas cancer and that in a murine pancreas cancer model induction of Treg seems to be transforming growth factor (TGF)-beta dependent. Here we provide additional evidence that Treg are increased locally within the tumor microenvironment by a mechanism that seems dependent on TGF-beta receptor expression and the presence of tumor derived TGF-beta. The murine pancreas cancer cell line Pan02 produces high levels of TGF-beta both in vitro and in vivo. In contrast, the esophageal murine cancer cell line, Eso2, does not. Immunohistochemical staining of Foxp3 in explanted tumors shows an identifiable population of Treg in the Pan02 (TGF-beta positive) tumors but not Eso2 (TGF-beta negative). Naive CD4+25-Foxp3- T cells, when adoptively transferred into Rag-/- mice, are converted into Foxp3+ Treg in the presence of Pan02 but not Eso2 tumors. Induction of Treg in Pan02 mice is blocked by systemic injection of an anti-TGF-beta antibody. If Rag-/- mice are instead reconstituted with naive CD4+25- T cells expressing a mutated TGF-beta receptor, induction of Foxp3+ Treg in Pan02 bearing mice is blocked. Collectively, these observations further support the role of TGF-beta in the induction of Treg in pancreas adenocarcinoma.


Sickness behaviors in response to unusual external events in healthy cats and cats with feline interstitial cystitis.
To compare sickness behaviors (SB) in response to unusual external events (UEE) in healthy cats with those of cats with feline interstitial cystitis (FIC). Prospective observational study. 12 healthy cats and 20 donated cats with FIC. Cats were housed in a vivarium. Sickness behaviors referable to the gastrointestinal and urinary tracts, the skin, and behavior problems were recorded by a single observer for 77 weeks. Instances of UEE (eg, changes in caretakers, vivarium routine, and lack of interaction with the investigator) were identified during 11 of the 77 weeks. No instances of UEE were identified during the remaining 66 weeks, which were considered control weeks. An increase in age and exposure to UEE, but not disease status, significantly increased total number of SB when results were controlled for other factors. Evaluation of individual SB revealed a protective effect of food intake for healthy males. An increase in age conferred a small increase in relative risk (RR) for upper gastrointestinal tract signs (RR, 1.2) and avoidance behavior (1.7). Exposure to UEE significantly increased the RR for decreases in food intake (RR, 9.3) and for no eliminations in 24 hours (6.4). Exposure to UEE significantly increased the RR for defecation (RR, 9.8) and urination (1.6) outside the litter box. SB, including some of the most commonly observed abnormalities in client-owned cats, were observed after exposure to UEE in both groups. Because healthy cats and cats with FIC were comparably affected by UEE, clinicians should consider the possibility of exposure to UEE in cats evaluated for these signs.


Progress on methods of T lymphocyte development in vitro.
T lymphocytes (T cells) play an important role in adoptive cellular immunotherapy (ACT). T cells can be stably derived and easily obtained by various methods of T cell development in vitro, which have more advantages than traditional methods of T cells isolated from autologous or allogeneic tissues. At present, there are mainly three methods for T cell development in vitro: fetal thymus organ culture, recombinant thymus organ culture and two-dimensional culture driven by Notch signal. Fetal thymus organ culture is easy to operate, the isolated thymus can support T cell differentiation and development to maturity in vitro, but the intact thymus has problems of limited maintenance time and difficulty in cell harvesting. In recombinant thymic organ culture, various thymic stromal cells are dispersed and recombined to construct a three-dimensional culture environment, which can support T cell maturation in vitro and in vivo; however, biomaterials and three-dimensional environment may lead to limited culture maintenance time and cell yield. Two-dimensional culture method uses artificial presentation of Notch signaling pathway ligands to drive T cell differentiation and development; the culture architecture is simple and stable, but it can only support T cell development to the early immature stage. This article reviews the research progress of various culture methods of T cell development in vitro, and discusses the existing problems and the future development to facilitate the application of ACT.


Effects of Noise on the Behavioral and Neural Categorization of Speech.
We investigated whether the categorical perception (CP) of speech might also provide a mechanism that aids its perception in noise. We varied signal-to-noise ratio (SNR) [clear, 0 dB, -5 dB] while listeners classified an acoustic-phonetic continuum (/u/ to /a/). Noise-related changes in behavioral categorization were only observed at the lowest SNR. Event-related brain potentials (ERPs) differentiated category vs. category-ambiguous speech by the P2 wave (~180-320 ms). Paralleling behavior, neural responses to speech with clear phonetic status (i.e., continuum endpoints) were robust to noise down to -5 dB SNR, whereas responses to ambiguous tokens declined with decreasing SNR. Results demonstrate that phonetic speech representations are more resistant to degradation than corresponding acoustic representations. Findings suggest the mere process of binning speech sounds into categories provides a robust mechanism to aid figure-ground speech perception by fortifying abstract categories from the acoustic signal and making the speech code more resistant to external interferences.


[Treatment of neurotoxoplasmosis with the combination sulfamethoxazole-trimethoprim: report of 10 cases].
Toxoplasmosis is the most frequent parasitic infection of the CNS in the immunocompromised host. When promptly treated with the sulfadiazine-pyrimethamine combination patients with cerebral toxoplasmosis characteristically respond with clear clinical and CT improvement within 1-2 weeks. We report the results achieved with the combination sulfamethoxazole-trimethoprim, and conclude that both combinations have similar effects in the treatment of CNS toxoplasmosis.


Hydrogen-mediated magnetic domain formation and domain wall motion in Co30Pd70 alloy films.
In this study, the microscopic origin of the hydrogen effect on magnetic materials was explored through the characterization of time-dependent magnetic domain evolution. We prepared 25-nm Co30Pd70 alloy films with canted magnetic moment on SiO2/Si(001) substrates. From macroscopic Kerr hysteresis loops, considerable hydrogen-induced reduction of magnetic coercivity by a factor of 1/5 in a longitudinal direction and enhancement of magnetic remanence to saturation ratio from 60% to 100% were observed. The magnetic reversal behavior of the Co30Pd70 alloy films gradually transformed from nucleation- to domain-wall-motion dominance when H2 pressure was increased from a vacuum of 1 × 10-5 mbar to 0.8 bar. Domain size also increased considerably with H2 pressure. When H2 pressure was above 0.4 bar, the domain wall (DW) motion was clear to observe and the DW velocity was approximately 10-6-10-5 m/s. Greater hydrogen content in the Co30Pd70 alloy films promoted DW motion that was closer to the behavior of a thermally activated model. The hydrogen effects on magnetism were observed to be reversible and could have valuable future application in spintronic devices for hydrogen sensing.


Ursolic acid rich Ocimum sanctum L leaf extract loaded nanostructured lipid carriers ameliorate adjuvant induced arthritis in rats by inhibition of COX-1, COX-2, TNF-α and IL-1: Pharmacological and docking studies.
Ursolic acid (UA) is a promising molecule with anti-inflammatory, analgesic and potential anti-arthritic activity. This study was undertaken to make formulation and evaluation of Ocimum sanctum L. leaf extract (OLE) loaded nano-structured lipid carriers (OLE-NLCs) for improved transdermal delivery of UA. Different surfactants, solid lipids and liquid lipids were used for the preparation of NLCs. The NLCs were developed using emulsion solvent diffusion and evaporation method. Different physicochemical properties, entrapment efficacy, in vitro release evaluation, and ex vivo permeation studies of the prepared NLCs were carried out. The in vivo anti-arthritic activity of OLE-loaded NLC gel and control gel formulation (OLE free NLC gel) against Complete Freund's Adjuvant (CFA) induced arthritis in wister albino rats was also carried out. OLE-NLCs were composed of spherical particles having a mean particle size of ~120 nm, polydispersity index of ~0.162 and zeta potential of ~ -27 mV. The high entrapment efficiency (EE) of UA ~89.56% was attained. The in vitro release study demonstrated a prolonged release of UA from the NLCs up to 12 h. The developed formulation was found to be significantly better with respect to the drug permeation amount with an enhancement ratio of 2.69 as compared with marketed formulation. The in vivo biological activity investigations, studies showed that the newly prepared NLCs formulation of OLE showed excellent anti-arthritic activity and the results were found at par with standard marketed diclofenac gel for its analgesic and anti-arthritic activities. These results were also supported by radiological analysis and molecular docking studies. The overall results proved that the prepared OLE-NLCs were very effective for the treatment of arthritis and the results were found at par with standard marketed the standard formulation of diclofenac gel.


Atmospheric carbon dioxide and carbon reservoir changes.
The net release of CO(2) from the biosphere to the atmosphere between 1850 and 1950 is estimated to amount to 1.2 x 10(9) tons of carbon per year. During this interval, changes in land use reduced the total terrestrial biomass by 7 percent. There has been a smaller reduction in biomass over the last few decades. In the middle 19th century the air had a CO(2) content of approximately 268 parts per millon, and the total increase in atmospheric CO(2) content since 1850 has been 18 percent. Major sinks for fossil fuel CO(2) are the thermocline regions of large oceanic gyres. About 34 percent of the excess CO(2) generated so far is stored in surface and thermocline gyre waters, and 13 percent has been advected into the deep sea. This leaves an airborne fraction of 53 percent.


Low-density lipoprotein receptor-related protein 1 (LRP1) regulates the stability and function of GluA1 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor in neurons.
The low-density lipoprotein receptor-related protein 1 (LRP1) is a multifunctional endocytic receptor abundantly expressed in neurons. Increasing evidence demonstrates that LRP1 regulates synaptic integrity and function at the post synapses, at least partially by regulating glutamate receptors. The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) are critical ionotropic glutamate receptors consisting of homotetramer or heterotetramer of GluA1-4 subunits and play an essential role in synaptic transmission and synaptic plasticity. Our previous work has shown that neuronal deletion of the Lrp1 gene in mice leads to decreased level of GluA1 and reduced long-term potentiation. To understand the underlying mechanism, we investigated the cellular and functional consequences of LRP1 deletion in primary neurons. Here, we show that LRP1 interacts with and regulates the cellular distribution and turnover of GluA1. LRP1 knockdown in mouse primary neurons led to accelerated turnover and decreased cell surface distribution of GluA1, which correspond to decreased phosphorylation of GluA1 at S845 and S831 sites. Decreased LRP1 expression also attenuated AMPA-evoked calcium influx and reduced GluA1-regulated neurite outgrowth and filopodia density. Our results reveal a novel mechanism by which LRP1 controls synaptic integrity and function, specifically by regulating GluA1 trafficking, phosphorylation and turnover. They further demonstrate that LRP1-GluA1 pathway may hold promises as a therapeutic target for restoring synaptic functions in neurodegenerative diseases.


[The in vitro antibacterial activity of cefozopran against clinically isolated bacteria].
The in vitro antibacterial activity of cefozopran (CZOP) against recent clinical isolates was evaluated and compared with those of ceftazidime (CAZ), cefpirome (CPR), cefepime (CFPM), cefotaxime (CTX), sulbactam/cefoperazone (S/C), imipenem (IPM), oxacillin (MPIPC), and flomoxef (FMOX). MIC80 values of CZOP for methicillin-susceptible Staphylococcus aureus (MSSA, n = 41), methicillin-resistant Staphylococcus aureus (MRSA, n = 57), Streptococcus pneumoniae (n = 45), Enterococus faecalis (n = 49), Enterobacter cloacae (n = 50), Citrobacter freundii (n = 45), Serratia marcescens (n = 45), and Pseudomonas aeruginosa (n = 100) were 1, 32, 2, 16, 4, 1, 0.25, 8 micrograms/ml, respectively. CZOP was more active than CPR against P. aeruginosa and exhibited similar activity to CPR against other species. CZOP was especially active against S. marcescens with MIC values lower than 1 microgram/ml against all strains tested. CZOP was similarly active to or more active than CFPM against all species except for C. freundii. CZOP was not active against MRSA. Thus, we investigated the in vitro combination effects of CZOP/vancomycin (VCM) and CZOP/arbekacin (ABK) using the checkerboard method. The interaction between CZOP and VCM ranged from additive activity (0.5 < FIC index < or = 1.00, n = 37) to synergistic activity (FIC index < 0.50, n = 1), except for one strain showing indifference (1.00 < FIC index < or = 2.00). The interaction between CZOP and ABK ranged from additive activity (n = 22) to synergistic activity (n = 1). These date suggest the potential effect of combination therapy of (CZOP) and VCM or ABK against MRSA. The combined therapy is suggested to be useful to reduce side effects in patients with impared renal function, to reduce the administration dose of VCM or to treat infections of sites where achievable drug concentrations are lower than those commonly achieved in the bloodstream. We also investigated the combination effects of CZOP/AMK and CZOP/GM against CZOP-resistant P. aeruginosa (MIC > 16 micrograms/ml). The combination of CZOP/AMK showed additive activity (n = 9) to synergistic activity (n = 2). The combination of CZOP/GM showed additive activity (n = 5). These results suggest that combinations of CZOP with AMK or GM are effective in treating P. aeruginosa.


Measles outbreak in Macedonia: epidemiological, clinical and laboratory findings and identification of susceptible cohorts.
Despite a 92-99% national vaccination coverage since 2000, the former Yugoslav Republic of Macedonia experienced a large measles outbreak between 2010 and 2011. Here we investigate the characteristics of patients hospitalized during this outbreak at the Clinic of Infectious Diseases in Skopje. Epidemiological, clinical and laboratory data of 284 measles patients, including 251 from Skopje (43.80% of the 573 reported cases) and 33 from elsewhere in Macedonia were collected. The most affected age groups were children up to 4 years of age and adolescents/adults of 15 years and older. Most patients were unvaccinated (n=263, 92.61%) and many had non-Macedonian nationalities (n=156, 54.93%) or belonged to the Roma ethnicity (n=73, 25.70%). Bronchopneumonia and diarrhea were the most common complications. Eighty-two out of 86 tested patients (95.35%) had measles-specific IgM antibodies. The outbreak was caused by the measles variant D4-Hamburg. The epidemic identified pockets of susceptibles in Skopje and indicated that additional vaccination opportunities in particular for people with non-Macedonian nationality and traveler communities are warranted to ensure efficient measles control in Macedonia. The high attack rate among children of less than 1 year suggests that vaccination before 12 months of age should be considered in high risk settings.


Measurement of sexual identity in surveys: implications for substance abuse research.
Researchers are increasingly recognizing the need to include measures of sexual orientation in health studies. However, relatively little attention has been paid to how sexual identity, the cognitive aspect of sexual orientation, is defined and measured. Our study examined the impact of using two separate sexual identity question formats: a three-category question (response options included heterosexual, bisexual, or lesbian/gay), and a similar question with five response options (only lesbian/gay, mostly lesbian/gay, bisexual, mostly heterosexual, only heterosexual). A large probability-based sample of undergraduate university students was surveyed and a randomly selected subsample of participants was asked both sexual identity questions. Approximately one-third of students who identified as bisexual based on the three-category sexual identity measure chose "mostly heterosexual" or "mostly lesbian/gay" on the five-category measure. In addition to comparing sample proportions of lesbian/gay, bisexual, or heterosexual participants based on the two question formats, rates of alcohol and other drug use were also examined among the participants. Substance use outcomes among the sexual minority subgroups differed based on the sexual identity question format used: bisexual participants showed greater risk of substance use in analyses using the three-category measure whereas "mostly heterosexual" participants were at greater risk when data were analyzed using the five-category measure. Study results have important implications for the study of sexual identity, as well as whether and how to recode responses to questions related to sexual identity.


Synaptic activity unmasks dopamine D2 receptor modulation of a specific class of layer V pyramidal neurons in prefrontal cortex.
Dopamine D2 receptors (D2Rs) play a major role in the function of the prefrontal cortex (PFC), and may contribute to prefrontal dysfunction in conditions such as schizophrenia. Here we report that in mouse PFC, D2Rs are selectively expressed by a subtype of layer V pyramidal neurons that have thick apical tufts, prominent h-current, and subcortical projections. Within this subpopulation, the D2R agonist quinpirole elicits a novel afterdepolarization that generates voltage fluctuations and spiking for hundreds of milliseconds. Surprisingly, this afterdepolarization is masked in quiescent brain slices, but is readily unmasked by physiologic levels of synaptic input which activate NMDA receptors, possibly explaining why this phenomenon has not been reported previously. Notably, we could still elicit this afterdepolarization for some time after the cessation of synaptic stimulation. In addition to NMDA receptors, the quinpirole-induced afterdepolarization also depended on L-type Ca(2+) channels and was blocked by the selective L-type antagonist nimodipine. To confirm that D2Rs can elicit this afterdepolarization by enhancing Ca(2+) (and Ca(2+)-dependent) currents, we measured whole-cell Ca(2+) potentials that occur after blocking Na(+) and K(+) channels, and found quinpirole enhanced these potentials, while the selective D2R antagonist sulpiride had the opposite effect. Thus, D2Rs can elicit a Ca(2+)-channel-dependent afterdepolarization that powerfully modulates activity in specific prefrontal neurons. Through this mechanism, D2Rs might enhance outputs to subcortical structures, contribute to reward-related persistent firing, or increase the level of noise in prefrontal circuits.


Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.
We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives.


Structure and function of natural sulphide-oxidizing microbial mats under dynamic input of light and chemical energy.
We studied the interaction between phototrophic and chemolithoautotrophic sulphide-oxidizing microorganisms in natural microbial mats forming in sulphidic streams. The structure of these mats varied between two end-members: one characterized by a layer dominated by large sulphur-oxidizing bacteria (SOB; mostly Beggiatoa-like) on top of a cyanobacterial layer (B/C mats) and the other with an inverted structure (C/B mats). C/B mats formed where the availability of oxygen from the water column was limited (<5 μm). Aerobic chemolithotrophic activity of the SOB depended entirely on oxygen produced locally by cyanobacteria during high light conditions. In contrast, B/C mats formed at locations where oxygen in the water column was comparatively abundant (>45 μM) and continuously present. Here SOB were independent of the photosynthetic activity of cyanobacteria and outcompeted the cyanobacteria in the uppermost layer of the mat where energy sources for both functional groups were concentrated. Outcompetition of photosynthetic microbes in the presence of light was facilitated by the decoupling of aerobic chemolithotrophy and oxygenic phototrophy. Remarkably, the B/C mats conserved much less energy than the C/B mats, although similar amounts of light and chemical energy were available. Thus ecosystems do not necessarily develop towards optimal energy usage. Our data suggest that, when two independent sources of energy are available, the structure and activity of microbial communities is primarily determined by the continuous rather than the intermittent energy source, even if the time-integrated energy flux of the intermittent energy source is greater.


Age-Specific Differences in Online Grocery Shopping Behaviors and Attitudes among Adults with Low Income in the United States in 2021.
Background: Online grocery shopping has surged in popularity, but we know little about online grocery shopping behaviors and attitudes of adults with low income, including differences by age. Methods: From October to November 2021, we used a survey research firm to recruit a convenience sample of adults who have ever received Supplemental Nutrition Assistance Program (SNAP) benefits (n = 3526). Participants completed an online survey designed to assess diet and online food shopping behaviors. Using logistic regression, we examined the relationship between participant characteristics, including age, and the likelihood of online grocery shopping, and separately examined variation in the reasons for online grocery shopping by age. Results: About 54% of the participants reported shopping online for groceries in the previous 12 months. Odds of online shopping were higher for those aged 18−33 years (OR = 1.95 (95% CI: 1.52, 2.52; p < 0.001)) and 34−44 years (OR = 1.50 (95% CI: 1.19, 1.90; p < 0.001)) than for those aged ≥65 years. Odds were also higher for those who were food insecure and those with income below USD 20,000, higher educational attainment, and higher fruit and vegetable intake. Low prices were the most popular reason for online grocery shopping (57%). Adults aged 18−33 years old had higher odds of reporting low prices as a motivating factor than older adults (OR = 2.34 (95% CI: 1.78, 3.08; p < 0.001)) and lower odds of reporting being discouraged by lack of social interaction (OR = 0.34 (95% CI: 0.25, 0.45; p < 0.001)). Conclusion: Strategies for making online grocery shopping more affordable for adults with lower income may be promising, especially online produce. For older adults, additional support may be needed to make online shopping a suitable replacement for in-store shopping, such as education on technology and combining it with opportunities for social support.


Particle laden fluid interfaces: dynamics and interfacial rheology.
We review the dynamics of particle laden interfaces, both particle monolayers and particle+surfactant monolayers. We also discuss the use of the Brownian motion of microparticles trapped at fluid interfaces for measuring the shear rheology of surfactant and polymer monolayers. We describe the basic concepts of interfacial rheology and the different experimental methods for measuring both dilational and shear surface complex moduli over a broad range of frequencies, with emphasis in the micro-rheology methods. In the case of particles trapped at interfaces the calculation of the diffusion coefficient from the Brownian trajectories of the particles is calculated as a function of particle surface concentration. We describe in detail the calculation in the case of subdiffusive particle dynamics. A comprehensive review of dilational and shear rheology of particle monolayers and particle+surfactant monolayers is presented. Finally the advantages and current open problems of the use of the Brownian motion of microparticles for calculating the shear complex modulus of monolayers are described in detail.


Nonlinear optical imaging by detection with optical parametric amplification (invited paper).
Nonlinear optical imaging is a versatile tool that has been proven to be exceptionally useful in various research fields. However, due to the use of photomultiplier tubes (PMTs), the wide application of nonlinear optical imaging is limited by the incapability of imaging under ambient light. In this paper, we propose and demonstrate a new optical imaging detection method based on optical parametric amplification (OPA). As a nonlinear optical process, OPA intrinsically rejects ambient light photons by coherence gating. Periodical poled lithium niobate (PPLN) crystals are used in this study as the media for OPA. Compared to bulk nonlinear optical crystals, PPLN crystals support the generation of OPA signal with lower pump power. Therefore, this characteristic of PPLN crystals is particularly beneficial when using high-repetition-rate lasers, which facilitate high-speed optical signal detection, such as in spectroscopy and imaging. A PPLN-based OPA system was built to amplify the emitted imaging signal from second harmonic generation (SHG) and coherent anti-Stokes Raman scattering (CARS) microscopy imaging, and the amplified optical signal was strong enough to be detected by a biased photodiode under ordinary room light conditions. With OPA detection, ambient-light-on SHG and CARS imaging becomes possible, and achieves a similar result as PMT detection under strictly dark environments. These results demonstrate that OPA can be used as a substitute for PMTs in nonlinear optical imaging to adapt it to various applications with complex lighting conditions.


Neurogenesis response of middle-aged hippocampus to acute seizure activity.
Acute Seizure (AS) activity in young adult age conspicuously modifies hippocampal neurogenesis. This is epitomized by both increased addition of new neurons to the granule cell layer (GCL) by neural stem/progenitor cells (NSCs) in the dentate subgranular zone (SGZ), and greatly enhanced numbers of newly born neurons located abnormally in the dentate hilus (DH). Interestingly, AS activity in old age does not induce such changes in hippocampal neurogenesis. However, the effect of AS activity on neurogenesis in the middle-aged hippocampus is yet to be elucidated. We examined hippocampal neurogenesis in middle-aged F344 rats after a continuous AS activity for >4 hrs, induced through graded intraperitoneal injections of the kainic acid. We labeled newly born cells via daily intraperitoneal injections of the 5'-bromodeoxyuridine (BrdU) for 12 days, commencing from the day of induction of AS activity. AS activity enhanced the addition of newly born BrdU+ cells by 5.6 fold and newly born neurons (expressing both BrdU and doublecortin [DCX]) by 2.2 fold to the SGZ-GCL. Measurement of the total number of DCX+ newly born neurons also revealed a similar trend. Furthermore, AS activity increased DCX+ newly born neurons located ectopically in the DH (2.7 fold increase and 17% of total newly born neurons). This rate of ectopic migration is however considerably less than what was observed earlier for the young adult hippocampus after similar AS activity. Thus, the plasticity of hippocampal neurogenesis to AS activity in middle age is closer to its response observed in the young adult age. However, the extent of abnormal migration of newly born neurons into the DH is less than that of the young adult hippocampus after similar AS activity. These results also point out a highly divergent response of neurogenesis to AS activity between middle age and old age.


Clinical Features of the 60 Years and Older Patients Infected with 2019 Novel Coronavirus: Can We Predict Mortality Earlier?
The novel coronavirus (COVID-19), which has affected over 100 countries in a short while, progresses more mortally in elderly patients with comorbidities. In this study, we examined the epidemiological, clinical, and laboratory characteristics of the patients aged 60 and over who had been infected with COVID-19. The data of the patients admitted to the hospital within 1 month from May 8, 2020 onwards and hospitalized for COVID-19 pneumonia were obtained from the hospital medical records, and the epidemiological, clinical, and laboratory parameters of the patients during the admission to the emergency department were examined. Patients were divided into 2 groups regarding the criteria of having in-hospital mortality (mortality group) and being discharged with full recovery (survivor group). The factors, which could have an impact on the mortality, were investigated using a univariate and multivariate logistic regression analysis. This retrospective study included 113 patients aged 60 years and older, with a confirmed diagnosis of COVID-19 pneumonia. The mean age of the patients was 70.7 ± 7.9, and 64.6% (n = 73) of them were male. The mortality rate was 19.4% (n = 22). Among the comorbid illnesses, only renal failure was significant in the mortality group (p = 0.04). A CURB-65score ≥3 or pneumonia severity index (PSI) class ≥4 manifested a remarkable discrimination ability to predict 30-day mortality (p < 0.001). When the laboratory parameters were considered, the value of neutrophil to lymphocyte ratio (NLR) was significant in predicting mortality in univariate and multivariate analysis (odds ratio [OR] = 1.11; 95% confidence interval [95% CI], 1.03-1.21; p = 0.006, and OR = 1.51; 95% CI, 1.11-2.39; p = 0.044, respectively). In our study, NLR was determined to be an independent marker to predict in-hospital mortality among patients with COVID-19. PSI and CURB-65 revealed a considerably precise prognostic accuracy for the patients with COVID-19 in our study as well. Moreover, thanks to that NLR results in a very short time, it can enable the clinician to predict mortality before the scoring systems are calculated and hasten the management of the patients in the chaotic environment of the emergency room.


[Pain management in patients with AIDS: analysis of the management structure of a reference hospital].
The objective of this study was to analyze the structure for the management of pain in patients with AIDS in a reference hospital in Fortaleza, Brazil. This is a descriptive study with a qualitative approach, developed in 2010. Twenty interviews were performed with health care professionals (physicians and nurses), and analyzed according to the methodology of content analysis. Data were organized into categories: favorable and unfavorable structural conditions. A prevalence of unfavorable conditions was found in the discourse of the interviewees, such as an emphasis on pharmacologic treatment, absence of specific care strategies for pain, lack of experienced professionals in handling pain, and a high demand and failure in the referral and counter-referral system. It is suggested that a new management care model be instituted for patients with AIDS, emphasizing an interdisciplinary approach to pain, training of health care professionals and improvement of chart records for use in evaluating pain relief methods and more effective treatments.


Therapeutic strategies for uncommon testis cancer histologies: teratoma with malignant transformation and malignant testicular sex cord stromal tumors.
Testicular cancer is the most common solid malignancy in male adolescents and young adults, with germ cell derived seminomas and non-seminomas being by far the most common histologies. Teratoma with somatic-type malignancy is a rare chemo-resistant phenotype of testis cancer associated with poor prognosis in patients with advanced stage disease. Malignant gonadal-stromal tumors comprise 5% of testicular neoplasms and approximately 10% are malignant and considered chemo-radiation resistant. Prognostic factors and treatment strategies for these uncommon histologies are lacking.


System Thinking and Citizen Participation Is Still Missing in One Health Initiatives - Lessons From Fifteen Evaluations.
Tackling complex public health challenges requires integrated approaches to health, such as One Health (OH). A key element of these approaches is the integration of knowledge across sectors, disciplines and stakeholders. It is not yet clear which elements of knowledge integration need endorsement to achieve best outcomes. This paper assesses 15 OH initiatives in 16 African, Asian and European countries to identify opportunities to improve knowledge integration and to investigate geographic influences on knowledge integration capacities. Two related evaluation tools, both relying on semi-quantitative questionnaires, were applied to two sets of case studies. In one tool, the questions relate to operations and infrastructure, while the other assigns questions to the three phases of "design," "implementation," and "evaluation" of the project life cycle. In both, the question scores are aggregated using medians. For analysis, extreme values were identified to highlight strengths and weaknesses. Seven initiatives were assessed by a single evaluator external to the initiative, and the other eight initiatives were jointly assessed by several internal and external evaluators. The knowledge integration capacity was greatest during the project implementation stage, and lowest during the evaluation stage. The main weaknesses pointing towards concrete potential for improvement were identified to be a lack of consideration of systemic characteristics, missing engagement of external stakeholders and poor bridging of knowledge, amplified by the absence of opportunities to learn and evolve in a collective process. Most users were unfamiliar with the systems approach to evaluation and found the use of the tools challenging, but they appreciated the new perspective and saw benefits in the ensuing reflections. We conclude that systems thinking and associated practises for OH require not only specific education in OH core competencies, but also methodological and institutional measures to endorse broad participation. To facilitate meta-analyses and generic improvement of integrated approaches to health we suggest including knowledge integration processes as elements to report according to the COHERE guidelines.


Gustave Roussy Immune Score and Royal Marsden Hospital Prognostic Score Are Biomarkers of Immune-Checkpoint Inhibitor for Non-Small Cell Lung Cancer.
The Gustave Roussy Immune Score (GRIm-Score) and the Royal Marsden Hospital prognostic score (RMH score) were recently developed in order to improve a better participant selection for phase I trials. The GRIm-Score is formed by combination of lactate dehydrogenase (LDH), serum albumin concentration, and neutrophil-to-lymphocyte ratio (NLR). The RMH score is calculated by LDH, albumin, and number of metastases. These two scores have been validated only in phase I trials. The purpose of this study was to assess whether these scores are useful for practical treatment of immune-checkpoint inhibitor (ICI) monotherapy in pretreated non-small cell lung cancer (NSCLC). This was a retrospective and single-centered study of 76 NSCLC patients treated with ICI monotherapy between December 2015 and October 2018 at our hospital. We divided 76 patients into high and low GRIm-Score and RMH score groups. Comparison of overall survival (OS) and progression free survival (PFS) was performed by Kaplan-Meier curves and log-rank tests. Independent prognostic factors of OS and PFS were analyzed by multivariate Cox proportional hazard analyses. The OS of the high GRIm-Score group was significantly shorter than that of the low score group (low vs. high; median 19.9 vs. 3.2 months, P < 0.01), while no significant difference was observed in PFS (2.6 vs. 2.1 months, P = 0.13). The PFS of the high RMH score was significantly shorter than that of the low score group (low vs. high; 2.6 vs. 1.8 months, P = 0.01), while there was no significant difference in OS (16.0 vs. 10.4, P = 0.24). Multivariate analyses detected high GRIm-Score (hazard ratio (HR) 3.93, 95% confidence interval (CI) 2.04 - 7.58, P < 0.01), and high RMH score (HR 1.76, 95% CI 1.03 - 3.02, P = 0.04) as poor prognostic factors of OS and PFS, respectively. Baseline GRIm-Score and RMH score were independent prognostic factors of OS and PFS of ICI monotherapy for pretreated NSCLC patients, respectively. These two scores are not only selection biomarkers for patients in experimental trials, but also useful prognostic biomarkers for NSCLC patients practically treated with ICI therapy.


How COVID-19 pandemic is changing the Africa's elaborate burial rites, mourning and grieving.
There are diverse burial rites in Africa which have been practiced for decades depending on the deceased place of origin, culture, religion and the position held in the community. Unlike the developed countries where burials are usually conducted as private ceremonies, funerals in Africa are elaborate and are usually public ceremonies involving the entire members of families, friends and well-wishers. Religion and culture are usually the deciding factors when decisions are made on how the deceased should be buried but generally cremation is not commonly practiced in Africa. COVID-19 pandemic was generally accepted to originate from Wuhan in China and this pandemic has extended to Africa. Most countries in Africa responded to the COVID-19 pandemic by adopting the same strategies used by the Western countries in curbing the spread of the virus through the imposition of restrictions on movements, lock down and the introduction social distancing rules which are align to Africa way of living. These control strategies had put a lot of pressures on the weak mortuary services in Africa, altered the traditional methods of observing burial rites, mourning and grieving. COVID-19 pandemic has changed the various traditional ways Africans mourn grief and bury their love one. The dead bodies of people suspected or confirmed to have COVID-19 should be treated with respect, ensuring the rights of the dead to a dignifying burial are upheld while adhering to standard precautions including use of appropriate PPEs, hand hygiene before and after the burial procedure.


Genetic and epigenetic disease modifiers in an Italian C9orf72 family expressing ALS, FTD or PD clinical phenotypes.
Objective: The presence of the hexanucleotide repeat expansion (HRE) in C9orf72 gene is associated to the ALS/FTD spectrum, but also to parkinsonisms. We here describe an Italian family with the father diagnosed with Parkinson disease (PD) at the age of 67 and the two daughters developing FTD and ALS at 45 years of age. We searched for C9orf72 HRE with possible genetic and epigenetic modifiers to account for the intrafamilial phenotypic variability. Methods: C9orf72 mutational analysis was performed by fragment length analysis, Repeat-primed PCR and Southern blot. Targeted next generation sequencing was used to analyze 48 genes associated to neurodegenerative diseases. Promoter methylation was analyzed by bisulfite sequencing. Results: Genetic analysis identified C9orf72 HRE in all the affected members with a similar repeat expansion size. Both the father and the FTD daughter also carried the heterozygous p.Ile946Phe variant in ATP13A2 gene, associated to PD. In addition, the father also showed a heterozygous EIF4G1 variant (p.Ala13Pro), that might increase his susceptibility to develop PD. The DNA methylation analysis showed that all the 26 CpG sites within C9orf72 promoter were unmethylated in all family members. Conclusions: Neither C9orf72 HRE size nor promoter methylation act as disease modifiers within this family, at least in blood, not excluding HRE mosaicism and a different methylation pattern in the brain. However, the presence of rare genetic variants in PD genes suggests that they may influence the clinical manifestation in the father. Other genetic and/or epigenetic modifiers must be responsible for disease variability in this C9orf72 family case.


Spray-Dried Paracetamol/Polyvinylpyrrolidone Amorphous Solid Dispersions: Part I-Stability of Powders and Tablets.
The formulation of active pharmaceutical ingredients (APIs) in amorphous solid dispersions (ASDs) is a promising approach to improve the bioavailability of poorly soluble compounds. However, problems often arise in the production of tablets from ASDs regarding the compressibility and recrystallization of the API. In the present study, the preparation of spray-dried ASDs of paracetamol (PCM) and four different types of polyvinylpyrrolidone (PVP) and their further processing into tablets were investigated. The influence of PVP type on the glass transition temperature (Tg) and the physical stability of ASD powders were characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (XRD). ASD powders with 10 to 30% PCM were stable for at least 48 weeks. PCM contents of 40 to 50% led to recrystallization of the amorphous PCM within a few days or weeks. ASD with PVP/vinyl acetate (VA) copolymer (PVP/VA) was the most unstable and tended to recrystallize in PCM polymorphic form II. This formulation was therefore used for tablet studies. The influence of compression force on recrystallization, crushing strength, and drug release was investigated. Even high compression forces did not affect the stability of the ASD. However, the ASD tablets led to slow release of the API.


Evolution of wing shape in hornets: why is the wing venation efficient for species identification?
Wing venation has long been used for insect identification. Lately, the characterization of venation shape using geometric morphometrics has further improved the potential of using the wing for insect identification. However, external factors inducing variation in wing shape could obscure specific differences, preventing accurate discrimination of species in heterogeneous samples. Here, we show that interspecific difference is the main source of wing shape variation within social wasps. We found that a naive clustering of wing shape data from taxonomically and geographically heterogeneous samples of workers returned groups congruent with species. We also confirmed that individuals can be reliably attributed to their genus, species and populations on the basis of their wing shape. Our results suggested that the shape variation reflects the evolutionary history with a potential influence of other factors such as body shape, climate and mimicry selective pressures. However, the high dimensionality of wing shape variation may have prevented absolute convergences between the different species. Wing venation shape is thus a taxonomically relevant marker combining the accuracy of quantitative characters with the specificity required for identification criteria. This marker may also highlight adaptive processes that could help understand the wing's influence on insect flight.


Expression cloning of SR-BI, a CD36-related class B scavenger receptor.
Scavenger receptors are integral membrane proteins that mediate the endocytosis of modified lipoproteins. The first of these to be purified and cloned were the type I and II macrophage scavenger receptors (SR-AI and SR-AII; class A scavenger receptors). Subsequently, the cell surface protein CD36 was shown to bind oxidized low density lipoprotein (oxidized LDL). From a Chinese hamster ovary (CHO) cell variant we have cloned by expression the cDNA for a new member of the CD36 family of membrane proteins, SR-BI, whose predicted protein sequence of 509 amino acids is approximately 30% identical to those of the four previously identified family members. Both SR-BI and CD36 displayed high affinity binding for acetylated LDL with an apparent dissociation constant on the order of approximately 5 micrograms of protein/ml. The ligand binding specificities of CD36 and SR-BI, determined by direct binding or competition assays, were similar, but not identical; both bind modified proteins (acetylated LDL, oxidized LDL, maleylated bovine serum albumin), but not the broad array of other polyanions (e.g. fucoidin, polyguanosinic acid, carrageenan) which are ligands of the class A receptors. Thus, SR-BI and CD36 define a second class of scavenger receptors, designated class B. Native LDL, which does not bind to either class A receptors or CD36, unexpectedly bound with high affinity to SR-BI. Northern blot analysis of murine tissues showed that SR-BI was most abundantly expressed in fat and was present at moderate levels in lung and liver. Furthermore, SR-BI mRNA expression was induced upon differentiation of 3T3-L1 cells into adipocytes. Thus, the tissue distribution of expression and ligand binding properties of SR-BI raise the possibility that this cell surface receptor may play an important role in lipid metabolism.


Cytoglobin affects tumorigenesis and the expression of ulcerative colitis-associated genes under chemically induced colitis in mice.
Cytoglobin (Cygb) is a member of the hemoglobin family and is thought to protect against cellular hypoxia and oxidative stress. These functions may be particularly important in inflammation-induced cancer, e.g., in patients with ulcerative colitis (UC). In this study, we investigated the development of inflammation and tumors in a murine model of inflammation-induced colorectal cancer using a combined treatment of azoxymethane and dextran sulfate sodium. A bioinformatics analysis of genome-wide expression data revealed increased colonic inflammation at the molecular level accompanied by enhanced macroscopic tumor development in Cygb-deficient mice. Moreover, the expression of the UC-associated gene neurexophilin and PC-esterase domain family member 4 (Nxpe4) depended on the presence of Cygb in the inflamed colonic mucosa. Compared to wild type mice, RT-qPCR confirmed a 14-fold (p = 0.0003) decrease in Nxpe4 expression in the inflamed colonic mucosa from Cygb-deficient mice. An analysis of Cygb protein expression suggested that Cygb is expressed in fibroblast-like cells surrounding the colonic crypts. Histological examinations of early induced lesions suggested that the effect of Cygb is primarily at the level of tumor promotion. In conclusion, in this model, Cygb primarily seemed to inhibit the development of established microadenomas.


Update on the Methods of the U.S. Preventive Services Task Force: Methods for Understanding Certainty and Net Benefit When Making Recommendations.
Since the 1980s, the U.S. Preventive Services Task Force (USPSTF) has developed and used rigorous methods to make evidence-based recommendations about preventive services to promote health and well-being for all Americans. Recommendations are based on the evidence of magnitude of net benefit (benefits minus harms). Expert opinion is not substituted when evidence is lacking. Evidence gaps are common. Few preventive services are supported by high-quality studies that directly and comprehensively determine the overall magnitude of benefits and harms in the same study. When assessing the body of evidence, studies may not have been conducted in primary care settings, studies may not have sufficiently included populations of interest, and long-term outcomes may not have been directly assessed. When direct evidence is not available, the USPSTF uses the methodologies of applicability to determine whether evidence can be generalized to an asymptomatic primary care population; coherence to link bodies of evidence and create an indirect evidence pathway; extrapolation to make inferences across the indirect evidence pathway, extend evidence to populations not specifically studied, consider service delivery intervals, and infer long-term outcomes; and conceptual bounding to set theoretical lower or upper limits for plausible benefits or harms. The USPSTF extends the evidence only so far as to maintain at least moderate certainty that its findings are preserved. This manuscript details with examples of how the USPSTF uses these methods to make recommendations that truly reflect the evidence.


Reversal of Urinary tract diversion after recovery from hysterical conversion reaction.
We have described a case in which the diagnosis of multiple sclerosis with findings of progressive paraplegia and a neurogenic bladder led to supravesical urinary diversion. Pyocystis led to creation of a urethrovesicovaginal fistula. Psychotherapy later uncovered hysterical conversion reaction. Which was cured with hypnotherapy. The urinary tract diversion was subsequently reversed after reconstruction of the bladder and urethra.


Implementation of targeted interventions to control Escherichia coli O157:H7 in a commercial abattoir.
The objective of this study was to define locations on the carcass with highest contamination of E. coli O157 throughout the harvest process and implement targeted interventions to reduce or eliminate contamination. To establish a pathogen baseline, samples were collected at the foreshank, hindshank, inside round, neck and midline area and evaluated for E. coli O157:H7 presence. Environmental samples were also collected in the harvest area and the fabrication area of the facility. E. coli O157:H7 prevalence was highest on the foreshank, hindshank and inside rounds in the baseline study and steam vacuums/cones were implemented as an intervention in these specific areas on the harvest floor. At pre-evisceration, foreshank prevalence of E. coli O157:H7 was significantly (P<0.05) reduced from 21.7% to 3.1% after the application of steam interventions. At the final rail, foreshank prevalence in the baseline study was 4.2% while no E. coli O157:H7 was detected post-intervention implementation. E. coli O157:H7 on hindshanks and inside rounds was significantly reduced after intervention implementation from 24.2 to 11.5% and 37.5 to 16.7%, respectively at the final rail. Pathogen contamination of environmental samples collected in fabrication declined from 6.7% to 0.7% after slaughter interventions were implemented. Data indicate the identifying areas of contamination on the carcass and implementing interventions can significantly reduce E. coli O157 on the carcasses and in the fabrication environment.


Fabry-Perot interferometer embedded in a glass chip fabricated by femtosecond laser.
We report a simple Fabry-Perot interferometer (FPI) embedded in a glass chip, which is capable of precisely measuring the refractive indices of liquid samples. The microdevice is the integration of a single-mode optical fiber and a microchannel in the photosensitive glass fabricated by femtosecond laser followed by thermal treatment, wet etching, and annealing. The function of the FPI is demonstrated by measuring the refractive indices of water and methanol. The interference visibility is more than 4.0 dB, which is sufficient for most sensing applications. This refractive index sensor with rigid structure could be further integrated to become a more complex 3D lab-on-a-chip for reliable biomedical applications.


In vivo imaging and biodistribution of multimodal polymeric nanoparticles delivered to the optic nerve.
The use of nanoparticles for targeted delivery of therapeutic agents to sites of injury or disease in the central nervous system (CNS) holds great promise. However, the biodistribution of nanoparticles following in vivo administration is often unknown, and concerns have been raised regarding potential toxicity. Using poly(glycidyl methacrylate) (PGMA) nanoparticles coated with polyethylenimine (PEI) and containing superparamagnetic iron oxide nanoparticles as a magnetic resonance imaging (MRI) contrast agent and rhodamine B as a fluorophore, whole animal MRI and fluorescence analyses are used to demonstrate that these nanoparticles (NP) remain close to the site of injection into a partial injury of the optic nerve, a CNS white matter tract. In addition, some of these NP enter axons and are transported to parent neuronal somata. NP also remain in the eye following intravitreal injection, a non-injury model. Considerable infiltration of activated microglia/macrophages occurs in both models. Using magnetic concentration and fluorescence visualization of tissue homogenates, no dissemination of the NP into peripheral tissues is observed. Histopathological analysis reveals no toxicity in organs other than at the injection sites. Multifunctional nanoparticles may be a useful mechanism to deliver therapeutic agents to the injury site and somata of injured CNS neurons and thus may be of therapeutic value following brain or spinal cord trauma.


Is increased blinking a form of blepharospasm?
The aim of this study was to investigate whether increased blink rate (BR) is part of the clinical spectrum of primary blepharospasm (BSP). We enrolled 40 patients (16 patients with an increased BR but without typical orbicularis oculi [OO] spasms, and 24 patients with typical involuntary OO spasms) and 18 healthy subjects. The BR, blink reflex recovery cycle, and somatosensory temporal discrimination threshold (STDT) were tested in patients and controls. Patients who had typical OO spasms had an altered R2 recovery cycle whereas those who had an increased BR alone had a normal blink reflex recovery cycle. STDT values were higher in patients than in healthy subjects and no difference was found in the STDT abnormalities in the 2 groups of patients. Our study shows that, despite the similar STDT abnormalities, the different changes in the R2 recovery cycle in patients with BSP and those with increased BR alone suggest that these disorders arise from different pathologic mechanisms.


3D-cultured human placenta-derived mesenchymal stem cell spheroids enhance ovary function by inducing folliculogenesis.
Placenta-derived mesenchymal stem cells (PD-MSCs) have numerous advantages over other adult MSCs that make them an attractive cell source for regenerative medicine. Here, we demonstrate the therapeutic effect of PD-MSCs in ovariectomized (Ovx) rats and compare their efficacy when generated via a conventional monolayer culture system (2D, naïve) and a spheroid culture system (3D, spheroid). PD-MSC transplantation significantly increased the estradiol level in Ovx rats compared with the non-transplantation (NTx) group. In particular, the estradiol level in the Spheroid group was significantly higher than that in the Naïve group at 2 weeks. Spheroid PD-MSCs exhibited a significantly higher efficiency of engraftment onto ovarian tissues at 2 weeks. The mRNA and protein expression levels of Nanos3, Nobox, and Lhx8 were also significantly increased in the Spheroid group compared with those in the NTx group at 1 and 2 weeks. These results suggest that PD-MSC transplantation can restore ovarian function in Ovx rats by increasing estrogen production and enhancing folliculogenesis-related gene expression levels and further indicate that spheroid-cultured PD-MSCs have enhanced therapeutic potential via increased engraftment efficiency. These findings improve our understanding of stem-cell-based therapies for reproductive systems and may suggest new avenues for developing efficient therapies using 3D cultivation systems.


The association between HIV and atherosclerotic cardiovascular disease in sub-Saharan Africa: a systematic review.
Sub-Saharan Africa (SSA) has confronted decades of the HIV epidemic with substantial improvements in access to life-saving antiretroviral therapy (ART). Now, with improved survival, people living with HIV (PLWH) are at increased risk for non-communicable diseases (NCDs), including atherosclerotic cardiovascular disease (CVD). We assessed the existing literature regarding the association of CVD outcomes and HIV in SSA. We used the PRISMA guidelines to perform a systematic review of the published literature regarding the association of CVD and HIV in SSA with a focus on CVD surrogate and clinical outcomes in PLWH. From January 2000 until March 2017, 31 articles were published regarding CVD outcomes among PLWH in SSA. Data from surrogate CVD outcomes (n = 13) suggest an increased risk of CVD events among PLWH in SSA. Although acute coronary syndrome is reported infrequently in SSA among PLWH, limited data from five studies suggest extensive thrombus and hypercoagulability as contributing factors. Additional studies suggest an increased risk of stroke among PLWH (n = 13); however, most data are from immunosuppressed ART-naïve PLWH and thus are potentially confounded by the possibility of central nervous system infections. Given ongoing gaps in our current understanding of CVD and other NCDs in PLWH in SSA, it is imperative to ascertain the burden of CVD outcomes, and to examine strategies for intervention and best practices to enhance the health of this vulnerable population.


[A clinical study of tuberculous pleurisy].
A clinical study of 38 patients (28 men and 10 women) with tuberculous pleurisy was conducted. The age of these patients ranged from 19 to 92 years, with an average age of 48.9 years. In 30 patients, the chief complaint was fever, and other common complaints included chest pain, dyspnea, and coughing. Bacillus tuberculosis was found in the pleural fluid of 7.9% of the patients. Tuberculous pleurisy was diagnosed histologically, based on pleural biopsy, in 23.7% of the patients. The diagnosis rate of pleural biopsy was 47.4%. There were no significant differences in results of blood and pleural fluid tests between idiopathic pleurisy and concomitant pleurisy, but the tuberculin skin test was positive in only 50% of the patients with concomitant pleurisy. The tendency was that the longer the time period between symptom onset and first examination, the greater the pleural fluid retention. The diagnosis rate of pleural biopsy was influenced by the severity of pleural fluid retention. A thoracic cavity drain was inserted for continuous drainage in 15 patients, and every patient underwent INH + RFP-based chemotherapy. Tuberculous pleurisy is an important disease among patients with pleural fluid retention, thus clinicians need to know how to treat this disease.