Patient perceptions of the quality of health services.
As calls are made for a more patient-centered health care system, it becomes critical to define and measure patient perceptions of health care quality and to understand more fully what drives those perceptions. This chapter identifies conceptual and methodological issues that make this task difficult, including the confusion between patient perceptions and patient satisfaction and the difficulty of determining whether systematic variations in patient perceptions should be attributed to differences in expectations or actual experiences. We propose a conceptual model to help unravel these knotty issues; review qualitative studies that report directly from patients on how they define quality; provide an overview of how health plans, hospitals, physicians, and health care in general are currently viewed by patients; assess whether and how patient health status and demographic characteristics relate to perceptions of health care quality; and identify where further, or more appropriately designed, research is needed. Our aim is to find out what patients want, need and experience in health care, not what professionals (however well-motivated) believe they need or get.


Advantages of laparoscopic resection for ileocecal Crohn's disease.
Elective laparoscopic-assisted resection of terminal ileal Crohn's disease is slowly gaining acceptance as an alternative to conventional surgery, based on the advantages of earlier return of bowel function, reductions in length of stay, and smaller wounds in a population likely to require reoperation. There is limited documentation of the cost-effectiveness of this approach, particularly with the reported longer operating times. The purpose of this study was to compare laparoscopic and open resections for terminal ileal Crohn's disease. We compared contemporaneous cohorts of patients undergoing initial elective laparoscopic or open resection for ileocecal Crohn's disease between June 1, 1999 and October 31, 2000 at a single institution. Operative approach was at the discretion of the surgeon. Data collected included age, gender, body mass index, American Society of Anesthesiologists score, indication for surgery, morbidity, mortality, conversion (laparoscopic-resection group only), operating-room time, length of hospital stay, direct cost per case, 30-day readmission, and return to work. All data are presented as medians and interquartile ranges. Data analysis was performed with the Mann-Whitney U test, Fisher's exact test, and Student's t-test where appropriate. Significance was set at P < 0.05. There were 45 evaluable patients (laparoscopic-resection group, 21; open-resection group, 24). One procedure was considered a conversion because of the 13-cm incision required to exteriorize the phlegmon (conversion rate, 4.8 percent). The median age (laparoscopic-resection group, 31 years; open-resection group, 39 years) and gender distributions (male/female: laparoscopic-resection group, 129; open-resection group, 915) were significantly different between the two groups. Resumption of oral intake (operating-room day vs. second postoperative day; P < 0.05) and resumption of intestinal function (2 vs. 4 days; P < 0.05) were significantly faster in the laparoscopic-resection patients. The median length of hospital stay was significantly shorter for the laparoscopic-resection patients (3 (2-3) vs. 5 (4-6) days; P < 0.05). The 30-day readmission rate in the laparoscopic-resection group was 9.6 percent (221), whereas none of the open-resection patients required rehospitalization. The overall complication rates were comparable for the laparoscopic-resection and open-resection patients (14.3 vs. 16.7 percent; P not significant), although there was one anastomotic leak and one intra-abdominal abscess in the laparoscopic-resection group, requiring readmission and reintervention (9.6 percent; P not significant). The direct cost per case was significantly lower for the laparoscopic-resection group ($2,547 vs. $2,985; P < 0.05, Student's t-test). The laparoscopic-assisted approach to ileocecal Crohn's disease results in a shortened length of stay and seems economically advantageous to open surgery.


Organization and morphology of calcitonin gene-related peptide-immunoreactive axons in the whole mouse stomach.
Nociceptive afferent axons innervate the stomach and send signals to the brain and spinal cord. Peripheral nociceptive afferents can be detected with a variety of markers (e.g., substance P [SP] and calcitonin gene-related peptide [CGRP]). We recently examined the topographical organization and morphology of SP-immunoreactive (SP-IR) axons in the whole mouse stomach muscular layer. However, the distribution and morphological structure of CGRP-IR axons remain unclear. We used immunohistochemistry labeling and applied a combination of imaging techniques, including confocal and Zeiss Imager M2 microscopy, Neurolucida 360 tracing, and integration of axon tracing data into a 3D stomach scaffold to characterize CGRP-IR axons and terminals in the whole mouse stomach muscular layers. We found that: (1) CGRP-IR axons formed extensive terminal networks in both ventral and dorsal stomachs. (2) CGRP-IR axons densely innervated the blood vessels. (3) CGRP-IR axons ran in parallel with the longitudinal and circular muscles. Some axons ran at angles through the muscular layers. (4) They also formed varicose terminal contacts with individual myenteric ganglion neurons. (5) CGRP-IR occurred in DiI-labeled gastric-projecting neurons in the dorsal root and vagal nodose ganglia, indicating CGRP-IR axons were visceral afferent axons. (6) CGRP-IR axons did not colocalize with tyrosine hydroxylase or vesicular acetylcholine transporter axons in the stomach, indicating CGRP-IR axons were not visceral efferent axons. (7) CGRP-IR axons were traced and integrated into a 3D stomach scaffold. For the first time, we provided a topographical distribution map of CGRP-IR axon innervation of the whole stomach muscular layers at the cellular/axonal/varicosity scale.


Gamma Knife rhizotomy-induced histopathology in multiple sclerosis-related trigeminal neuralgia.
In this report, the authors describe the pathological changes in the human trigeminal nerve after Gamma Knife radiosurgery. Three trigeminal nerves of patients with multiple sclerosis (MS)-related trigeminal neuralgia (MSTN) after Gamma Knife radiosurgery and other ablative procedures were examined by a neuropathologist. These cases were compared with 3 patients with typical TN who underwent partial surgical rhizotomy following recurrent symptoms after gasserian injury procedures, as well as with autopsy specimens from patients with and without MSTN. The three irradiated MS-TN specimens exhibited axon loss, demyelination, myelin debris, and fibrosis. Mild lymphocytic infiltrate was present in all 3 samples from MS-TN patients. The nonirradiated trigeminal nerve samples were generally well myelinated with rare degenerating axons. The microscopic findings in trigeminal nerve autopsy specimens were normal in patients without TN, with MS but not TN, and MS-TN. The inflammation observed in MS-TN specimens collected following Gamma Knife radiosurgery has not previously been described in the literature. These data provide new insight into the changes that occur in trigeminal nerve following stereotactic radiosurgery.


Defining a Novel Role for the Coxsackievirus and Adenovirus Receptor in Human Adenovirus Serotype 5 Transduction In Vitro in the Presence of Mouse Serum.
Human adenoviral serotype 5 (HAdV-5) vectors have predominantly hepatic tropism when delivered intravascularly, resulting in immune activation and toxicity. Coagulation factor X (FX) binding to HAdV-5 mediates liver transduction and provides protection from virion neutralization in mice. FX is dispensable for liver transduction in mice lacking IgM antibodies or complement, suggesting that alternative transduction pathways exist. To identify novel factor(s) mediating HAdV-5 FX-independent entry, we investigated HAdV-5 transduction in vitro in the presence of serum from immunocompetent C57BL/6 or immunocompromised mice lacking IgM antibodies (Rag 2-/- and NOD-scid-gamma [NSG]). Sera from all three mouse strains enhanced HAdV-5 transduction of A549 cells. While inhibition of HAdV-5-FX interaction with FX-binding protein (X-bp) inhibited transduction in the presence of C57BL/6 serum, it had negligible effect on the enhanced transduction observed in the presence of Rag 2-/- or NSG serum. Rag 2-/- serum also enhanced transduction of the FX binding-deficient HAdV-5HVR5*HVR7*E451Q (AdT*). Interestingly, Rag 2-/- serum enhanced HAdV-5 transduction in a FX-independent manner in CHO-CAR and SKOV3-CAR cells (CHO or SKOV3 cells transfected to stably express human coxsackievirus and adenovirus receptor [CAR]). Additionally, blockade of CAR with soluble HAdV-5 fiber knob inhibited mouse serum-enhanced transduction in A549 cells, suggesting a potential role for CAR. Transduction of HAdV-5 KO1 and HAdV-5/F35 (CAR binding deficient) in the presence of Rag 2-/- serum was equivalent to that of HAdV-5, indicating that direct interaction between HAdV-5 and CAR is not required. These data suggest that FX may protect HAdV-5 from neutralization but has minimal contribution to HAdV-5 transduction in the presence of immunocompromised mouse serum. Alternatively, transduction occurs via an unidentified mouse serum protein capable of bridging HAdV-5 to CAR.IMPORTANCE The intravascular administration of HAdV-5 vectors can result in acute liver toxicity, transaminitis, thrombocytopenia, and injury to the vascular endothelium, illustrating challenges yet to overcome for HAdV-5-mediated systemic gene therapy. The finding that CAR and potentially an unidentified factor present in mouse serum might be important mediators of HAdV-5 transduction highlights that a better understanding of the complex biology defining the interplay between adenovirus immune recognition and cellular uptake mechanisms is still required. These findings are important to inform future optimization and development of HAdV-5-based adenoviral vectors for gene therapy.


Semiconducting single-walled carbon nanotubes sorting with a removable solubilizer based on dynamic supramolecular coordination chemistry.
Highly pure semiconducting single-walled carbon nanotubes (SWNTs) are essential for the next generation of electronic devices, such as field-effect transistors and photovoltaic applications; however, contamination by metallic SWNTs reduces the efficiency of their associated devices. Here we report a simple and efficient method for the separation of semiconducting- and metallic SWNTs based on supramolecular complex chemistry. We here describe the synthesis of metal-coordination polymers (CP-Ms) composed of a fluorene-bridged bis-phenanthroline ligand and metal ions. On the basis of a difference in the 'solubility product' of CP-M-solubilized semiconducting SWNTs and metallic SWNTs, we readily separated semiconducting SWNTs. Furthermore, the CP-M polymers on the SWNTs were simply removed by adding a protic acid and inducing depolymerization to the monomer components. We also describe molecular mechanics calculations to reveal the difference of binding and wrapping mode between CP-M/semiconducting SWNTs and CP-M/metallic SWNTs. This study opens a new stage for the use of such highly pure semiconducting SWNTs in many possible applications.


School Nurses' Perceived Challenges With Concussion Management Procedures in the Secondary School Setting.
School nurses have an integral role in managing student health concerns throughout the school day, yet little is known about their specific role in concussion management. Therefore, the purpose of this study was to explore the challenges encountered by school nurses regarding concussion management in the secondary school setting. Twenty-two school nurses employed in the secondary school setting were interviewed via phone. We analyzed the data via the consensual qualitative research paradigm. Overall, we found school nurses face consistent challenges with their role on the concussion management team, specifically related to education of school personnel, parents, and community health-care providers. Challenging topics included the inconsistency of community health-care provider recommendations and others' perceptions of school nurses' preparation and training to be important members of the concussion management team. Efforts to increase concussion education and improve communication across all stakeholders of the concussion management team should be implemented.


Activation of protein kinase C increases phosphorylation of the L-myc trans-activator domain at a GSK-3 target site.
The L-myc protein migrates as three distinct differentially phosphorylated bands in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This phosphorylation can be rapidly increased either by treatment with the protein kinase C (PKC) activator phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or by inhibition of serine/threonine protein phosphatases with okadaic acid. In vitro mutagenesis and phosphoamino acid analyses define the N-terminal serine residues 38 and 42 of L-myc as critical targets for the PKC-dependent phosphorylation. These are the exclusive sites of phosphorylation in the N-terminal third of the L-myc protein, and can be phosphorylated in vitro by glycogen synthase kinase 3 beta (GSK-3 beta). A mutant L-myc protein in which these serines have been replaced by alanine residues does not show heterogeneous electrophoretic migration or hyperphosphorylation in response to PKC activation, and is not a substrate for GSK-3 beta in vitro. Similar potential phosphorylation sites are present in c-myc and N-myc in a highly conserved region thought to represent a transcriptional activation domain. We suggest that N-terminal phosphorylation of the L-myc protein is a means of rapid regulation of this oncoprotein, possibly mediated in vivo by the action of GSK-3.


Chromate allergy: total chromium and hexavalent chromate in the air.
This is a study on atmospheric concentration of total chromium and hexavalent chromate and its role in chromate sensitivity. Air concentration of total chromium and hexavalent chromate in a construction factory, a busy city area, a suburban area, a residential area, and a heavy industrial area were measured by air sampling pumps. Hexavalent chromate was not detected in any sampled areas. Two (concreting areas) of 8 locations in the construction factory had total chromium of 0.2 and 2.3 micrograms/m3 in the atmosphere. It appeared that the atmospheric concentration of total chromium and hexavalent chromate was negligible. These findings indicate that unexplained chromate sensitivity, as so often seen in patients attending a contact dermatitis clinic, is not attributable to exposure to hexavalent chromate in the air.


Why internet-based education?
This essay illustrates five ways that Internet-based higher education can capitalize on fundamental principles of learning. Internet-based education can enable better mastery through distributed (shorter, more frequent) practice rather than massed (longer, less frequent) practice; it can optimize performance because it allows students to learn at their peak time of their day; it can deepen memory because it requires cheat-proof assignments and tests; it can promote critical thinking because it necessitates intellectual winnowing and sifting; and it can enhance writing skills by requiring students to write frequently and for a broad audience.


Conserved surface accessible nucleoside ABC transporter component SP0845 is essential for pneumococcal virulence and confers protection in vivo.
Streptococcus pneumoniae is a leading cause of bacterial pneumonia, sepsis and meningitis. Surface accessible proteins of S. pneumoniae are being explored for the development of a protein-based vaccine in order to overcome the limitations of existing polysaccharide-based pneumococcal vaccines. To identify a potential vaccine candidate, we resolved surface-associated proteins of S. pneumoniae TIGR4 strain using two-dimensional gel electrophoresis followed by immunoblotting with antisera generated against whole heat-killed TIGR4. Ten immunoreactive spots were identified by mass spectrometric analysis that included a putative lipoprotein SP0845. Analysis of the inferred amino acid sequence of sp0845 homologues from 36 pneumococcal strains indicated that SP0845 was highly conserved (>98% identity) and showed less than 11% identity with any human protein. Our bioinformatic and functional analyses demonstrated that SP0845 is the substrate-binding protein of an ATP-binding cassette (ABC) transporter that is involved in nucleoside uptake with cytidine, uridine, guanosine and inosine as the preferred substrates. Deletion of the gene encoding SP0845 renders pneumococci avirulent suggesting that it is essential for virulence. Immunoblot analysis suggested that SP0845 is expressed in in vitro grown pneumococci and during mice infection. Immunofluorescence microscopy and flow cytometry data indicated that SP0845 is surface exposed in encapsulated strains and accessible to antibodies. Subcutaneous immunization with recombinant SP0845 induced high titer antibodies in mice. Hyperimmune sera raised against SP0845 promoted killing of encapsulated pneumococcal strains in a blood bactericidal assay. Immunization with SP0845 protected mice from intraperitoneal challenge with heterologous pneumococcal serotypes. Based on its surface accessibility, role in virulence and ability to elicit protective immunity, we propose that SP0845 may be a potential candidate for a protein-based pneumococcal vaccine.


Smart nanomaterials.
"Smart" materialsmaterials that respond to a stimulus or their environment to produce a dynamic and reversible change in critical propertieshave enabled progress in many areas, including display technologies, drug delivery, and self-healing materials for coating applications, among others. Many of the current examples of smart materials are biomimetic, since nature employs and depends on dynamic and rapid switching for critical functions such as vision, camouflage, and ion channel regulation. Despite progress in designing smart materials and surfaces, much work is still needed in this area to increase their implementation in useful applications. In this Perspective, the challenges and outlook in this field are highlighted, including the work of Balazs and co-workers found in this issue of ACS Nano.


[The procedure for the surgical treatment of intracranial arterial aneurysms in cerebral vascular spasm and ischemia].
Analysis of the data of clinical neurological examinations, cerebral angiography, computed tomography, and electroencephalography in 77 patients with early cerebral aneurysmal rupture made it possible to identify three clinical types of vascular spasm-induced cerebral ischemia: compensated, subcompensated, and decompensated. specific characteristics of each type of cerebral ischemia are given. It is shown that early surgical treatment policy for aneurysms in vascular spasm must be determined by the clinical type of cerebral ischemia.


Allergic disease, immunoglobulins, exposure to mercury and dental amalgam in Swedish adolescents.
High-dose exposure to inorganic mercury in man can influence the immune system and in rare cases cause immune-related disease. Some experimental animals also react with autoimmunity after low doses of inorganic mercury. Glomerulonephritis and an increased formation of immunoglobulin type E (IgE) are characteristic of these reactions. A recent study of 15-year-old adolescents demonstrated an association between immunoglobulin type A (IgA) and mercury concentration in plasma (P-Hg). There was also an association between allergic disease and IgA levels. The present study included 54 male and 23 female 19-year-old students who were recruited from a cohort that had been previously defined in a survey of allergic disease. Of the students, 39 (51%) had asthma, allergic rhinoconjunctivitis or eczema. Similar amalgam burden and P-Hg levels were observed in students with (n = 39) and without (n = 38) allergic disease (P = 0.48 and P = 0.98, respectively). As expected, IgE levels were significantly higher in the group with allergic disease (P = 0.006), but there was no association between P-Hg and IgE. The P-Hg levels were very low (median 1.50 nmol/l) and correlated significantly (r = 0.31) with the small number of amalgam surfaces (P = 0.007). Thirty-seven students had no amalgam fillings. P-Hg levels did not associate significantly with IgA, but did so with IgG2 (r = 0.33; P = 0.003). No conclusive correlation was observed between IgG2 and amalgam fillings. The findings of this study in 19-year-old subjects differ from earlier data obtained in a sample 4 years younger. The possibility of chance in the association between P-Hg levels and IgG2 must, however, be considered.


The effects of gastrointestinal disturbances on the onset of depression and anxiety.
Stomach pain is an ailment that occurs frequently in the general population. It is not unusual if such stomach issues produce some amount of stress in an individual, but it can be worrying if these pains lead to significant mental health problems. The relationship between some abdominal pain, such as bowel syndrome, and depression or anxiety has been gaining much interest. However, previous studies that have empirically investigated this relationship are scarce. To analyze the impact of having gastrointestinal problems, among other socioeconomic conditions, on the onset of depression and anxiety in the Spanish population, we compare treating gastrointestinal diseases as exogenous in a single-equation probit model with a bivariate probit model in which this variable is treated as endogenous. A likelihood-ratio test of the correlation coefficient of the disturbances suggests that gastrointestinal problems are endogenous. Thus, the approach taken herein allows the direct testing of the hypothesis that having gastrointestinal problems and the onset of mental illnesses such as depression and anxiety are jointly determined by certain socioeconomic factors. A cross-sectional analytical study was analyzed using data from a 2017 survey of health indicators and life conditions that was developed by the Statistics Spanish Office. The probability of having depression or anxiety increases with age, stress, daily limitations and gastrointestinal disorders. On the other hand, the probability is lower for men, married people and those who engage in exercise several times per week. Our findings estimate that having gastrointestinal problems increases the probability of having depression in 7% and the probability of anxiety in 8.8% of the sample. Our empirical results suggest that not considering the endogeneity of gastrointestinal problems could result in an overestimate of the impact of this factor on the development of depression or anxiety.


Diagnosis is a team sport - partnering with allied health professionals to reduce diagnostic errors: A case study on the role of a vestibular therapist in diagnosing dizziness.
Diagnostic errors are the most common, most costly, and most catastrophic of medical errors. Interdisciplinary teamwork has been shown to reduce harm from therapeutic errors, but sociocultural barriers may impact the engagement of allied health professionals (AHPs) in the diagnostic process. A qualitative case study of the experience at a single institution around involvement of an AHP in the diagnostic process for acute dizziness and vertigo. We detail five diagnostic error cases in which the input of a physical therapist was central to correct diagnosis. We further describe evolution of the sociocultural milieu at the institution as relates to AHP engagement in diagnosis. Five patients with acute vestibular symptoms were initially misdiagnosed by physicians and then correctly diagnosed based on input from a vestibular physical therapist. These included missed labyrinthine concussion and post-traumatic benign paroxysmal positional vertigo (BPPV); BPPV called gastroenteritis; BPPV called stroke; stroke called BPPV; and multiple sclerosis called BPPV. As a consequence of surfacing these diagnostic errors, initial resistance to physical therapy input to aid medical diagnosis has gradually declined, creating a more collaborative environment for 'team diagnosis' of patients with dizziness and vertigo at the institution. Barriers to AHP engagement in 'team diagnosis' include sociocultural norms that establish medical diagnosis as something reserved only for physicians. Drawing attention to the valuable diagnostic contributions of AHPs may help facilitate cultural change. Future studies should seek to measure diagnostic safety culture and then implement proven strategies to breakdown sociocultural barriers that inhibit effective teamwork and transdisciplinary diagnosis.


A homology model of the pore domain of a voltage-gated calcium channel is consistent with available SCAM data.
In the absence of x-ray structures of calcium channels, their homology models are used to rationalize experimental data and design new experiments. The modeling relies on sequence alignments between calcium and potassium channels. Zhen et al. (2005. J. Gen. Physiol. doi:10.1085/jgp.200509292) used the substituted cysteine accessibility method (SCAM) to identify pore-lining residues in the Ca(v)2.1 channel and concluded that their data are inconsistent with the symmetric architecture of the pore domain and published sequence alignments between calcium and potassium channels. Here, we have built K(v)1.2-based models of the Ca(v)2.1 channel with 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET)-modified engineered cysteines and used Monte Carlo energy minimizations to predict their energetically optimal orientations. We found that depending on the position of an engineered cysteine in S6 and S5 helices, the ammonium group in the long flexible MTSET-modified side chain can orient into the inner pore, an interface between domains (repeats), or an interface between S5 and S6 helices. Different local environments of equivalent positions in the four repeats can lead to different SCAM results. The reported current inhibition by MTSET generally decreases with the predicted distances between the ammonium nitrogen and the pore axis. A possible explanation for outliers of this correlation is suggested. Our calculations rationalize the SCAM data, validate one of several published sequence alignments between calcium and potassium channels, and suggest similar spatial dispositions of S5 and S6 helices in voltage-gated potassium and calcium channels.


Emergency twist drill trephination.
We have used the rapid progression of post-traumatic uncal herniation in spite of intensive medical therapy as the indication for twist drill trephination in the emergency department. During a 54-month period, 51 trephinations were performed on 41 patients. The trephine was placed through the temporal bone ipsilateral to the dilated pupil, and the dura mater was opened to allow partial evacuation of the hematoma. All patients subsequently underwent craniotomy, autopsy, and/or cerebral computed tomography (CT). The trephination was diagnostically accurate for the absence or presence of an extracerebral hematoma in 42 of 51 trephinations (82%). In 6 of these cases the dilated pupil responded to partial hematoma evacuation by decreasing in size. In 3 of the 6 there was a marked overall improvement in neurological status subsequent to trephination. These 3 patients later recovered to an independent functional state. Only 23 of these 41 patients (56%) with herniation profiles actually had significant extracerebral hematomas. This fact emphasizes the inadvisability of taking this type of patient directly to the operating room without a diagnostic study. A rapidly performed CT scan is the obvious first choice. However, if there is any delay in obtaining this study or when uncal herniation occurs rapidly, a twist drill trephination can be of value in diagnosing the absence or presence of a treatable extracerebral hematoma. There were no complications related to this procedure in this group.


Point and planar ultraviolet excitation/detection of hydroxyl-radical laser-induced fluorescence through long optical fibers.
We demonstrate an all-fiber-coupled, UV, laser-induced-fluorescence (LIF) detection system of the hydroxyl radical (OH) in flames. The nanosecond-pulsed excitation of the (1,0) band of the OH A(2)∑(+)-X(2)Π system at ∼283 nm is followed by fluorescence detection from the (0,0) and (1,1) bands around 310 nm. The excitation-laser beam is delivered through a 400 μm core UV-grade optical fiber of up to 10 m in length, and the fluorescence signal collected is transmitted through a 1.5 mm core 3 m long fiber onto the remote detector. Single-laser-shot planar LIF (PLIF) imaging of OH in flames is also demonstrated using fiber-based excitation. The effects of delivering intense UV beams through long optical fibers are investigated, and the system improvements for an all-fiber-coupled OH-PLIF imaging system are discussed. Development of such fiber-based diagnostics and imaging systems constitutes a major step in transitioning laser diagnostic tools from research laboratories to reacting flow facilities of practical interest.


Assessment of a head support system to prevent pediatric out-of-position: an observational study.
Head injuries are the most common severe injuries sustained by pediatric occupants in road traffic crashes. Preventing children from adopting positions that can result in an increased injury risk due to unfavorable interactions with the restraints is fundamental. The objective of this paper was to assess the effect of a head support system (SS) on the lateral position of the head, the vertical position of the sternum and the shoulder belt fit. Thirty pediatric rear-seat passengers were exposed to two 75-minute trials. Volunteers were restrained by a three-point belt and, if needed, used the appropriate child restraint system for their anthropometry (high-back booster, low-back booster, no booster). A case crossover study was designed in which the volunteers used the head support system (SS) during one of the trials, acting as their own controls (No SS) in the other. Compared to the control group, the head support reduced significantly the 90(th) percentile value of the absolute value of the relative lateral motion of the head, regardless of the restraint used. The system also reduced the maximum downward position of the sternal notch within the low-back booster group. As for the belt fit, the use of the head support improved significantly the position of the shoulder belt on the occupant in the low-back booster and in the no booster groups.


Hemoglobin North Shore: a variant hemoglobin associated with the phenotype of beta-thalassemia.
Hemoglobin (Hb) North Shore (beta 134 val leads to glu) is a mutant hemoglobin that is associated with the phenotype of mild heterozygous beta-thalassemia. Heterozygotes are characterized low normal hemoglobin levels or mild anemia, microcytosis, increased HbA2, and 34%-38% Hb North Shore. The mechanism of the anemia and microcytosis associated with Hb North Shore was explored by studies of hemolysate thermal instability, peripheral blood globin biosynthesis, and whole blood oxygen affinity. Hb North Shore was mildly heat unstable in comparison to normal adult hemolysate. Pulse labeling of reticulocytes with 3H-leucine showed an alpha/beta ratio of 1.35 (normal 1.0). The beta North Shore/alpha ratio was 0.22-0.27, which was less than expected on the basis of gene dosage and less than that seen for most beta-chain variants. The beta A/alpha ratio was 0.50, as would be expected. The beta North Shore/alpha ratio was 0.26 after a 15-min pulse and did not decrease during 120 min of chase. These findings suggest that suboptimal synthesis rather than posttranslational degradation is responsible for the thalassemic phenotype associated with this variant hemoglobin. These observations parallel the findings in heterozygous HbE. It is not presently known whether the thalassemia phenotype is conferred by the structural mutation itself or by another mutation cis to the beta North Shore gene.


The Neuroprotective Effect of Puerarin in Acute Spinal Cord Injury Rats.
Acute spinal cord injury (SCI) leads to permanent disabilities. This study evaluated the neuroprotective effect of puerarin, a natural extract, in a rat model of SCI. Acute SCI models were established in rats using a modified Allen's method. Locomotor function was evaluated using the BBB test. The histological changes in the spinal cord were observed by H&E staining. Neuron survival and glial cells activation were evaluated by immunostaining. ELISA and realtime PCR were used to measure secretion and gene expression of cytokines. TUNEL staining was used to examine cell apoptosis and western blot analysis was used to detect protein expression. Puerarin significantly increased BBB score in SCI rats, attenuated histological injury of spinal cord, decreased neuron loss, inhibited glial cells activation, alleviated inflammation, and inhibited cell apoptosis in the injured spinal cords. In addition, the downregulated PI3K and phospho-Akt protein expression were restored by puerarin. Puerarin accelerated locomotor function recovery and tissue repair of SCI rats, which is associated with its neuroprotection, glial cell activation suppression, anti-inflammatory and anti-apoptosis effects. These effects may be associated with the activation of PI3K/Akt signaling pathway.


Perivascular spaces in eccrine spiradenoma. A clue to its histological diagnosis.
Perivascular spaces were found to represent a useful histological clue to the diagnosis of eccrine spiradenoma. They were observed in eight of nine eccrine spiradenomas but not in syringomas, nodular basal cell carcinomas, or glomangiomas. Perivascular spaces in spiradenomas consisted of variably sized spaces around one or more central blood vessels, bordered at the periphery by a palisade of tumor cells and lined at both sides by basement membrane collagen type IV. Perivascular spaces contained variable numbers of T lymphocytes in all cases and could undergo fibrosis, cystic dilatation, or hyalinization. In analogy to similar structures in thymomas, we suggest that perivascular spaces in spiradenomas are involved in the traffic of lymphocytes toward the tumor.


Laryngeal cancer: in relation to oxidative stress.
This study was designed to investigate the oxidative stress parameters in laryngeal cancer and cancer-free adjacent tissues. Lipid peroxidation end product and the endogenous antioxidant components-CuZn superoxide dismutase (CuZn SOD) glutathione peroxidase (GSH Px), glutathione reductase (GSSG Rd) and glutathione (GSH)-were analysed by spectrophotometric and kinetic methods. Laryngeal cancer tissue exhibited higher lipid peroxidation than cancer free adjacent tissue. CuZn SOD and GSH Px activities and GSH level were significantly higher and GSSG Rd activity significantly lower in the cancer tissue. Detection of the antioxidant status may be useful to determine the tumour resistance to therapy, to choose the correct radiotherapy/chemotherapy and to monitor the effectiveness of the therapetic strategy.


Dendritically targeted Bdnf mRNA is essential for energy balance and response to leptin.
Mutations in the Bdnf gene, which produces transcripts with either short or long 3' untranslated regions (3' UTRs), cause human obesity; however, the precise role of brain-derived neurotrophic factor (BDNF) in the regulation of energy balance is unknown. Here we show the relationship between Bdnf mRNA with a long 3' UTR (long 3' UTR Bdnf mRNA), leptin, neuronal activation and body weight. We found that long 3' UTR Bdnf mRNA was enriched in the dendrites of hypothalamic neurons and that insulin and leptin could stimulate its translation in dendrites. Furthermore, mice harboring a truncated long Bdnf 3' UTR developed severe hyperphagic obesity, which was completely reversed by viral expression of long 3' UTR Bdnf mRNA in the hypothalamus. In these mice, the ability of leptin to activate hypothalamic neurons and inhibit food intake was compromised despite normal activation of leptin receptors. These results reveal a novel mechanism linking leptin action to BDNF expression during hypothalamic-mediated regulation of body weight, while also implicating dendritic protein synthesis in this process.


Does Positive Airway Pressure Therapy Result in Improved Sleep Quality?
Positive airway pressure (PAP) therapy is the gold-standard for obstructive sleep apnea (OSA) management. While it is known that PAP is efficacious for controlling breathing events during sleep when it is worn at the right pressure for the amount of time prescribed, there is less clear data on how well it improves sleep quality. There are few studies that have examined the effectiveness of PAP therapy on sleep quality. OSA participants (n = 241) from a larger trial examining a PAP adherence were included. Participants were provided with PAP instruction and followed at 2 months and 4 months. PAP adherence was measured as the number of hours per night at prescribed pressure, an objective measure of treatment adherence. The Pittsburgh Sleep Quality Index (PSQI) was used as the primary measure of sleep quality. The PSQI was significantly correlated with PAP adherence at both the 2-month and 4-month time points, such that lower sleep quality was associated with lower PAP use. This finding held for the sleep disturbance subscale of the PSQI. Over 55% of those using PAP therapy at the 4-month time point continued to report significantly disturbed sleep. This study shows that PAP therapy does not appear to improve sleep quality to a degree that would be expected. Over half of those patients using PAP therapy still experienced disturbed sleep. Whether the disturbed sleep is directly attributable to the PAP device itself or to disturbed sleep secondary to uncontrolled OSA when PAP is not worn is worthy of further investigation.


Ectopic pregnancy adjacent to iliac vessels managed successfully by minimally invasive treatment using local methotrexate injection: An extremely rare case and literature review.
A case report of successfully treated retroperitoneal ectopic pregnancy (REP) is presented. A 36-year-old woman, gravida 3, para 2, was admitted to hospital for suspected ectopic pregnancy with light vaginal bleeding and mild abdominal pain for 3 days at 45 days of gestation by the last menstrual period.Multiple transvaginal ultrasonography and two times laparoscopic probes led to the diagnosis of REP located to the iliac blood vessels closely. Eventually the patient was cured with the treatment using local methotrexate injection under real-time ultrasound guidance and systemic methotrexate administration. We also summarized another 31 cases of REP to further understand this disease, sharing them to arouse clinical attention for the diagnosis and treatment of REP timely.


Changes in cuticular lipids, water loss and desiccation resistance in a tropical drosophilid: analysis of variation between and within populations.
We investigated within as well as between population variability in desiccation resistance, cuticular lipid mass per fly and cuticular water loss in nine geographical populations of a tropical drosophilid, Zaprionus indianus. Interestingly, the amount of cuticular lipids and desiccation resistance in this non-melanic species are significantly higher as compared with melanic Drosophila melanogaster. On the basis of isofemale line analysis, within population trait variability in cuticular lipid mass per fly is positively correlated with desiccation resistance and negatively correlated with cuticular water loss but show lack of correlation with body size. We observed geographical variation in the amount of cuticular lipid mass per fly in Zaprionus indianus but no such divergence was found in D.melanogaster. In both the species, geographical variations in desiccation resistance are negatively correlated with cuticular water loss but the underlying mechanisms for changes in cuticular permeability are quite different. Thus, we may suggest that body melanisation and cuticular lipids may represent alternative strategies for coping with dehydration stress in melanic versus non-melanic drosophilids. For both the species, desiccation resistance and cuticular water loss are correlated with regular increase in aridity in the northern subtropical localities as compared with southern peninsular humid tropical localities. The role of climatic selection is evident from multiple regression analysis with seasonal changes in temperature and humidity (Tcv and RHcv) of the sites of origin of populations of Zaprionus indianus along latitude.


Correlation between plasma and hepatic phosphatidylcholine hydroperoxide, energy charge, and total glutathione content in ischemia reperfusion injury of rat liver.
Oxygen-derived free radicals are believed to be responsible for the hepatocellular injury leading to liver failure following ischemia-reperfusion in liver, endotoxemia and many other life-threatening illnesses. This study was designed to investigate the reactive oxygen species interaction in lipid peroxidation, the adenosine and energy charge levels of liver cells, and total glutathione content in ischemic-reperfusion injury of liver in rat. To prevent intestinal congestion during the clamping of vascular structures, subcutaneous transposition of the spleen was done beforehand. Four to six weeks later, after the development of natural portal-systemic shunts, occlusion of the portal vein, hepatic artery and bile duct was performed for different periods; blood and liver samples were taken at different intervals after the release. On the basis of the ischemia-reperfusion time, the rats were divided into the following 9 groups: 30/0, 30/30, 30/60, 60/0, 60/30, 60/60, 90/0, 90/30, and 90/60. The following parameters were measured: total hepatic glutathione content, adenosine values (ATP, ADP, AMP), energy charge, phosphatidylcholine hydroperoxide (PCOOH) concentrations in liver and plasma, and serum transaminases (AST, ALT). Decreased liver glutathione stores (an indicator of increased oxidative stress), increased serum hepatic transaminases (an indicator of hepatocellular injury), and increased PCOOH (an indicator of cellular-membrane lipid peroxidation) were noted. The ATP level and energy charge diminished significantly with the increase in duration of ischemia and reperfusion. A close correlation between the PCOOH levels in plasma and liver was observed. Extreme damage was noted in the 90-minute ischemia with 60-minute reperfusion group. The hepatic total glutathione level was reduced to the lowest level in the 90/60 group and it correlated with the energy charge level, denoting the highest degree of oxidative stress sustained by the liver cells in this group. These results indicated that prolonged hepatic ischemia with reperfusion produced bursts of oxygen-derived free radicals which overwhelmed the defense mechanisms of the cells, with a resultant decrease in energy charge associated with an increase in membrane lipid peroxidation. These findings not only provide confirmation of previously reported hepatocellular injury by free radicals generated after reperfusion, but they also establish the use of PCOOH analysis in liver and plasma as a sensitive and specific indicator of the injury process in time. The plasma PCOOH level may be a useful indicator of free radical induced hepatic membrane lipid peroxidation during ischemia-reperfusion, and might be employed in clinical studies of the therapeutic effects of drugs in various liver diseases, as well as for determining the prognosis after different kinds of hepatic operations.


Lymphoblastic lymphoma in adults: results of a pilot protocol.
Thirteen adult patients with histologically confirmed lymphoblastic lymphoma were treated with an intensive chemotherapy program consisting of induction with cyclophosphamide, adriamycin, vincristine, and prednisone (modified CHOP); consolidation and central nervous system (CNS) prophylaxis with methotrexate intrathecally and by high-dose intravenous injection, citrovorum factor and L-asparaginase; reinforcement with CHOP; and maintenance with 6-mercaptopurine and methotrexate. Treatment duration was 1 yr. A 14th patient with T-cell acute lymphoblastic leukemia was also treated at presentation by the same regimen. Thirteen patients had at least a mediastinal mass or abnormal cells in the bone marrow; one presented with CNS disease. The median age was 22 yr (range 16--50), and male--female ratio was 2.5:1. All patients had a rapid complete clinical response. Of the 13 patients without initial CNS disease, 4 have relapsed, 3 with primary CNS relapse and 1 with a recurrent abdominal mass. Five patients have died, 2 from drug toxicity, 2 from CNS relapse, and 1 from chronic myelogenous leukemia, which was diagnosed simultaneously with the lymphoblastic lymphoma. The median follow-up is 19 mo, and all patients have completed their planned therapy. At 3 yr, the actuarial survival is 61% and relapse-free survival is 56%.


The human immunodeficiency virus type-1 transcription factor Tat produces elevations in intracellular Ca2+ that require function of an N-methyl-D-aspartate receptor polyamine-sensitive site.
Human immunodeficiency virus type-1 (HIV-1) infection is commonly associated with neuronal loss, as well as, cognitive and motor deficits collectively termed HIV-1-associated dementia (HAD). Function of the HIV-1 transcription factor Tat, activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors, and subsequent rapid rises in free intracellular Ca2+ have been implicated in the development of this neurological disorder. However, the role of specific NMDA receptor modulatory sites in mediating effects of Tat has not been examined. The present studies examined the ability of two variants of Tat protein (1-100 nM), Tat 1-72 and Tat 1-86, to produce rapid rises in intracellular Ca2+ in organotypic slice cultures of rat hippocampus. Further, these studies evaluated the role of an NMDA receptor polyamine-sensitive site in mediating Tat-induced elevations in intracellular Ca2+. Brief exposure (10 min) to each variant of Tat protein (>1 nM) markedly increased levels of intracellular Ca2+ in each region of the hippocampus to as much as 145% of controls. In contrast, exposure of cultures to a deletion mutant of Tat protein devoid of amino acids 31-61 (Tat Delta31-61) did not produce changes in intracellular Ca2+ levels. Most significantly, exposure to the NMDA receptor antagonist dizocilpine (MK801 20 microM) and the polyamine site antagonist arcaine (10 microM) significantly attenuated increases in intracellular Ca2+ levels when co-administered with either the Tat 1-72 or Tat 1-86 amino acid variant of Tat. Thus, exposure of the hippocampus to Tat produces increases in intracellular Ca2+ levels that require function of an NMDA receptor polyamine-sensitive site and this may well contribute to the neurotoxic effects of HIV-1 infection. Polyamine-sensitive portions of this receptor may then represent novel therapeutic targets in the pharmacologic treatment of HAD-related neurotoxicity.


Do pH changes in the leaf apoplast contribute to rapid inhibition of leaf elongation rate by water stress? Comparison of stress responses induced by polyethylene glycol and down-regulation of root hydraulic conductivity.
We have dissected the influences of apoplastic pH and cell turgor on short-term responses of leaf growth to plant water status, by using a combination of a double-barrelled pH-selective microelectrodes and a cell pressure probe. These techniques were used, together with continuous measurements of leaf elongation rate (LER), in the (hidden) elongating zone of the leaves of intact maize plants while exposing roots to various treatments. Polyethylene glycol (PEG) reduced water availability to roots, while acid load and anoxia decreased root hydraulic conductivity. During the first 30 min, acid load and anoxia induced moderate reductions in leaf growth and turgor, with no effect on leaf apoplastic pH. PEG stopped leaf growth, while turgor was only partially reduced. Rapid alkalinization of the apoplast, from pH 4.9 ± 0.3 to pH 5.8 ± 0.2 within 30 min, may have participated to this rapid growth reduction. After 60 min, leaf growth inhibition correlated well with turgor reduction across all treatments, supporting a growth limitation by hydraulics. We conclude that apoplastic alkalinization may transiently impair the control of leaf growth by cell turgor upon abrupt water stress, whereas direct hydraulic control of growth predominates under moderate conditions and after a 30-60 min delay following imposition of water stress.


Diffusion-weighted MR spectroscopy: Consensus, recommendations, and resources from acquisition to modeling.
Brain cell structure and function reflect neurodevelopment, plasticity, and aging; and changes can help flag pathological processes such as neurodegeneration and neuroinflammation. Accurate and quantitative methods to noninvasively disentangle cellular structural features are needed and are a substantial focus of brain research. Diffusion-weighted MRS (dMRS) gives access to diffusion properties of endogenous intracellular brain metabolites that are preferentially located inside specific brain cell populations. Despite its great potential, dMRS remains a challenging technique on all levels: from the data acquisition to the analysis, quantification, modeling, and interpretation of results. These challenges were the motivation behind the organization of the Lorentz Center workshop on "Best Practices & Tools for Diffusion MR Spectroscopy" held in Leiden, the Netherlands, in September 2021. During the workshop, the dMRS community established a set of recommendations to execute robust dMRS studies. This paper provides a description of the steps needed for acquiring, processing, fitting, and modeling dMRS data, and provides links to useful resources.


Low T3 syndrome and long-term mortality in chronic hemodialysis patients.
To investigate the predictive value of low freeT3 for long-term mortality in chronic hemodialysis (HD) patients and explore a possible causative role of chronic inflammation. One hundred fourteen HD patients (84 males) consecutively entered the study and were assessed for thyroid function and two established markers of inflammation, high sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). Monthly blood samples were obtained from all patients for three consecutive months during the observation period for evaluation of thyroid function and measurement of inflammatory markers. The patients were then divided in two groups based on the cut-off value of 1.8 pg/mL for mean plasma freeT3, and were prospectively studied for a mean of 50.3 ± 30.8 mo regarding cumulative survival. The prognostic power of low serum fT3 levels for mortality was assessed using the Kaplan-Meier method and univariate and multivariate regression analysis. Kaplan-Meier survival curve showed a negative predictive power for low freeT3. In Cox regression analysis low freeT3 remained a significant predictor of mortality after adjustment for age, diabetes mellitus, hypertension, hsCRP, serum creatinine and albumin. Regarding the possible association with inflammation, freeT3 was correlated with hsCRP, but not IL-6, and only at the first month of the study. In chronic hemodialysis patients, low plasma freeT3 is a significant predictor of all-cause mortality. Further studies are required to identify the underlying mechanisms of this association.


The values of web archives.
This article considers how the development, promotion and adoption of a set of core values for web archives, linked to principles of "good governance", will help them to tackle the challenges of sustainability, accountability and inclusiveness that are central to their long-term societal and cultural worth. It outlines the work that has already been done to address these questions, as web archiving begins to move out of its establishment phase, and then discusses seven key principles of good governance that might be adapted by and embedded within web archives: participation, consensus, accountability, transparency, effectiveness and efficiency, inclusivity and legality. The article concludes with a call to action for researchers and archivists to co-create the core values for web archives that will be required if they are to remain a vital part of our cultural heritage infrastructure.


Characterization of platelet factor 4 amino acids that bind pathogenic antibodies in heparin-induced thrombocytopenia.
Essentials Many patients produce antibodies but few lead to heparin-induced thrombocytopenia (HIT). Pathogenic epitopes are difficult to identify as HIT antibodies are polyclonal and polyspecific. KKO binding to platelet factor 4 (PF4) depends on 13 amino acids, three of which are newly observed. Five amino acids in PF4 can help distinguish pathogenic from non-pathogenic antibodies. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction that results in thrombocytopenia and, in some patients, thrombotic complications. HIT is mediated by antibodies that bind to complexes of platelet factor 4 (PF4) and heparin. The antigenic epitopes of these anti-PF4/heparin antibodies have not yet been precisely defined, because of the polyspecific immune response that characterizes HIT. Objectives To identify PF4 amino acids essential for binding pathogenic HIT antibodies. Methods Alanine scanning mutagenesis was utilized to produce 70 single point mutations of PF4. Each PF4 mutant was used in an enzyme immunoassay (EIA) to test their capacity to bind a platelet-activating murine monoclonal anti-PF4/heparin antibody (KKO) and HIT patient sera (n = 9). Results and Conclusions We identified 13 amino acids that were essential for binding KKO because they directly affected either the binding site or the antigenic conformation of PF4. We also identified 10 amino acids that were required for the binding of HIT patient sera and five of these amino acids were required for binding both KKO and the HIT patient sera. The 10 amino acids required for binding HIT sera were further tested to differentiate pathogenic HIT antibodies (platelet activating, n = 45) and non-pathogenic antibodies (EIA-positive but not platelet activating, n = 28). We identified five mutations of PF4 that were recognized to be essential for binding pathogenic HIT antibodies. Using alanine scanning mutagenesis, we characterized possible binding sites of pathogenic HIT antibodies on PF4.


Phase II multicenter study of induction chemotherapy followed by concurrent efaproxiral (RSR13) and thoracic radiotherapy for patients with locally advanced non-small-cell lung cancer.
Efaproxiral (RSR13) reduces hemoglobin oxygen-binding affinity, facilitates oxygen release, and increases tissue pO2. We conducted a phase II multicenter study that assessed the efficacy and safety of efaproxiral when administered with thoracic radiation therapy (TRT), following induction chemotherapy, for treatment of locally advanced non-small-cell lung cancer (NSCLC). Fifty-one patients with locally advanced NSCLC were enrolled at 13 sites. Treatment comprised two cycles of paclitaxel (225 mg/m2) and carboplatin (area under the curve, 6), 3 weeks apart, followed by TRT (64 Gy/32 fractions) with concurrent efaproxiral (50 to 100 mg/kg). Survival results were compared with results of study Radiation Therapy Oncology Group (RTOG) 94-10. Overall response rate was 75% (37 of 49 patients). Complete and partial response rates were 6% (three of 49 patients) and 69% (34 of 49 patients), respectively. Median survival time (MST) was 20.6 months (95% CI, 14.0 to 24.2); overall survival rates at 1- and 2-years were 67% and 37%, respectively. Survival results were compared with the sequential (S-CRT) and concurrent (C-CRT) chemoradiotherapy arms of RTOG 94-10. MSTs for cases matched by stage, Karnofsky performance status, and age were: RT-010, 20.6 months; S-CRT, 15.1 months; and C-CRT, 17.9 months. Grade 3 to 4 toxicities related to efaproxiral that occurred in more than one patient included transient hypoxemia (19%), radiation pneumonitis (11%), and fatigue (4%). Addition of efaproxiral to S-CRT represents a promising approach in NSCLC treatment, and a randomized study should be pursued. The low incidence of grade 3 to 4 toxicities suggests that the use of efaproxiral instead of a cytotoxic agent, as a radiation sensitizer, may be advantageous.


Association of Rhinoplasty With Perceived Attractiveness, Success, and Overall Health.
To date, the impact of rhinoplasty surgery on social perceptions has not been quantified. To measure the association of rhinoplasty with observer-graded perceived attractiveness, success, and overall health. In a web-based survey, blinded casual observers viewed independent images of 13 unique patient faces before or after rhinoplasty. Delphi method was used to select standardized patient images, confirming appropriate patient candidacy and overall surgical effect. Observers rated the attractiveness, perceived success, and perceived overall health for each patient image. Facial perception questions were answered on a visual analog scale from 0 to 100, where higher scores corresponded to more positive responses. A multivariate mixed-effects regression model was used to determine the effect of rhinoplasty while accounting for observer biases. To further characterize the effect of rhinoplasty, estimated ordinal rank change was calculated for each domain. The primary objective was to measure the effect of rhinoplasty on observer-graded perceived attractiveness, success, and overall health. A total of 473 observers (mean age, 29 years [range, 18-73 years]; 305 [70.8%] were female) successfully completed the survey. On multivariate regression, patients after rhinoplasty were rated as significantly more attractive (rhinoplasty effect, 6.26; 95% CI, 5.10-7.41), more successful (rhinoplasty effect, 3.24; 95% CI, 2.32-4.17), and overall healthier (rhinoplasty effect, 3.78; 95% CI, 2.79-4.81). The ordinal rank change for an average individual's perceived attractiveness, success, and overall health was a positive shift of 14, 9, and 10 out of 100 rank positions, respectively. As perceived by casual observers, rhinoplasty surgery was associatedwith perceptions that in patients appeared significantly more attractive, more successful, and healthier. These results suggest patients undergoing rhinoplasty may derive a multifaceted benefit when partaking in social interactions. Furthermore, these results facilitate improved patient discussions aiming to provide more precise surgical expectations with an understanding that these results represent optimal outcomes. NA.


Localization of Staphylococcus aureus in tissue from the nasal vestibule in healthy carriers.
Colonization of the body is an important step in Staphylococcus aureus infection. S. aureus colonizes skin and mucous membranes in humans and several animal species. One important ecological niche of S. aureus is the anterior nares. More than 60% of the S. aureus in the nose are found in vestibulum nasi. Our aim was to describe the localization of S. aureus in nasal tissue from healthy carriers. Punch skin biopsies were taken from vestibulum nasi from healthy volunteers (S. aureus carriers and non-/intermittent carriers, n = 39) attending the population-based Tromsø 6 study. The tissue samples were processed as frozen sections before immunostaining with a specific S. aureus antibody, and finally evaluated by a confocal laser-scanning microscope. Our results suggest that S. aureus colonize both the upper and lower layers of the epidermis within the nasal epithelium of healthy individuals. The number of S. aureus in epidermis was surprisingly low. Intracellular localization of S. aureus in nasal tissue from healthy individuals was also detected. Knowledge of the exact localization of S. aureus in nasal tissue is important for the understanding of the host responses against S. aureus. Our results may have consequences for the eradication strategy of S. aureus in carriers, and further work can provide us with tools for targeted prevention of S. aureus colonisation and infection.


Cervical Nerve Projections to the Auditory Pathway in Tinnitus.
Cervical spinal nerves project to the auditory system and take part in the pathology of tinnitus. The intention of our research was to estimate the outcome of treatment of C6 and C7 to lessen tinnitus intensity and to find criteria for a long-term success. Subjects were 78 tinnitus patients who were treated with infiltration of the sixth and seventh cervical nerve. Clinical data form these patients were reviewed retrospectively. An independent perceiver evaluated the long-term effect of the therapy by telephone interview. In a cohort of tinnitus patients, 18% had less tinnitus after treatment of C6 and C7. The majority of the patients announced a moderate easing of their tinnitus. At 2,5 months, half of the patients with a positive response still had benefit. The combination of hearing loss at 8 kHz and the highness of the intervertebral disc at C4-C5 forecasted a beneficial result of therapy of C6 and C7 with a longer period of relief. Treating afferent cervical nerves can lessen tinnitus. Therapy of C6 and C7 caused less tinnitus for 18% of the tinnitus patients. Especially patients with no hearing loss at 8 kHz and no disc degeneration at C4-C5 forecasted a beneficial result of therapy of C6 and C7 on tinnitus with a longer period of relief.


Primate TNF promoters reveal markers of phylogeny and evolution of innate immunity.
Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type- and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF.


Phase-plane analysis of gaze stabilization to high acceleration head thrusts: a continuum across normal subjects and patients with loss of vestibular function.
We investigated the vestibulo-ocular reflex (VOR) during high-acceleration, yaw-axis, head rotations in 12 normals and 15 patients with vestibular loss [7 unilateral vestibular deficient (UVD) and 8 bilateral vestibular deficient (BVD)]. We analyzed gaze stabilization within a 200-ms window after head rotation began, using phase planes, which allowed simultaneous analysis of gaze velocity and gaze position. These "gaze planes" revealed critical dynamic information not easily gleaned from traditional gain measurements. We found linear relationships between peak gaze-velocity and peak gaze-position error when normalized to peak head speed and position, respectively. Values fell on a continuum, increasing from normals, to normals tested with very high acceleration (VHA = 10,000-20,000 degrees/s2), to UVD patients during rotations toward the intact side, to UVD patients during rotations toward the lesioned side, to BVD patients. We classified compensatory gaze corrections as gaze-position corrections (GPCs) or gaze-velocity error corrections (GVCs). We defined patients as better-compensated when the value of their end gaze position was low relative to peak gaze position. In the gaze plane this criterion corresponded to relatively stereotyped patterns over many rotations, and appearance of high velocity (100-400 degrees/s) GPCs in the gaze plane ending quadrant (150-200 ms after head movement onset). In less-compensated patients, and normals at VHA, more GVCs were generated, and GPCs were generated only after gaze-velocity error was minimized. These findings suggest that challenges to compensatory vestibular function can be from vestibular deficiency or novel stimuli not previously experienced. Similar patterns of challenge and compensation were observed in both patients with vestibular loss and normal subjects.


Disparities in kidney transplantation accessibility among immigrant populations in Europe: A systematic review and meta-analysis.
Disparities in access to healthcare for patients with an immigration background are well-known. The aim of this study was to determine whether disparities among immigrant populations translate into a relative difference in the number of kidney transplants (KT) performed in documented immigrant patients (first and second generation) relative to native-born patients in Europe. A literature search was performed in PubMed from inception to 11-10-2022. Studies were eligible if: (1) written in English, (2) included immigrant and native-born KT patients, (3) performed in countries registered as Council of Europe members, (4) focused on documented first- and second-generation immigrant populations [1]. Systematic reviews, literature reviews, and case reports or articles about emigration, non-KT, and undocumented immigrants were excluded. The outcome measurement was a relative percentage of KTs to the total population per 100.000 residents. By dividing the immigrant percentages by the native-born resident percentages, the odds ratio (OR) was calculated in a meta-analysis. The risk of bias was assessed; articles with high risk of bias were excluded in a second meta-analysis. Out of 109 articles, 5 were included (n = 24,614). One Italian study (n = 24,174) had a ratio below 1, being 0.910 (95%CI 0.877-0.945). The other four articles (n = 196, n = 283, n = 77, n = 119) had ratios above 1: 1.36 (95%CI 0.980-1.87), 2.04 (95%CI 1.56-2.68), 2.23 (95%CI 1.53-3.25) and 2.64 (95%CI 1.68-4.15). After performing a meta-analysis, the OR did not show a significant difference: 1.68 (95%CI 1.03-2.75). After bias correction, this remained unchanged: 1.78 (95%CI 0.961-3.31). In our meta-analysis we did not find a significant difference in the relative number of KTs performed in immigrant versus native-born populations in Europe. However, a lesser likelihood for immigrants to receive a pre-emptive kidney transplantation was found. Large heterogeneity between studies (e.g. different sample size, patient origins, study duration, adult vs children patients) was a shortcoming to our analysis. Nevertheless, our article is the first review in this understudied topic. As important questions (e.g. on ethnicity, living donor rate) remain, future studies are needed to address them.


The dentine-sealer interface: Modulation of antimicrobial effects by irrigation.
Assess whether sodium hypochlorite (NaOCl) or chlorhexidine (CHX) and two irrigation protocols may alter the antibacterial properties of dentine and three endodontic sealers using a novel ex vivo tooth model. Prior to antibacterial testing, the tooth model was validated by means of scanning electron microscopy (SEM) to evaluate the separation between dentine and sealer surfaces. Root blocks prepared from extracted human roots were pre-treated with 17% EDTA + 0.9% saline and subsequently treated with 1% NaOCl (G1), 2% CHX (G2) or no irrigant (G3). Two irrigation protocols were further investigated, "1% NaOCl + 17% EDTA" (P1) and "1% NaOCl + 17% EDTA + 2% CHX" (P2). Following irrigation, the root blocks were either filled with AH Plus, BioRoot RCS and Pulp Canal Sealer (PCS), or left empty. All groups were incubated for 1, 7 and 28 days. Direct contact tests for planktonic E. faecalis and 48 h E. faecalis biofilms were performed at the level of dentine and sealer surfaces. Statistical analysis was performed on the bacterial survival between irrigants (G1, G2 and G3) and between irrigation protocols (P1 and P2); p < .05. The model was considered reproducible as SEM examination of dentine samples indicated consistent separation between dentine and sealer surfaces. Irrigation with CHX (G2) and irrigation protocol P2 enhanced the antibacterial properties of dentine without sealer application as well as dentine in contact with all three sealers tested, especially against planktonic E. faecalis. G2 and P2 also improved the antibacterial effect of AH Plus surfaces for all three incubation times. No irrigation groups (G1, G2) or irrigation protocols (P1, P2) altered the antibacterial properties of BioRoot RCS surfaces against planktonic bacteria or biofilms. Only BioRoot RCS surfaces eliminated the planktonic E. faecalis in all irrigation groups (G1, G2, G3) and protocols (P1, P2) investigated whilst PCS surfaces eliminate E. faecalis in biofilms in all groups up to 7 days. The tooth model was reproducible. CHX improved the antibacterial activity upon both sealer and dentine surfaces. Amongst sealers, BioRoot RCS was less affected by NaOCl and CHX, and exhibited high antibacterial properties regardless the irrigation applied.


Critical Role of Boundary Conditions in Sorption Kinetics Measurements.
In order to characterize the hygroscopic properties of cellulose-based materials, which can absorb large amounts of water from vapor in ambient air, or the adsorption capacity of pollutants or molecules in various porous materials, it is common to rely on sorption-desorption dynamic tests. This consists of observing the mass variation over time when the sample is placed in contact with a fluid containing the elements to be absorbed or adsorbed. Here, we focus on the case of a hygroscopic material in contact with air at a relative humidity (RH) differing from that at which it has been prepared. We show that the vapor mass flux going out of the sample follows from the solution of a vapor convection-diffusion problem along the surface and is proportional to the difference between the RH of the air flux and that along the surface with a multiplicative factor (δ) depending only on the characteristics of the air flux and the geometry of the system, including the surface roughness. This factor may be determined from independent measurements in which the RH along the surface is known while keeping all other variables constant. Then we show that the apparent sorption or desorption kinetics critically depend on the competition between boundary conditions and transport through the material. For sufficiently low air flux intensities or small sample thicknesses, the moisture distribution in the sample remains uniform and evolves toward the equilibrium with a kinetics depending on the value of δ and the material thickness. For sufficiently high air flux intensities or large sample thicknesses, the moisture distribution is highly inhomogeneous, and the kinetics reflect the ability of water transport by diffusion through the material. We illustrate and validate this theoretical description on the basis of magnetic resonance imaging experiments on drying cellulose fiber stacks.


A person-centered approach to resilience and vulnerability in emerging adulthood: Predictions from parenting and personality in adolescence.
In this person-centered study, we identified different profiles of resilience and vulnerability in emerging adulthood in response to previously experienced stressful life events. Additionally, we examined whether mothers' and fathers' parenting and participants' personality traits in adolescence predicted these profiles. Data from the Flemish Study on Parenting, Personality, and Development (N = 346 families) were used. At T1 (2004; Mage = 11 years), T2 (2007), and T3 (2009), mothers and fathers reported on their parenting and their child's personality. At T4 (2018; Mage = 25 years), emerging adults retrospectively self-reported the occurrence and impact of 22 stressful life events and rated current behavior problems and subjective well-being. Latent profile analysis revealed three profiles: Competent (71%; low stress, low behavior problems, high subjective well-being), Vulnerable (21%; average stress, high behavior problems, low subjective well-being), and Resilient (9%; high stress, average behavior problems, average subjective well-being). Emerging adults in the Resilient profile had experienced higher levels of maternal positive parenting and were less emotionally stable and conscientious than those in the Competent profile. Furthermore, emerging adults in the Vulnerable profile were less emotionally stable than their peers in the Competent profile. These findings reveal new insights into the heterogeneous patterns of emerging adults' adaptation following stressful life events.


Natural products with 1,2-oxazine scaffold: occurrence, chemical diversity, bioactivity, synthesis, and biosynthesis.
Covering: up to the end of July, 20231,2-Oxazine is a heterocyclic scaffold rarely found in natural products and is characterized by a directly connected N-O bond in a six-membered ring. Since the discovery of geneserine, the first 1,2-oxazine-containing natural product (1,2-oxazine NP) being isolated from Calabar bean (Physostigma venenosum) in 1925, a total of 76 naturally occurring 1,2-oxazine NPs have been isolated and identified from various sources, which have attracted the attention of researchers in the field of natural product chemistry, organic synthesis, biosynthesis, and pharmacology. This review summarizes the chemical family of 1,2-oxazine NPs, focusing on their source organisms, structural diversities, chemical synthesis, and biosynthesis.


An unknown endogenous inhibitor of Na/Ca exchange can enhance the cardiac muscle contractility.
The cardiac sarcolemma Na/Ca exchanger is a key system for controlling the intracellular calcium levels during the excitation-contraction coupling. Here, we test the hypothesis that the heart tissue contains a putative endogenous factor having a capacity to modulate the Na/Ca exchanger and muscle contractility. The concentrated cardiac extracts inhibit the Na(i)- or Ca(i)-dependent (45)Ca uptakes in isolated cardiac sarcolemma vesicles as well as the Na(o)-dependent Ca efflux, monitored by extravesicular Ca probe fluo-3. The inhibitory activity has been purified approximately 2000-fold by normal and reversed-phase HPLC procedures. The inhibitory activity is eluted from the Sephadex G-10 in the range of 350-550 Da, suggesting that the inhibitory factor is a low-molecular-weight substance. The mass spectra analysis shows a number of signals within m/z 380-560; however, it is not clear at this moment whether these recordings represent the mass of putative inhibitory factor or irrelevant impurities. The endogenous inhibitory factor of Na/Ca exchange does not resemble the properties (HPLC retention time, mass spectra, amino acid analysis, etc.) of autoinhibitory XIP peptide. The addition of inhibitory factor to muscle strip of guinea pig ventricles induces 2- to 5-fold enhancement of isometric contractions, thereby exhibiting a strong positive inotropic effect. This effect is a dose-dependent phenomenon, which can be reversed by washing the inhibitory factor from the organ bath. Assuming a molecular weight of 350-550 Da, the effective concentrations of putative inhibitor must be <10(-6) M. Therefore, the present findings demonstrate that the mammalian heart contains a low-molecular-weight factor that can inhibit Na/Ca exchange and enhance the cardiac contractility.


Increased STAT3 Activation in Periodontitis Drives Inflammatory Bone Loss.
Periodontitis is one of the most prevalent human inflammatory diseases. It is characterized by periodontal tissue destruction, progressively driven by the host response. In this regard, cytokines associated with tissue destruction, such as interleukin (IL)-6 and IL-23, use a common signaling pathway mediated by STAT3. This transcription factor is also needed for IL-17A production, a key mediator in periodontitis pathogenesis. Although several studies have reported increased activation of STAT3 in experimental periodontitis, a detailed characterization of STAT3 activation in human gingival tissues and its involvement in alveolar bone loss has yet to be explored. Using a cross-sectional study design, we detected increased proportions of pSTAT3-positive cells during periodontitis compared with health, particularly in epithelial cells and T cells. Other cell types of hematopoietic and nonhematopoietic origin also display STAT3 activation in gingival tissues. We detected increased STAT3 phosphorylation and expression of STAT3-related genes during experimental periodontitis. Next, we evaluated the role of STAT3 in alveolar bone destruction using a mouse model of STAT3 loss of function (mut-Stat3 mice). Compared with controls, mut-Stat3 mice had reduced alveolar bone loss following ligature-induced periodontitis. We also evaluated pharmacologic inhibition of STAT3 in ligature-induced periodontitis. Like mut-Stat3 mice, mice treated with STAT3 small-molecule inhibitor had reduced bone loss compared with controls. Our results demonstrate that STAT3 activation is increased in epithelial and T cells during periodontitis and indicate a pathogenic role of STAT3 in inflammatory alveolar bone loss.


Phytomedicines (medicines derived from plants) for sickle cell disease.
Sickle cell disease, a common recessively inherited haemoglobin disorder, affects people from sub-Saharan Africa, the Middle East, Mediterranean basin, Indian subcontinent, Caribbean and South America. It is associated with complications and a reduced life expectancy. Phytomedicines (medicine derived from plants in their original state) encompass many of the plant remedies from traditional healers which the populations most affected would encounter. Laboratory research and limited clinical trials have suggested positive effects of phytomedicines both in vivo and in vitro. However, there has been little systematic appraisal of their benefits. This is an updated version of a previously published Cochrane Review. To assess the benefits and risks of phytomedicines in people with sickle cell disease of all types, of any age, in any setting. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, the International Standard Randomised Controlled Trial Number Register (ISRCTN), the Allied and Complimentary Medicine Database (AMED), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). Dates of most recent searches: Cochrane Cystic Fibrosis and Genetic Disorders Haemoglobinopathies Trials Register: 17 March 2020; ISRCTN: 19 April 2020; AMED: 18 May 2020; ClinicalTrials.gov: 24 April 2020; and the WHO ICTRP: 27 July 2017. Randomised or quasi-randomised trials with participants of all ages with sickle cell disease, in all settings, comparing the administration of phytomedicines, by any mode to placebo or conventional treatment, including blood transfusion and hydroxyurea. Both authors independently assessed trial quality and extracted data. Three trials (212 participants) of three phytomedicines: Niprisan® (also known as Nicosan®), Ciklavit® and a powdered extract of Pfaffia paniculata were included. The Phase IIB (pivotal) trial suggests that Niprisan® may be effective in reducing episodes of severe painful sickle cell disease crisis over a six-month period (low-quality evidence). It did not appear to affect the risk of severe complications or the level of anaemia (low-quality evidence). The single trial of Cajanus cajan (Ciklavit®) reported a possible benefit to individuals with painful crises, and a possible adverse effect (non-significant) on the level of anaemia (low-quality evidence). We are uncertain of the effect of Pfaffia paniculata on the laboratory parameters and symptoms of SCD (very low-quality of evidence). No adverse effects were reported with Niprisan® and Pfaffia paniculata (low- to very low-quality evidence). While Niprisan® appeared to be safe and effective in reducing severe painful crises over a six-month follow-up period, further trials are required to assess its role in managing people with SCD and the results of its multicentre trials are awaited. Currently, no conclusions can be made regarding the efficacy of Ciklavit® and the powdered root extract of Pfaffia paniculata in managing SCD. Based on the published results for Niprisan® and in view of the limitations in data collection and analysis of the three trials, phytomedicines may have a potential beneficial effect in reducing painful crises in SCD. This needs to be further validated in future trials. More trials with improved study design and data collection are required on the safety and efficacy of phytomedicines used in managing SCD.


Subunit-specific radioimmunoassay for aldolase A, B, and C subunits: clinical significance.
Radioimmunoassays specific for fructose-1, 6-diphosphate aldolase isozymes were developed for the quantification of human aldolase A, B and C. The method is a double-antibody radioimmunoassay using radioiodinated purified aldolase A, B and C as ligand, chicken antibodies to aldolase A, B and C, and rabbit antibodies to chicken IgG. The Iodogen method was used for the iodination of aldolase A, B and C in this study. Aldolase A was predominantly high in concentration in muscle, aldolase B was high in normal adult liver, and aldolase C was high in adult brain. Aldolase A was elevated in hepatoma tissue and hepatoma cell lines, where aldolase B was distinctly low. Normal serum levels for the three isozymes were determined. The aldolase A levels in serum obtained from 41 normal subjects were 170 +/- 39 ng/ml. Serum aldolase A levels were increased in many patients with cancer and muscle diseases, but were not increased in patients with hepatitis or other benign diseases. Serum aldolase B levels obtained from 11 normal subjects were 28.5 +/- 9.2 ng/ml. Serum aldolase B levels were increased in patients with hepatitis and correlated well with serum GPT levels. Serum aldolase C levels obtained from 12 normal subjects were 2.4 +/- 0.7 ng/ml. The determination of aldolase A, B and C by radioimmunoassay may be a valuable tool in biochemical and clinical studies of aldolase isozymes.


Candidate genes that may be responsible for the unusual resistances exhibited by Bacillus pumilus SAFR-032 spores.
The spores of several Bacillus species, including Bacillus pumilus SAFR-032 and B. safensis FO-36b, which were isolated from the spacecraft assembly facility at NASA's Jet Propulsion Laboratory, are unusually resistant to UV radiation and hydrogen peroxide. In order to identify candidate genes that might be associated with these resistances, the whole genome of B. pumilus SAFR-032, and the draft genome of B. safensis FO-36b were compared in detail with the very closely related type strain B. pumilus ATCC7061(T). 170 genes are considered characteristic of SAFR-032, because they are absent from both FO-36b and ATCC7061(T). Forty of these SAFR-032 characteristic genes are entirely unique open reading frames. In addition, four genes are unique to the genomes of the resistant SAFR-032 and FO-36b. Fifty three genes involved in spore coat formation, regulation and germination, DNA repair, and peroxide resistance, are missing from all three genomes. The vast majority of these are cleanly deleted from their usual genomic context without any obvious replacement. Several DNA repair and peroxide resistance genes earlier reported to be unique to SAFR-032 are in fact shared with ATCC7061(T) and no longer considered to be promising candidates for association with the elevated resistances. Instead, several SAFR-032 characteristic genes were identified, which along with one or more of the unique SAFR-032 genes may be responsible for the elevated resistances. These new candidates include five genes associated with DNA repair, namely, BPUM_0608 a helicase, BPUM_0652 an ATP binding protein, BPUM_0653 an endonuclease, BPUM_0656 a DNA cytosine-5- methyltransferase, and BPUM_3674 a DNA helicase. Three of these candidate genes are in immediate proximity of two conserved hypothetical proteins, BPUM_0654 and BPUM_0655 that are also absent from both FO-36b and ATCC7061(T). This cluster of five genes is considered to be an especially promising target for future experimental work.


Interferon gamma upregulates frataxin and corrects the functional deficits in a Friedreich ataxia model.
Friedreich's ataxia (FRDA) is the most common hereditary ataxia, affecting ∼3 in 100 000 individuals in Caucasian populations. It is caused by intronic GAA repeat expansions that hinder the expression of the FXN gene, resulting in defective levels of the mitochondrial protein frataxin. Sensory neurons in dorsal root ganglia (DRG) are particularly damaged by frataxin deficiency. There is no specific therapy for FRDA. Here, we show that frataxin levels can be upregulated by interferon gamma (IFNγ) in a variety of cell types, including primary cells derived from FRDA patients. IFNγ appears to act largely through a transcriptional mechanism on the FXN gene. Importantly, in vivo treatment with IFNγ increases frataxin expression in DRG neurons, prevents their pathological changes and ameliorates the sensorimotor performance in FRDA mice. These results disclose new roles for IFNγ in cellular metabolism and have direct implications for the treatment of FRDA.


Destruction of cytochrome P-450 by ethylene. Structure of the resulting prosthetic heme adduct.
The prosthetic heme of cytochrome P-450 is converted during the metabolism of ethylene into an abnormal hepatic porphyrin. This porphyrin has been isolated, purified, and characterized by field desorption mass spectrometry and 360-MHz nuclear magnetic resonance spectroscopy. It has been unambiguously identified as one of the four possible isomers of N-(2-hydroxyethyl)protoporphyrin IX (isolated as the dimethyl ester). The isomer which is obtained bears the N-alkyl group on one of the two propionic acid-substituted pyrrole rings in the porphyrin. Strong support is provided by the structure of this porphyrin for our contention that the prosthetic heme of cytochrome P-450 is alkylated during attempted transfer of the catalytically-activated oxygen to the pi-bond of destructive unsaturated substrates.


Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B.
The genetic landscape of male infertility is highly complex. It is estimated that at least 4000 genes are involved in human spermatogenesis, but only few have so far been extensively studied. In this study, we investigated by whole exome sequencing two cases of idiopathic non-obstructive azoospermia (NOA) due to severe hypospermatogenesis. After variant filtering and prioritizing, we retained for each patient a homozygous loss-of-function (LoF) variant in a testis-specific gene, C1orf185 (c.250C>T; p.Gln84Ter) and CCT6B (c.615-2A>G), respectively. Both variants are rare according to the gnomAD database and absent from our local control cohort (n = 445). To verify the implication of these candidate genes in NOA, we used the CRISPR/Cas9 system to invalidate the mouse orthologs 4930522H14Rik and Cct6b and produced two knockout (KO) mouse lines. Sperm and testis parameters of homozygous KO adult male mice were analyzed and compared with those of wild-type animals. We showed that homozygous KO males were fertile and displayed normal sperm parameters and a functional spermatogenesis. Overall, these results demonstrate that not all genes highly and specifically expressed in the testes are essential for spermatogenesis, and in particular, we conclude that bi-allelic variants of C1orf185 and CCT6B are most likely not to be involved in NOA and male fertility.


[Tienilic acid, hyperuricemia and kidney function].
Tienilic acid (Diflurex) was given to 10 patients with secondary hyperuricemia following hydrochlorothiazide or furosemide administration. Eight of these 10 patients suffered acute worsening of renal function reflected in a significant increase in plasma creatinine. Plasma urates fell in all patients. Plasma creatinine returned to pretreatment levels in all patients within 4 to 15 days. Extreme caution should be exercised in prescribing tienilic acid to hyperuricemic patients, in view of the significant risk of reversible renal impairment.


Intersex (ix) mutations of Drosophila melanogaster cause nonrandom cell death in genital disc and can induce tumours in genitals in response to decapentaplegic (dpp(disk)) mutations.
In Drosophila melanogaster, the intersex (ix) is a terminally positioned gene in somatic sex determination hierarchy and function with the female specific product of double sex (DSX(F)) to implement female sexual differentiation. The null phenotype of ix is to transform diplo-X individuals into intersexes while leaving haplo-X animals unaffected. This study on the effect of different intersex mutations on genital disc development provides the following major results: (i) similar range of a characteristic array of morphological structures (from almost double sex terminalia to extreme reduction of terminal appendages) was displayed by the terminalia of XX ix(1)/ix(1) , XX ix(2)/ix(2) and XX ix(5)/ix(5) individuals; (ii) an increased number of apoptotic cells were found to occur in a localized manner in mature third instar larval genital discs of ix individuals; (iii) ix mutations can induce high frequency of neoplastic tumours in genitals in the presence of decapentaplegic (dpp(disk)) mutations; and (iv) heteroallelic combinations of dpp(disk) mutations can also induce tumours in intersex genitals with variable expressivity. On the basis of these findings, we suggest that: (i) loss of function of ix causes massive cell death in both male and female genital primordia of genital discs, resulting phenotype mimicking in male and female characteristics in genitals; and (ii) at the discs, the apoptotic cells persist as 'undead' cells that can induce oncogenic transformation in the neighbouring disc cells when dpp signalling is blocked or reduced by dpp(disk) mutations.


Frailty predicts adverse outcomes in older people with diabetes.
The greatest proportional increase in the number of people with diabetes by age group is predicted to occur in those aged 60 to 79. In older people living with diabetes, geriatric syndromes, which indicate frailty, are emerging as a third category of complications in addition to the traditional microvascular and macrovascular sequelae. Frailty is defined by the presence of three or more phenotypes (weight loss, weakness, decreased physical activity, exhaustion and slow gait speed). The presence of one or two phenotypes describes a pre-frail state, and the absence of phenotypes describes a non-frail person. Sarcopenia, or loss of muscle mass, is the muscular manifestation of frailty phenotype and is defined as a generalised loss of skeletal muscle mass and strength that leads to low physical performance. Persistent hyperglycaemia has been shown to be associated with poor muscle quality, performance and strength independent of age, race, sex, weight, height and physical activity. The coexistence of dementia and diabetes also increases the risk of frailty. There is evidence that midlife behaviours such as smoking, alcohol consumption, poor diet and low levels of physical activity are associated with frailty and dementia in later life. Frailty is a dynamic condition which can worsen or improve over time. Patients may progress from a non-frail to pre-frail or frail state. With timely intervention, there is a greater chance for an individual to recover from pre-frail to non-frail than to deteriorate into frailty. The progression of frailty is likely to be multifactorial, therefore multimodal intervention, including maintenance of adequate nutrition, physical exercise, and glycaemic control, may help to delay or prevent the development of frailty and to improve outcomes.


KnobSlider: Design of a Shape-Changing Parameter Control UI and Study of User Preferences on Its Speed and Tangibility.
Professionals such as sound engineers or aircraft pilots heavily use physical knobs and sliders on their interfaces. The interfaces have advantages over touchscreen interfaces, especially when the users need to quickly and eyes-freely respond to changing situations such as when musicians are improvising, or there is smoke in a cockpit. However, unlike touchscreen interfaces, the physical interfaces are often bulky and crowded and lack of adaptability to user preferences or small spaces. To have advantages from both physical and touchscreen control interfaces, we explore design space of control interfaces and suggest design guidelines in the following steps. We first conduct a formative study with eight professionals who use knobs and sliders. Based on their feedback, we propose design requirements for future parameter control interfaces. We then introduce the design of the KnobSlider, a shape-changing device that combines the advantages of a physical knob and a slider in a time- and space-multiplexing way. To increase users' acceptance on shape-changing control interfaces, we investigate subjective preference on speed of shape-changes by using pairwise comparison with different maximum speeds. We also investigate how tangibility-showing KnobSlider on a video or showing it in the physical world-affects users preference and suggest speed design guidelines for future studies.


Single-cell analysis challenges the connection between autophagy and senescence induced by DNA damage.
Autophagy and senescence have been described as central features of cell biology, but the interplay between these mechanisms remains obscure. Using a therapeutically relevant model of DNA damage-induced senescence in human glioma cells, we demonstrated that acute treatment with temozolomide induces DNA damage, a transitory activation of PRKAA/AMPK-ULK1 and MAPK14/p38 and the sustained inhibition of AKT-MTOR. This produced a transient induction of autophagy, which was followed by senescence. However, at the single cell level, this coordinated transition was not observed, and autophagy and senescence were triggered in a very heterogeneous manner. Indeed, at a population level, autophagy was highly negatively correlated with senescence markers, while in single cells this correlation did not exist. The inhibition of autophagy triggered apoptosis and decreased senescence, while its activation increased temozolomide-induced senescence, showing that DNA damage-induced autophagy acts by suppressing apoptosis.


Advances in glucocorticoid-induced osteoporosis.
Glucocorticoid-induced osteoporosis (GIOP) is one of the most important side effects of glucocorticoid use, as it leads to an increased risk of fractures. Recently, many published studies have focused on the cellular and molecular mechanisms of bone metabolism, the pathophysiology of GIOP, and the intervention options to prevent GIOP. In this review, recent advances in GIOP are summarized, particularly recent progress in our understanding of the mechanisms of GIOP resulting in improved insight that might result in the development of new treatment options in the near future.


A comparison study of periapical repair in dogs' teeth using RoekoSeal and AH plus root canal sealers: a histopathological evaluation.
The objective of the study was to evaluate the biocompatibility of RoekoSeal sealer Roeko (Dental Products, Langenau, Germany) with the periapical tissues of dogs and compare it with AH Plus sealer (Dentsply/De Trey, Konstanz, Germany). The pulps of 32 root canals were removed, the apical cementum layer perforated, the biomechanical preparation performed, and the root canals filled by lateral condensation technique. Ninety days after the surgery, the animals were euthanized, the bone with teeth removed, and the samples prepared for histopathological analysis. In group 1 (RoekoSeal Automix), deposition of mineralized tissue was observed, with complete newly mineralized apical formed tissue in 43.8% and partial sealing in 56.2%. In group 2 (AH Plus), in 12.5% there was complete newly mineralized apical formed tissue, in 75% the sealing was partial, and in 12.5% there was no sealing (p < 0.05). There were no differences between the groups in relation to the inflammatory infiltrate; thickness of the periodontal ligament; and the resorption of dentin, cementum or bone (p > 0.05).