Born with a Plastic Spoon in Their Mouth? - Substitution, Interchangeability, and Marketing of Biosimilars.
Biosimilar medicines have the potential to increase medicine access and bring cost savings to consumers, but uptake has been slow for a range of reasons. This article analyses one such reason, namely the potential for competitors' promotional materials to use certain terms with technical meanings, such as "interchangeable" and "substitution", in a misleading way. Against the backdrop of a flawed co-regulatory system for pharmaceutical marketing, the article identifies a need for clear regulatory statements about appropriate uses of such terms in pharmaceutical marketing and promotion.


Probing extreme states of matter using ultra-intense x-ray radiation.
Extreme states of matter, that is, matter at extremes of density (pressure) and temperature, can be created in the laboratory either statically or dynamically. In the former, the pressure-temperature state can be maintained for relatively long periods of time, but the sample volume is necessarily extremely small. When the extreme states are generated dynamically, the sample volumes can be larger, but the pressure-temperature conditions are maintained for only short periods of time (ps toμs). In either case, structural information can be obtained from the extreme states by the use of x-ray scattering techniques, but the x-ray beam must be extremely intense in order to obtain sufficient signal from the extremely-small or short-lived sample. In this article I describe the use of x-ray diffraction at synchrotrons and XFELs to investigate how crystal structures evolve as a function of density and temperature. After a brief historical introduction, I describe the developments made at the Synchrotron Radiation Source in the 1990s which enabled the almost routine determination of crystal structure at high pressures, while also revealing that the structural behaviour of materials was much more complex than previously believed. I will then describe how these techniques are used at the current generation of synchrotron and XFEL sources, and then discuss how they might develop further in the future at the next generation of x-ray lightsources.


[On the abortive and teratogenous action of volatile and gaseous anaesthetis agents (author's transl)].
The abortive and teratogenic effect of inhalational anaesthetics is well established. This cannot be explained by metabolic activation of the halogenated hydrocarbons but could be due to a noxious effect on the mitotoc spindle. The inhibition of mitosis is correlated with the lipid solubility and the anaesthetic effect. Numerous experiments give evidence that the effect of anaesthetics can be explained by their reversible binding to nonpolar sites of protein by Van der Waals' bonds affecting protein conformation. The tubular protein of mitotic spindle seems to be highly sensitive to this change of conformation. To prevent abortion and miscarriage in female operating room personnel it is essential not only to remove the halogenated compunds from room atmosphere but also all other anaesthetic gases and vapors such as nitrous oxide and diethyl ether.


Detection of bacteria in histological sections of the dental pulp.
A series of deep cavities with and without traumatic pulpal exposures were prepared in the maxillary molars of albino rats. They were left untreated for various time intervals before killing. Demineralized sections were prepared in a mesiodistal plane and stained to demonstrate the presence of bacteria. In the cavities and coronal pulps that were grossly contaminated, bacteria were detected in the majority of sections. In the root canals and periapical tissues, bacteria were detected in only a minority of sections. It is considered that serial sections stained to demonstrate bacteria are necessary for the detection of bacteria that are present in only small numbers in the tissues. The demonstration of small numbers of micro-organisms in specific zones of the pulp remains problematic. Failure to detect stained bacteria in histological sections is not absolute proof of their absence.


Serial analysis of gene expression in neurofibromatosis type 2-associated vestibular schwannoma.
The genesis, morphology, and growth characteristics of vestibular schwannomas are determined by genetic alterations which vary gene transcript expression and this transcript expression can be qualitatively and quantitatively evaluated using the SAGE technique. By use of such technique, gene products with tumorigenic potential may be identified, providing insight and targets for future study. Serial analysis of gene expression (SAGE) is a powerful new technique that allows detailed qualitative and quantitative evaluation of cellular gene transcript expression. Tissue in limited quantity (5 x 10 to 2 x 10 cells) may be analyzed by a modified version of SAGE called microSAGE. Application of SAGE or microSAGE to study vestibular schwannoma gene expression has not been previously reported. Fresh, vestibular schwannoma specimen from an individual with the diagnosis of neurofibromatosis type 2 was attained intraoperatively and maintained in a sealed container at -80degreesC until the time of analysis. The tissue was processed according to the microSAGE protocol, using 180 mg of vestibular schwannoma as starting material. The protocol resulted in the generation and sequencing of a tag library involving 458 tags representing 277 different gene products, including many transcripts known to be expressed in vestibular schwannomas. Several gene products with tumorigenic potential were identified. These data demonstrate that microSAGE is a useful technique to study vestibular schwannoma gene expression. Future studies will include building more comprehensive libraries and comparing libraries from various vestibular schwannoma phenotypes to identify useful diagnostic or prognostic markers, and targets for therapeutic intervention.


Plant defence against aphids: the PAD4 signalling nexus.
In Arabidopsis thaliana, PHYTOALEXIN DEFICIENT 4 (PAD4) functions as a key player in modulating defence against the phloem sap-feeding aphid Myzus persicae (Sülzer), more commonly known as the green peach aphid (GPA), an important pest of a wide variety of plants. PAD4 controls antibiosis and antixenosis against the GPA. In addition, PAD4 deters aphid feeding from sieve elements on Arabidopsis. In the past few years, substantial progress has been made in dissecting the role of PAD4 and its interaction with other signalling components in limiting aphid infestation. Several key genes/mechanisms involved in providing aphid resistance/susceptibility in Arabidopsis regulate the aphid infestation-stimulated expression of PAD4. Together, PAD4 and its interacting signalling partners provide a critical barrier to curtail GPA colonization of Arabidopsis.


Illness perceptions amongst individuals with dental caries.
To assess individuals' perception of dental caries, in order to explain how illness representations might influence their coping with the disease. Cross-sectional questionnaire study. 520 consecutive patients (aged ≥18 years) of the General Dentistry Clinic at Universidad Cooperativa de Colombia, Pasto, Colombia who had experienced dental caries. Illness perception of dental caries was assessed using the Illness Perception Questionnaire Revised (IPQ-R). The most frequent self-reported symptoms associated with dental caries were "toothache" (56.2%), "tooth sensitivity" (53.8%) and "mild to sharp pain when eating or drinking" (51.2%). The dimensions of illness perception were related to socio-economic status (SES). Symptoms of "loose or separating teeth" and "pus in your tooth" were associated with dental caries by low SES participants, while "bleeding while brushing, flossing or eating hard food" and "mild to sharp pain when eating or drinking something sweet, hot or cold" were related more to higher SES. Perceptions of caries were related to socioeconomic status. Interventions to promote health literacy in order to improve the capacity to obtain, process and understand basic oral health information could increase an early detection of caries.


Korean Red Ginseng enhances cardiac hemodynamics on doxorubicin-induced toxicity in rats.
Korean Red Ginseng (KRG) has been known to possess many ginsenosides. These ginsenosides are used for curing cardiovascular problems. The present study show the protective potential of KRG against doxorubicin (DOX)-induced myocardial dysfunction, by assessing electrocardiographic, hemodynamic, and biochemical parameters and histopathological findings. Animals were fed a standard chow and adjusted to their environment for 3 days before the experiments. Next, the rats were equally divided into five groups (n = 9, each group). The animals were administered with KRG (250 and 500 mg/kg) for 10 days and injected with DOX (20 mg/kg, subcutaneously, twice at a 24-h interval) on the 8th and 9th day. Electrocardiography and echocardiography were performed to study hemodynamics. Plasma levels of superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde were measured. In addition, the dose of troponin I and activity of myeloperoxidase in serum and cardiac tissue were analyzed, and the histopathological findings were evaluated using light microscopy. Administration of KRG at a dose of 250 and 500 mg/kg recovered electrocardiographic changes, ejection fraction, fractional shortening, left ventricular systolic pressure, the maximal rate of change in left ventricle contraction (+dP/dtmax), and left ventricle relaxation (-dP/dtmax). In addition, KRG treatment significantly normalized the oxidative stress markers in plasma, dose dependently. In addition, the values of troponin I and myeloperoxidase were ameliorated by KRG treatment, dose dependently. And, KRG treatment showed better histopathological findings when compared with the DOX control group. These mean that KRG mitigates myocardial damage by modulating the hemodynamics, histopathological abnormality, and oxidative stress related to DOX-induced cardiomyopathy in rats. The results of the present study show protective effects of KRG on cardiac toxicity.


Project Optimus, an FDA initiative: Considerations for cancer drug development internationally, from an academic perspective.
Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, short- and long-term tolerability has not always accompanied it. The choice of dose and schedule is often in the upper range of the therapeutic window, driven by the maximum tolerated dose (MTD) model of previous cytotoxic agents. There is increasing recognition that this needs to change, by taking a more holistic approach to determine the optimal dose for desired biological effects and tolerability early in clinical development. In the US, the FDA's Oncology Centre of Excellence is addressing this via the Project Optimus initiative: aiming to reform dose optimisation studies so that they can demonstrate the most appropriate dose selection. Early clinical development will need to demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for dose selection. Regulatory agencies outside the US are similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore and Switzerland, the UK participates in Project Orbis, a collaborative program with the FDA to accelerate patient access to new cancer medicines through coordinated regulatory review. Close alignment with Project Optimus will be important internationally and will require changes across industry, including for academic units and small biotech. We discuss our perspective on the implications, and opportunities, for early phase oncology trials as a uniquely charity-funded drug development facility, the Centre for Drug Development within the Cancer Research UK charity.


First report on the probiotic potential of Mammaliicoccus sciuri isolated from raw goat milk.
Probiotics are considered effective microbial dietary supplements that provide beneficial effects to consumers, usually by restoring or improving gut microflora. Goat milk is one of the rich sources of probiotics as well as nutrients. Therefore, the primary aim of this research was to isolate and evaluate the potential of novel indigenous probiotic strains present in goat milk. Six different raw goat milk samples were collected from different areas of Multan, Pakistan. For bacterial characterization, samples were cultured and isolated on MRS agar plates for different morphological and biochemical tests. The probiotic potential of the six isolates, all of which were gram positive (G1, G2, G3, G4, G5, and G6) and five of which were catalase negative (all except G1), were assessed via a milk coagulation assay and antimicrobial activity, pH tolerance, phenol tolerance, and sodium chloride (NaCl) tolerance tests, which revealed that all the isolates coagulated in milk and showed protease and lipase activity, except G3. All six isolates showed tolerance against 0.2% phenol and 2-4% NaCl and were able to survive in both alkaline and acidic conditions. Only five isolates showed antimicrobial activity against indicator strain Aspergillus niger strain STA9, validating their probiotic nature. The most potent bile-tolerant and bacteriocin-producing isolate, G1, also showed γ-hemolytic activity and resistance to penicillin but showed susceptibility to other antibiotics. The lactic acid-producing (0.60% titratable acidity) G1 isolate was identified as a novel strain of Mammaliicoccus sciuri based on 16S rDNA sequencing. The above findings suggest that the potent M. sciuri GMN01 strain can serve as a potential probiotic strain. A potent probiotic strain isolated from raw goat milk could be utilized as a dietary supplement, and goat milk could become an alternative to other sources of milk, particularly cow milk. However, safety aspects of this strain require further investigation because the present safety tests are insufficient to conclude that the GMN01 isolate is safe.


Testicular development induced by GnRH-IS in budgerigar (Melopsittacus undulatus).
Nowadays, the third part of parrots in the world is endangered or vulnerable; an alternative for their preservation is assisted reproduction in captivity through hormonal manipulation. In birds, GnRH is the main hormone which controls reproductive physiology, it is known there are three types: GnRH-I, GnRH-II and GnRH-III, involved in the release or inhibition of luteinizing hormone and follicle stimulant hormone to control gonadal and gametic development. The objective of this study was, to evaluate the effect of administrating synthetic GnRH-I in the testicular development of Melopsittacus undulatus. Twenty-eight adult budgerigars were randomly divided in two groups: control (n=14) and treated (n=14) with a unique dose of synthetic GnRH-I. Testicular development was assessed through ultrasonography and density was evaluated with pixels. Germinal diameter and thickness of germinal epithelium were determined with histology; there were identified and countified different cellular strains in seminiferous tubules therefore spermatobioscopy. Results. Ecographic density was: control group: 76 ± 7 pixels, treated group 41 ± 3 pixels. Thickness of germinal epitellium, 51.5 ± 2.9µm and 73.1 ± 3.1µm, for control group and treated group respectively. Sperm concentration in the treated group was 300% superior than in control group. It is concluded that the administration of synthetic GnRH-I, is a viable alternative to be used as part of the assisted reproductive techniques to induce reproduction.


Exploring the non-monotonic DNA capture behavior in a charged graphene nanopore.
Nanopore-based biomolecule detection has emerged as a promising and sought-after innovation, offering high throughput, rapidity, label-free analysis, and cost-effectiveness, with potential applications in personalized medicine. However, achieving efficient and tunable biomolecule capture into the nanopore remains a significant challenge. In this study, we employ all-atom molecular dynamics simulations to investigate the capture of double-stranded DNA (dsDNA) molecules into graphene nanopores with varying positive charges. We discover a non-monotonic relationship between the DNA capture rate and the charge of the graphene nanopore. Specifically, the capture rate initially decreases and then increases with an increase in nanopore charge. This behavior is primarily attributed to differences in the electrophoretic force, rather than the influence of electroosmosis or counterions. Furthermore, we also observe this non-monotonic trend in various ionic solutions, but not in ionless solutions. Our findings shed light on the design of novel DNA sequencing devices, offering valuable insights into enhancing biomolecule capture rates in nanopore-based sensing platforms.


Evaluation of plasma levels of melatonin after midazolam or sodium thiopental anesthesia in children.
Midazolam and sodium thiopental are two commonly used drugs in anesthesia for minor surgical procedures in children. A relationship exists between benzodiazepines (BNZ), barbiturates and melatonin. Whereas these drugs increase pineal melatonin production, the indoleamine amplifies the effects of both BNZ and barbiturates on the central nervous system (CNS). Our purpose was thus to analyze the plasma levels of melatonin before and during midazolam or sodium thiopental anesthesia in children subjected to ambulatory surgical procedures. Midazolam (0.4 mg/kg) or sodium thiopental (5 mg/kg) were administered i.v. to 33 and 32 children (aged between 2 and 14 yr), respectively, and blood samples were taken before and 5, 10 and 20 min after the drugs were administered. Melatonin was measured in plasma by a commercial radioimmunoassay kit previously standardized in our laboratory. The results showed that neither midazolam nor sodium thiopental anesthesia significantly affected the levels of melatonin studied at anytime. Significant correlations were found comparing the levels of melatonin between the different times studied. These results suggest that midazolam or sodium thiopental did not affect melatonin production by the pineal gland, thus avoiding a possible potentiating effect of the indoleamine on the central effects of these drugs during anesthesia. However, the possibility that changes in melatonin had been masked by the antioxidant role of the neurohormone are discussed.


Gambling behavior of students in grades seven and eight in Alberta, Canada.
This article reports results from a survey of gambling activities of seventh and eighth grade students in northeastern Alberta, Canada. Results confirmed that gambling practices are common among young adolescents. During the 12 months preceding the survey, virtually all respondents (98%) had gambled. Playing scratch tickets was the gambling activity most often played by young adolescents, followed by bingo. Boys were more likely than girls to engage in all forms of gambling activities. Sports betting and wagering on games of skill dimension were mostly male domains, whereas games of chance were female pursuits. Survey implications for public health officials are discussed.


Transvaginal sonography.
Transvaginal sonography can overcome some of the inherent limitations of the transabdominal technique. Scanning with a transvaginal probe often provides increased resolution and greater patient comfort. This technique is likely to be employed more frequently in the future for the evaluation of numerous gynecologic problems.


Mechanisms in noise-induced permanent hearing loss: an evoked otoacoustic emission and auditory brainstem response study.
In this study 22 patients (44 ears) with noise-induced permanent hearing loss were audiologically evaluated using transient-evoked otoacoustic emissions (TEOAE) and auditory brain-stem response (ABR). Twenty-one normal subjects (42 ears) without exposure to occupational noise were used as controls. Based upon the hearing loss at 4, 3, 2 and 1 kHz on the pure-tone audiogram, they were classified into four groups. In group 1 (eight ears), emissions were present in all ears but their TEOAE-noise level and their reproducibility (percentage) proved to be weak. The auditory brain-stem response (ABR) indicated that the I/V amplitude ratio, the latency values of wave V and the I-V intervals fell within the normal range in all ears. In Group 2 (14 ears), 40 per cent had no emissions, whereas the remaining ears showed weak emissions. The ABR revealed that in all ears the I/V amplitude ratio became small while wave V peak latency as well as I-V intervals were within the normal range. In Group 3 (10 ears), emissions were absent in 50 per cent, while in the other ears the emissions were very weak. The ABR revealed that the I/V amplitude ratio, which could be calculated in the 60 per cent in which wave I was present, was smaller than in Group 2. Wave V latency as well as I-V intervals were within the normal range. In Group 4 (12 ears), none of the ears showed emissions. The ABR indicated that the I/V amplitude ratio was much smaller when wave I was present (27 per cent) as well as I-V interval values being within the normal range. Wave V absolute latency value (delta V index) indicated a positive index in 17 per cent of this group (two ears) when wave I was absent. In the present study a dynamic process from cochlear outer hair cells to cochlear neurons was seen, correlating with an increasing hearing loss.


Using Standardized Patients to Teach Complete Denture Procedures in Second Year of Dental School.
Second-year dental students are commonly instructed on the process of complete denture fabrication with a traditional didactic lecture and preclinical dental laboratory education model. The problem with this limited mode of instruction is that dental students often fail to understand the various chairside procedures required to fabricate a complete denture. The aim of this study was to investigate the use of standardized dental patients to enhance students' understanding of the procedures involved with each appointment in the complete denture process. The Midwestern University College of Dental Medicine-Arizona created an event using standardized patients in four simulated chairside dental appointments for complete denture instruction of second-year dental students. Each appointment simulated the various sequential chairside procedures required to fabricate complete dentures. Following the didactic and dental laboratory instruction and the standardized patient event, a survey was conducted requesting the students' response to six statements regarding their understanding of the denture fabrication process. Of the 110 students who participated in the instructional events, 107 responded to the survey (97% response rate). These students responded very favorably to the simulated appointments, with the majority agreeing or strongly agreeing that their best understanding of the complete denture process was obtained through the standardized patient experiences. The use of standardized patients in simulated denture fabrication appointments enhanced the educational experience of these students when added to the traditional didactic lecture and preclinical laboratory education format. The experience has since been incorporated into the school's second-year oral health science laboratory curriculum.


Vibronic interactions and possible electron pairing in positively charged cyanodienes.
The conditions under which the attractive electron-electron interactions are realized in the monocations of sigma-conjugated cyanodienes such as C(6)N(4)H(4), C(8)N(6)H(4), and C(10)N(8)H(4) and of pi-conjugated acenes are discussed. The total electron-phonon coupling constants for the monocations l(HOMO) of cyanodienes are much larger than those for the monocations of acenes. The strong sigma orbital interactions between two neighboring atoms in the highest occupied molecular orbitals (HOMO) of sigma-conjugated cyanodienes are the main reason for the calculated results. Furthermore, we discuss how the conditions under which the monocation crystals become good conductor are related to the molecular size. Both the l(HOMO) values and the reorganization energies between the neutral molecules and the monocations decrease with an increase in molecular size in cyanodienes. The calculated results for the sigma-conjugated cyanodienes are compared with those for the pi-conjugated acenes in order to investigate how the CH-N substitutions in cyanodienes are closely related to the l(HOMO) values and the reorganization energies. Both the l(HOMO) and the reorganization energies in the positively charged sigma-conjugated cyanodienes are much larger than those in the positively charged pi-conjugated acenes. This means that in order to become good conductors, the positively charged sigma-conjugated cyanodienes need larger overlap integral between two adjacent molecules than the positively charged pi-conjugated acenes. On the other hand, since the l(HOMO) values for cyanodienes are much larger than those for acenes, the condition of attractive electron-electron interactions is more easily to be realized in the monocations of cyanodienes than in the monocations of acenes. It is suggested that the positively charged sigma-conjugated cyanodienes cannot easily become good conductors, but the conditions under which the electron-electron interactions become attractive are realized more easily in the positively charged sigma-conjugated cyanodienes than in the positively charged pi-conjugated acenes.


Oophoropexy to the Round Ligament after Recurrent Adnexal Torsion.
Recurrent adnexal torsion is a rare gynecological emergency. We report a case of recurrent ipsilateral adnexal torsion in a woman with polycystic ovaries, previously submitted to a laparoscopic plication of the utero-ovarian ligament. Due to the recurrence after the plication of the utero-ovarian ligament, the authors performed a laparoscopic oophoropexy to the round ligament, which is an underreported procedure. The patient was asymptomatic for 1 year, after which she had a new recurrence and needed a unilateral laparoscopic adnexectomy. Since then, she regained the quality of life without any gynecological symptoms.Oophoropexy to the round ligament may be considered when other techniques fail or, perhaps, as a first option in selected cases of adnexal torsion, as it may allow the prevention of recurrence without increasing morbidity while preserving the adnexa.


Schizophrenia two-hit hypothesis in velo-cardio facial syndrome.
Deletion of chr22q11 gives rise to velo-cardio facial syndrome (VCFS) and increases schizophrenia risk. The source of this elevated risk although unknown could result from stochastic, environmental, or genetic factors, the latter encompassing a range of complexity from polygenic mechanisms to "second-hit" mutations. For this study we tested the two-hit hypothesis where additional risk is conferred through a second CNV. We identified large (>100 kb) CNVs in 48 VCFS cases (23 with psychosis--25 without) and show in the psychotic VCFS group there is a significant (P = 0.02) increase in the average size of CNVs (354-227 kb). To identify second-hit loci we focused on individuals possessing gene-centric CNVs and through literature mining identified 4 (31%) psychotic VCFS individuals (n = 13) that overlapped loci previously implicated in neuropsychiatric disorders compared to 1 (10%) from the non-psychotic VCFS individuals (n = 10). For replication 17 VCFS patients with schizophrenia from the molecular genetics of schizophrenia dataset were used to identify further CNVs. Thirteen individuals possessing gene-centric CNVs were identified including 3 (23%) individuals possessing a potential second-hit, taking the overall total in the psychotic VCFS group (n = 26) to 7 (27%) potential second-hit loci. Notably a deletion in a psychotic VCFS patient at 2q23.1 hit the gene MBD5 which when deleted gives rise to intellectual disability, epilepsy, and autistic features. Through this study we potentially extend this phenotypic spectrum to include schizophrenia. Our results suggest the two-hit hypothesis may be relevant to a proportion of VCFS patients with psychosis but sample sizes are small and further studies warranted.


Identification of the protein targets of the reactive metabolite of teucrin A in vivo in the rat.
Covalent modification of proteins is associated with the toxicity of many electrophiles, and the identification of relevant in vivo protein targets is a desirable but challenging goal. Here, we describe a strategy for the enrichment of adducted proteins utilizing single-chain fragment variable (ScFv) antibodies selected using phage-display technology. Teucrin A is a furan-containing diterpenoid found in the herb germander that is primarily responsible for the herb's hepatotoxicity in rodents and humans following metabolic activation by cytochrome P450 enzymes. Conjugates of the 1,4-enedial derivative of teucrin A, its presumed toxic metabolite, with lysine- and cysteine-containing peptides were synthesized and used to select ScFvs from a rodent phage-displayed library, which recognized the terpenoid moiety of the teucrin-derived adducts. Immunoaffinity isolation of adducted proteins from rat liver homogenates following administration of a toxic dose of teucrin A afforded a family of proteins that were identified by liquid chromatography/tandem mass spectrometry. Of the 46 proteins identified in this study, most were of mitochondrial and endoplasmic reticulum origin. Several cytosolic proteins were found, as well as four peroxisomal and two secreted proteins. Using Ingenuity Pathway Analysis software, two significant networks involving the target genes were identified that had major functions in gene expression, small molecule biochemistry, and cellular function and maintenance. These included proteins involved in lipid, amino acid, and drug metabolism. This study illustrates the utility of chemically synthesized biological conjugates of reactive intermediates and the potential of the phage display technology for the generation of affinity reagents for the isolation of adducted proteins.


Atrophy of the hippocampus, parietal cortex, and insula in Alzheimer's disease: a volumetric magnetic resonance imaging study.
The hippocampus, parietal cortex, and insula were measured on volumetric magnetic resonance imaging to determine whether patients with early Alzheimer's disease had significantly more atrophy than healthy controls. To determine whether the atrophy is limited to certain cortical regions, the striate cortex was measured because this area is not usually neuropathologically involved early in Alzheimer's disease. Eight mildly to moderately impaired patients who met National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable Alzheimer's disease and eight controls who matched for age, gender, and educational level were studied. Atrophy was quantified in the following regions: hippocampus, parietal cortex, insular cortex, and striate cortex. The authors found significantly more atrophy of the hippocampus (p < 0.0001), parietal cortex (p < 0.025), and insula (p < 0.003) in the Alzheimer's patients. Measures of the striate cortex did not differ between the groups. There were no significant left-right differences in any of the regions measured. Their findings show that mildly to moderately impaired Alzheimer's patients have significantly more atrophy of the hippocampus, parietal cortex, and insula than healthy age-matched controls. Furthermore, this atrophy is probably discrete because the groups did not differ on measures of the striate cortex. Selective atrophy of the parietal and insular cortices has not previously been reported using the authors' methodology on volumetric magnetic resonance imaging. Their data suggest that the insula may be involved early in Alzheimer's disease and that atrophy of the insular cortex may contribute to the cognitive deficits typical of early Alzheimer's disease.


Improved hematopoietic differentiation efficiency of gene-corrected beta-thalassemia induced pluripotent stem cells by CRISPR/Cas9 system.
The generation of beta-thalassemia (β-Thal) patient-specific induced pluripotent stem cells (iPSCs), subsequent homologous recombination-based gene correction of disease-causing mutations/deletions in the β-globin gene (HBB), and their derived hematopoietic stem cell (HSC) transplantation offers an ideal therapeutic solution for treating this disease. However, the hematopoietic differentiation efficiency of gene-corrected β-Thal iPSCs has not been well evaluated in the previous studies. In this study, we used the latest gene-editing tool, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9), to correct β-Thal iPSCs; gene-corrected cells exhibit normal karyotypes and full pluripotency as human embryonic stem cells (hESCs) showed no off-targeting effects. Then, we evaluated the differentiation efficiency of the gene-corrected β-Thal iPSCs. We found that during hematopoietic differentiation, gene-corrected β-Thal iPSCs showed an increased embryoid body ratio and various hematopoietic progenitor cell percentages. More importantly, the gene-corrected β-Thal iPSC lines restored HBB expression and reduced reactive oxygen species production compared with the uncorrected group. Our study suggested that hematopoietic differentiation efficiency of β-Thal iPSCs was greatly improved once corrected by the CRISPR/Cas9 system, and the information gained from our study would greatly promote the clinical application of β-Thal iPSC-derived HSCs in transplantation.


Biochemical characterization of a novel extended-spectrum beta-lactamase from Pseudomonas aeruginosa 802.
Pseudomonas aeruginosa 802 was isolated at Rabta hospital in Tunis and was resistant to extended-spectrum cephalosporins and aztreonam. It produced a pI 7.6 extended-spectrum beta-lactamase (ESBL). The ESBL, named LBT 802, was purified to homogeneity by filtration on Sephadex G-75 followed by CM-Sepharose chromatography and high-performance liquid chromatography (HPLC) on a TSK-gel SP-5PW column. The LBT 802 enzyme had a molecular mass of 30 kDa. It showed a broad-substrate profile by hydrolyzing benzylpenicillin, ampicillin, cephalothin, cephaloridine, cefotaxime, ceftriaxone, and cefpirome but not ceftazidime, cefoxitin, imipenem, or aztreonam. The highest hydrolytic efficiency (Vmax/Km) was obtained for ampicillin, cephalothin, cephaloridine, and benzylpenicillin. Among extended-spectrum cephalosporins the best substrate was ceftriaxone followed by cefotaxime and cefpirome. LBT 802 activity was inhibited by clavulanic acid, sulbactam, imipenem, cefoxitin, and aztreonam. It showed its lowest Ki values for clavulanic acid, imipenem and sulbactam.


A case of acanthosis nigricans coexisting with mycosis fungoides.
Acanthosis nigricans maligna (ANM) is a paraneoplastic phenomenon most commonly associated with visceral adenocarcinoma, in particular, gastric adenocarcinoma. Clinically, AMN is characterized by rapidly progressive symmetrical skin thickening and hyperpigmentation of the intertriginous areas with peripheral acrochorda. The diagnosis is made by a detailed medical work-up for occult malignancies with particular emphasis on endocrinological diseases. We report a 67-year-old man that presented clinically with acanthosis nigricans, in which a subsequent diagnosis of mycosis fungoides was made.


Potentiation of cell invasion and matrix metalloproteinase production by alpha3beta1 integrin-mediated adhesion of gastric carcinoma cells to laminin-5.
We previously reported that the adhesion of gastric carcinoma cells to the peritoneum mediated by the alpha3beta1 integrin-laminin interaction is a key step in the initial process of peritoneal metastatic dissemination. Carcinoma cells subsequently invade through the intercellular gaps of mesothelial linings. In this study, we examined the role of the interaction of carcinoma cells with laminin-5, which is a major component of submesothelial basement membranes and serves as a high-affinity ligand for alpha3beta1 integrin, in carcinoma cell invasion. Human gastric carcinoma cell lines (MKN1, GT3TKB, and NUGC-4) adhered in an alpha3beta1 integrin-dependent manner to the extracellular matrix deposited by peritoneal mesothelial cells. An in vitro invasion assay using the Boyden chamber system revealed that MKN1 cell migration through the membranes increased when the membranes were coated with matrices produced by mesothelial cells or with laminin-5-containing Matrigel as compared to Matrigel alone. The cell migration promoted by laminin-5-containing Matrigel was inhibited by the presence of anti-alpha3 integrin antibody. When MKN1 cells were cultured in a laminin-5-coated plate, these cells were promoted to produce matrix metalloproteinase (MMP)-9, as assessed by gelatin zymography, enzyme-linked immunosorbent assay, and reverse transcription-polymerase chain reaction. These results suggest that the production of MMP-9 by MKN1 cells was potentiated by the alpha3beta1 integrin-laminin-5 interaction, which facilitated their invasion via degradation of the matrix.


Whipple disease.
Whipple disease is a rare disease caused by infection with the bacterium Tropheryma whippelii. Humans are the only known host for the infection. The signs of systemic infection include gastrointestinal problems, weight loss, and arthritis. Signs of central nervous system infection include cognitive changes, supranuclear gaze palsy, altered level of consciousness, and movement disorders. The diagnosis is based on clinical findings as well as microscopic examination of biopsy specimens and, more recently, polymerase chain reaction (PCR) analysis, which has high sensitivity and specificity. Although the organism historically has been difficult to culture, several recent attempts have been successful. Antibiotic treatment is recommended for 1 year while monitoring the clinical signs and cerebrospinal fluid PCR results.


4-Hy-droxy-6-(4-meth-oxy-phen-yl)-4-phenyl-1,3-diazinane-2-thione.
In the title compound, C(17)H(18)N(2)O(2)S, the 1,3-diazinane-2-thione ring system is not coplanar with the benzene ring and meth-oxy-phenyl ring system, the dihedral angle between the planes being 65.58 (13) and 89.18 (10)°, respectively. The crystal structure is characterized by inter-molecular O-H⋯S, N-H⋯S, N-H⋯O and C-H⋯S hydrogen bonding.


Diabetes in Cushing Disease.
This review focuses on the pathophysiological and clinical aspects of diabetes mellitus occurring in patients with Cushing disease (CD). Insulin resistance and impairment in insulin secretion are both involved in the pathogenesis of glucocorticoid-induced diabetes. Correction of glucocorticoid excess does not always resolve abnormalities of glucose homeostasis, and correction of hyperglycaemia is specifically required. In fact, insulin resistance may persist even after correction of glucocorticoid excess and diabetes needs to be treated for long term. On the other hand, emerging drugs used in the treatment of CD, such as the novel somatostatin analog pasireotide, may have direct effects on glucose homeostasis regardless of control of cortisol excess. Diabetes mellitus is a frequent and early complication of CD with important diagnostic, prognostic and therapeutic implications. Specifically, diagnosis of CD in patients with diabetes may be difficult due to potential misinterpretation of markers of cortisol hypersecretion. Moreover, diabetes mellitus is often difficult to be controlled in CD requiring a careful and dedicated therapeutic approach. Finally, the coexistence of diabetes may influence the therapeutic decision making in CD, since drugs used in this setting may variably influence glucose homeostasis regardless of control of hypercortisolism.


Augmentation with citalopram for suicidal ideation in middle-aged and older outpatients with schizophrenia and schizoaffective disorder who have subthreshold depressive symptoms: a randomized controlled trial.
To examine the effects of citalopram augmentation of antipsychotics on suicidal ideation in middle-aged and older people with schizophrenia and subthreshold depressive symptoms. In this placebo-controlled trial conducted from September 1, 2001, to August 31, 2007, 198 outpatients > or = 40 years old with DSM-IV-diagnosed schizophrenia or schizoaffective disorder and subthreshold depressive symptoms were randomly assigned to flexible-dose citalopram (n = 104) or placebo (n = 94) augmentation of their antipsychotic for 12 weeks. Depression was measured with the Hamilton Depression Rating Scale (HDRS) and Calgary Depression Rating Scale (CDRS). Primary suicidal ideation measures were the Clinical Global Impressions-Severity of Suicide scale (CGI-SS) and the InterSePT Scale for Suicidal Thinking (ISST); secondary outcomes were the Scale for Suicidal Ideation (SSI), Beck Hopelessness Scale (BHS), HDRS item 3, and CDRS item 8. Compared to placebo, at the final visit, citalopram was associated with lower BHS scores (4.21 vs 4.98; P < .05) and lower likelihood of having suicidal ideation on the ISST (17.7% vs 38.7%; P < .005) and HDRS item 3 (14.4% vs 22.6%; P < .05). Among the 114 participants with no baseline suicidal ideation, there were no significant differences between citalopram and placebo regarding "emergent" ideation on either primary outcome. Among the 55 participants with baseline suicidal ideation, fewer treated with citalopram had endpoint ideation on the ISST (28.6% vs 66.7%; P < .05). Significantly more depression responders than nonresponders went from having baseline suicidal ideation to no suicidal ideation on both the ISST (75.0% vs 31.4%; P < .05) and CGI-SS (84.6% vs 31.3%; P < .05). Treatment-emergent suicidal ideation was no more common with citalopram than placebo. In participants with baseline suicidal ideation, citalopram reduced suicidal ideation, especially in those whose depressive symptoms responded to treatment.


[Babesiasis, pediatric malaria: does confusion exist in Africa?].
The authors describe a case of febrile disease acquired by a nursling in Africa: was it induced by Pl. falciparum or by Babesia sp.? In spite of numerous microscopic and serological appraisals from veterinary and medical authorities, it is difficult to state definitively this subject, but it is more probably a babesiosis of canine or rodent origin.


Association between prehospital medication and fatal outcomes in a cohort of hospitalized patients due to coronavirus disease-2019 in a referral hospital in Peru.
To explore the association between the use of prehospital medications and the development of fatal outcomes in patients who required hospitalization due to coronavirus disease-2019 (COVID-19). This retrospective cohort study included adult patients who were hospitalized due to COVID-19. Demographic, clinical, and laboratory data, prehospital medication history, and fatal outcome development (use of high-flow oxygen therapy, intensive care unit [ICU] admission, or mortality) were extracted from the medical records of patients who were admitted due to COVID-19 to the Carlos Seguín Escobedo National Hospital of Arequipa, Peru during July to September 2021, the period after the second wave of COVID-19 cases in Peru. Survival was analyzed using the Cox proportional hazards model, and crude hazard ratios and adjusted hazard ratios (aHR) with their respective 95% confidence intervals (95% CI) were calculated. A total of 192 patients were evaluated, of whom 62% were males and 46.9% did not require oxygen support at admission. Additionally, 64.6% used nonsteroidal anti-inflammatory drugs, 35.4% used corticosteroids, 28.1% used macrolides or ceftriaxone, 24.5% used ivermectin, and 21.9% used warfarin before hospitalization. Of the patients, 30.2% developed a fatal outcome during follow-up. The multivariate analysis revealed that prehospital corticosteroid use was independently associated with the fatal outcome due to COVID-19 with an aHR = 5.29 (95%CI: 1.63-17.2). Prehospital corticosteroid use was associated with a 5-fold increased risk of fatal outcome development.


Salivary miRNA Profiles in COVID-19 Patients with Different Disease Severities.
The oral mucosa is the first site of SARS-CoV-2 entry and replication, and it plays a central role in the early defense against infection. Thus, the SARS-CoV-2 viral load, miRNAs, cytokines, and neutralizing activity (NA) were assessed in saliva and plasma from mild (MD) and severe (SD) COVID-19 patients. Here we showed that of the 84 miRNAs analyzed, 8 were differently expressed in the plasma and saliva of SD patients. In particular: (1) miRNAs let-7a-5p, let-7b-5p, and let-7c-5p were significantly downregulated; and (2) miR-23a and b and miR-29c, as well as three immunomodulatory miRNAs (miR-34a-5p, miR-181d-5p, and miR-146) were significantly upregulated. The production of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8, IL-9, and TNFα) and chemokines (CCL2 and RANTES) increased in both the saliva and plasma of SD and MD patients. Notably, disease severity correlated with NA and immune activation. Monitoring these parameters could help predict disease outcomes and identify new markers of disease progression.


Choroidal thickness in diabetic retinopathy in relation to long-term systemic treatments for diabetes mellitus.
To measure central choroidal thickness (CCT) in patients with diabetic retinopathy (DR) and analyze the correlation with clinical backgrounds regarding medications for diabetes mellitus (DM). We retrospectively identified 86 patients with DR (172 eyes) and 43 healthy subjects (57 eyes) who underwent spectral-domain optical coherence tomography. Among the 86 patients with DM who had received no intraocular treatments, 61 were diabetic patients who had continuously received systemic treatments for DM (under treatment group). Twenty-five were patients who had discontinued the treatments or had not received any treatment for DM until this study started (no treatment group). The results of CCT acquired by 2 masked raters showed a significant correlation coefficient (r = 0.98), indicating high reproducibility in this study. No correlation of CCT was noted between normal (272 ± 71 µm) and DM eyes (264 ± 77 µm), the presence of diabetic macular edema, or CCT and the severity of DR in the patients examined. Interestingly, there was a significant decrease in CCT (175 ± 42 µm) in eyes with mild/moderate nonproliferative DR (NPDR) in the no treatment group (p<0.05), whereas CCT was prominently thicker in eyes with severe NPDR (354 ± 76 µm) and proliferative DR (286 ± 74 µm) than in eyes without DR. This study demonstrated that CCT was significantly decreased in the presence of mild/moderate NPDR in the no treatment group, suggesting that a continuously high blood sugar state caused by insufficient treatments for DM may facilitate vascular damage in the choroid in the early stage of DR.


Electroconvulsive therapy in treatment-resistant schizophrenia: prediction of response and the nature of symptomatic improvement.
The clinical features of patients with schizophrenia who respond to electroconvulsive therapy (ECT) are uncertain. There is a longstanding belief that the duration of illness and/or the presence of affective symptoms associate with good prognosis. There is also little information on the nature of symptomatic improvement with this treatment. We examined the demographic and clinical history features associated with response, the symptom profile predictive of response, and the profile of symptomatic improvement. Using a standardized protocol, 253 patients with treatment-resistant schizophrenia were prospectively treated with a combination of ECT and flupenthixol. Of this group, 138 patients (54.5%) met the response criteria. Independence of sex, longer duration of current episode, and greater severity of baseline negative symptoms were predictive of poorer outcome. Duration of illness had weak relations with outcome only among females. There were marked sex differences in other clinical features and symptoms associated with response. In contrast, no sex differences were observed in the nature of symptomatic improvement. Treatment resulted in marked improvement in specific positive symptoms, with an intermediate effect on affective symptoms and no effect or worsening of specific negative symptoms. The findings challenge recommendations that long duration of illness or absence of affective symptoms portends poor response to ECT in patients with treatment-resistant schizophrenia. Sex may play a critical role in determining the features of the illness that predict outcome.


STABILIZING SELECTION AND THE COMPARATIVE ANALYSIS OF ADAPTATION.
Comparative studies tend to differ from optimality and functionality studies in how they treat adaptation. While the comparative approach focuses on the origin and change of traits, optimality studies assume that adaptations are maintained at an optimum by stabilizing selection. This paper presents a model of adaptive evolution on a macroevolutionary time scale that includes the maintenance of traits at adaptive optima by stabilizing selection as the dominant evolutionary force. Interspecific variation is treated as variation in the position of adaptive optima. The model illustrates how phylogenetic constraints not only lead to correlations between phylogenetically related species, but also to imperfect adaptations. From this model, a statistical comparative method is derived that can be used to estimate the effect of a selective factor on adaptive optima in a way that would be consistent with an optimality study of adaptation to this factor. The method is illustrated with an analysis of dental evolution in fossil horses. The use of comparative methods to study evolutionary trends is also discussed.


Comparison of intravitreal bevacizumab, intravitreal triamcinolone acetonide, and macular grid augmentation in refractory diffuse diabetic macular edema: A prospective, randomized study.
In spite of laser being the gold standard treatment for Diabetic Macular edema (DME), some patients do not respond to laser. Various treatment modalities are being tried in the management of refractory diffuse DME (DDME). To compare the efficacy of intravitreal bevacizumab (IVB), intravitreal triamcinolone acetonide (IVTA), and macular grid augmentation in the management of refractory DDME. Prospective randomized study in a tertiary eye care center. SIXTY PATIENTS WITH REFRACTORY DDME WERE RANDOMLY ASSIGNED TO THREE GROUPS: Group 1 received IVB (1.25 mg/0.05 ml), Group 2 received IVTA (4 mg/0.1ml), and Group 3 underwent laser augmentation. Primary outcome measures were best corrected visual acuity (BCVA) and central macular thickness (CMT) at the end of 6 months. Analysis was performed using SPSS 14.0 Group 1 and 2 showed significant improvement in mean BCVA from 20/160 at baseline to 20/80 and from 20/125 to 20/63, respectively, at 6 months (P < 0.05). These groups also showed a significant reduction in the mean CMT from 457 ± 151 μ at baseline to 316 ± 136 μ and from 394 ± 61 μ to 261 ± 85 μ, respectively, at 6 months (P < 0.05). Group 3 showed only small improvement in mean BCVA from 20/100 to 20/80 (P = 1.0) while mean CMT increased from 358 ± 89 μ at baseline to 395 ± 127 μ at 6 months (P = 0.191). Eight (40%) eyes in Group 2 had intraocular pressure (IOP) rise and 10 (50%) eyes developed cataract. Both IVB and IVTA may be effective in the treatment of refractory DDME compared with macular grid augmentation. IVTA may be associated with side effects such as IOP rise and cataract formation.


Structural and functional organization of a diencephalic sensory-motor interface in the gymnotiform fish, Eigenmannia.
The diencephalic nucleus electrosensorius (nE) of gymnotiform fish comprises a series of finely tuned neuronal filters for control of the jamming avoidance response (JAR) and probably other electromotor tasks as well. The nE receives electrosensory input from the dorsal torus semicircularis (TSd) and octavolateral input from the ventral torus (TSv). The nE, in turn, projects to various hypothalamic and thalamic nuclei, including the prepacemaker nucleus (PPn), which can modulate the frequency of electric organ discharges (EODs) via its unique input to the medullary pacemaker nucleus. Four subdivisions of the nE can now be recognized: 1) The beat-related area (nEb)--a rostral cluster of tightly packed cells which receives TSd input and projects to the inferior lobe, anterior tuberal nucleus, anterior thalamic nucleus, central posterior thalamic nucleus, and PPn. The nEb contains neurons responsive to beat patterns caused by jamming stimuli. Stimulation of the nEb with L-glutamate, however, fails to induce any EOD-frequency shift. 2) The area causing EOD-frequency rises (nE increases)--a horizontal band of cells at the dorsal aspect of the caudal nE which receives TSd input and projects to the PPn and vicinity and to the cerebellum; nE increases stimulation induces slow EOD-frequency rises characteristic of the JAR. Responses of these cells to jamming stimuli are not yet known. 3) The area causing EOD-frequency falls (nE decreases)--a horizontal band of cells at the ventral aspect of the caudal nE which receives TSd input and projects only to the PPn and vicinity; nE decreases stimulation induces slow EOD-frequency falls characteristic of the JAR. The responses of these cells to jamming stimuli are not yet known. 4) The acousticolateral region (nEar)--a complex medial region of the nE which receives input predominantly from the ventral torus and projects to the inferior lobe, anterior tuberal nucleus, central posterior thalamic nucleus, PPn, and cerebellum; the sensory and motor properties of this region are not known in detail, although auditory and mechanosensory responses have been recorded here. Projections to the PPn and its vicinity suggest direct control of electromotor behaviors by the nE, whereas thalamic and hypothalamic projections may provide a substrate for electrosensory influences on neuroendocrine and motivational control centers. The optic tectum projects strongly to the pretectum and various other diencephalic nuclei in the vicinity of the nE, but it does not innervate the nE itself. Accordingly, ablation of the tectum does not affect the performance of the JAR.


[The wakefulness-sleep cycle during antiorthostatic hypokinesia].
Studies on the wake-sleep cycle with participation of eight female volunteers were performed before, during, and after a 120-day bed rest with the head-end of bed tilted down at 6 degrees (HDT). Methods of polysomnography and actography were applied. The test-subjects were assigned into 2 groups. Group A was prescribed to use countermeasures throughout the experiment; no countermeasures was administered by group B. Evidence of significant alteration in sleep structure at different time points in HDT is given in comparison with data about females of the control group under the conditions of everyday activity. Sleep deviations in the subjects were reordered at each of the three points of investigation and differed from those in control. HDT was shown to modify the sleep structure in experimental groups A and B. A supposition is made that under these conditions the dynamics of physical activity during night sleep had an adaptive character.


Ceruloplasmin and myeloperoxidase in complex affect the enzymatic properties of each other.
Ceruloplasmin (CP), the multicopper oxidase of plasma, interacts with myeloperoxidase (MPO), an enzyme of leukocytes, and inhibits its peroxidase and chlorinating activity. Studies on the enzymatic properties shows that CP behaves as a competitive inhibitor impeding the binding of aromatic substrates to the active centre of MPO. The contact between CP and MPO probably entails conformational changes close to the p-phenylenediamine binding site in CP, which explains the observed activation by MPO of the substrate's oxidation. CP subjected to partial proteolysis was virtually unable to inhibit activity of MPO. The possible protein-protein interface is comprised of the area near active site of MPO and the loop linking domains 5 and 6 in CP. One of the outcomes of this study is the finding of a new link between antioxidant properties of CP and its susceptibility to proteolysis.


Histamine poisoning after ingestion of spoiled raw tuna in a patient taking isoniazid.
An 83-year-old woman taking isoniazid (INH) suddenly developed a headache, palpitations, and skin eruptions with itching while eating raw tuna. The symptoms were compatible with those of histamine intoxication. When given fresh raw tuna to eat, no such reactions were evoked in this patient. The episode was speculated to be due to two conditions; eating spoiled raw tuna and at the same time being on a course of INH, a potent histaminase inhibitor. We should therefore be aware of the possible adverse effects due to the interactions between drugs and foods.


Urea-induced drying of carbon nanotubes suggests existence of a dry globule-like transient state during chemical denaturation of proteins.
Atomistic dynamics simulations of purely hydrophobic carbon nanotubes in 8 M urea are performed to dissect the role of dispersion interactions in the denaturing power of urea. The enhanced population of urea and a paucity of water in proximity of nanotubes suggest that the stronger dispersion interaction of urea than water with nanotube triggers drying of its interior. The preferential intrusion of urea over water within nanotube interiors irrespective of their diameters directly implies a "dry globule"-like transient intermediate formation in the initial stage of protein unfolding in urea.


MXenes Quantum Dots for Biomedical Applications: Recent Advances and Challenges.
MXenes have aroused widespread interest in the biomedical field owing to their remarkable photo-thermal conversion capabilities combined with large specific surface areas. MXenes quantum dots (MQDs) have been synthesized either by the physical or chemical methods based on MXenes as precursors, which possess smaller size, higher photoluminescence, coupled with low cytotoxicity and many beneficial properties of MXenes, thereby having potential biomedical applications. Given this, this review summarized the synthesis methods, optical, surface and biological properties of MQDs along with their practical applications in the field of biomedicine. Finally, the authors make an outlook towards the synthesis, properties and applications of MQDs in the future biomedicine field.


Effect of stress-shielding-induced bone resorption on glenoid loosening in reverse total shoulder arthroplasty.
Aseptic loosening of the glenoid component is one of the main reasons for the high revision rates of reverse total shoulder arthroplasty (RTSA). It has been reported that the bulky implant designs may lead to stress shielding. However, it is uncertain whether the shielding effect is severe enough to lead to bone resorption and glenoid loosening. The purpose of this study was to evaluate the level of stress-shielding and assess whether bone resorption plays a role in aseptic glenoid loosening following RTSA. A cadaveric in vitro test model was used to validate a finite element model (FEM) of the scapula. The FEM of the scapula, incorporating adaptive bone remodeling algorithms, was used to predict changes in postoperative bone density after RTSA. Changes in bone strength after implantation were also analyzed. The strain values predicted from the FEM of the scapula were in agreement with the in vitro measurements. Analysis of postoperative bone adaptation revealed that strain-induced bone resorption began at the peg of the implant and around the resected bone surface and then gradually expended to the peripheral regions. The bone strength also reduced postoperatively and appeared particularly around the implant peg. Strain-induced bone resorption is a likely source of the bone loss commonly observed in RTSA. The finite element glenoid bone remodeling simulation may be used as a tool to evaluate glenoid implant design.


Covariates and prevalence of obesity among adult North Indian population.
The present study was aimed to investigate the prevalence of obesity and its covariates including age among adult Khatri males and females. A total of 805 subjects (male = 381, female = 424) between age of 18 yr to 71 + yr residing in Shahjahanpur city, Uttar Pradesh, India were studied cross sectionally. The study highlights the trend of obesity in the population and also discusses in detail, the factors that cause it. An inverse relationship was obtained between level of physical activity and different relative weight categories based on body mass index in both the sexes. Similar association was observed in case of television watching time and overweight/obesity. With increase in hours of television watching the prevalence of overweight/obese also increased among both Khatri males and females.


Chemical synthesis and characterization of the epidermal growth factor-like module of human complement protease C1r.
C1r is one of the two serine proteases of C1, the first component of complement, in which it is associated in a calcium-dependent manner to the homologous serine protease C1s. This interaction is mediated by the N-terminal region of C1r, which comprises a single epidermal growth factor (EGF)-like module containing the consensus sequence required for calcium binding, surrounded by two CUB modules. With a view to determine the structure of the EGF-like module of C1r and evaluate its contribution to calcium binding, this module [C1r(123-175)] was synthesized by automated solid-phase methodology using the Boc strategy. A first synthesis using the Boc-His(Z) derivative gave very low yield, due to partial deprotection of His residues leading to chain termination by acetylation, and to insertion of glycine residues. This could be circumvented by using the Boc-His(DNP) derivative and by condensation of appropriate glycine-containing segments. The synthetic peptide was efficiently folded under redox conditions to the species with three correct disulfide bridges, as determined by mass spectrometry and N-terminal sequence analyses of thermolytic fragments. The homogeneity of the synthetic peptide was assessed by reversed-phase HPLC and electrospray mass spectrometry. One-dimensional 1H NMR spectroscopic analysis provided evidence that the EGF-like module had a well defined structure, and was able to bind calcium with an apparent Kd of 10 mM. This value, comparable to that found for the isolated EGF-like modules of coagulation factors IX and X, is much higher than that measured for native C1r. As already proposed for factors IX and X, it is suggested that neighbouring module(s), most probably the N-terminal CUB module, contribute(s) to the calcium binding site.


A randomized clinical trial of adolescents with HIV/AIDS: pediatric advance care planning.
The objective of this study is to determine if pediatric advance care planning (pACP) increases adolescent/family congruence in end-of-life (EOL) treatment preferences longitudinally. Adolescents aged 14-21 years with HIV/AIDS and their families were randomized (N = 105 dyads) to three-60-minute sessions scheduled one week apart: either the pACP intervention (survey administered independently, facilitated conversation with adolescent and family present, completion of legal advance directive document with adolescent and family present) or an active control (developmental history, safety tips, nutrition and exercise education). This longitudinal, single-blinded, multi-site, randomized controlled trial was conducted in six pediatric hospital-based HIV-clinics, located in high HIV mortality cities. The Statement of Treatment Preferences measured adolescent/family congruence in EOL treatment preferences at immediately following the facilitated pACP conversation (Session 2), and at 3-month post-intervention. The mean age of adolescent participants was 18 years (range 14-21 years); 54% were male; and 93% were African-American. One-third had an AIDS diagnosis. Immediately post-intervention the Prevalence Adjusted Bias Adjusted Kappa showed substantial treatment preference agreement for pACP dyads compared to controls (High burden/low chance of survival, PABAK = 0.688 vs. 0.335; Functional impairment, PABAK = 0.687 vs. PABAK= 0.34; Mental impairment, PABKA = 0.717 vs. 0.341). Agreement to limit treatments was greater among intervention dyads than controls (High burden: 14.6% vs. 0%; Functional impairment = 22.9% vs. 4.4%; and Mental impairment: 12.5% vs. 4.4%). Overall treatment preference agreement among pACP dyads was high immediately post-intervention, but decreased over time. In contrast, treatment agreement among control dyads was low and remained low over time. As goals of care change over time with real experiences, additional pACP conversations are needed.


AICRG, Part I: A 6-year multicentered, multidisciplinary clinical study of a new and innovative implant design.
Repetitive microstrains, which occur at the bone-implant interface during function, can lead to implant loss. In an attempt to improve survival by directing the stresses during function away from the dense cortical bone and toward the resilient trabecular bone, the Ankylos implant was developed with a roughened, progressive thread and a smooth cervical collar. The highly polished collar reduces the stresses in areas of the crestal bone. A precisely machined Morse taper prevents rotation of the abutment on the implant and eliminates the microgap present in many 2-stage implant systems. Clinical studies of other implants at different clinical research centers have demonstrated varying degrees of survival. The purpose of this paper was (1) to assess the overall clinical survival of this new implant design and (2) to compare implant stability (ie, Periotest values [PTVs]) over time with other implants. The investigation represented a comprehensive, multicentered, international clinical study conducted over a period of 6 years. It was conducted under an Investigational Device Exemption (IDE) protocol that was reviewed and accepted in the United States by the Food and Drug Administration (FDA). Over 1500 implants were placed and restored, and follow-up data were gathered for a period of up to 3 to 5 years. Over 44% of the clinical research centers reported no failures (100% survival). A total of 63% of the centers had none or only 1 failure during the study. One center reported 6 failures in 1 patient, which were not related to the implant design. Overall survival for implants in function for 3 to 5 years was 97.5%. Using failure criteria of earlier studies of other implants, 5-year survival was 98.3%. Higher handpiece speeds were associated with an increase in the number of failures. This new design produced a slightly more resilient trabecular bone-implant complex with a difference of about 1 PTV in all bone densities when compared with other implants. The following conclusions can be made: (1) the implant design was effective under all clinical conditions; (2) no significant and unexpected complications or risk factors were evident; (3) survival was found to be excellent; and (4) this implant is well suited for use in the restoration of masticatory function and esthetics in patients with missing natural teeth.


Methanol related deaths in Edirne.
In this retrospective autopsy study, a detailed analysis of methanol related deaths in Trakya region of Turkey is presented and departmental autopsy records, toxicology and histopathology results are analyzed. We found that methanol poisonings comprise 2.83% of all forensic autopsies (n:18), 88.8% of the cases were male, most of the victims were aged between 41 and 45. Blood methanol concentrations range widely from 55 to 479 mg per 100ml. Ethyl alcohol was detected in 44.4% of the cases. Most of the cases died in hospital and were poisoned through the consumption of alcoholic beverages from illicit sources and colognes. It is important for physicians to be aware of methanol poisoning symptoms and for forensic pathologists to obtain samples for toxicology during autopsies. Some preventative strategies including to routine control of the stores, to prevent the production of illegal alcoholic beverages, etc. should be developed.


Array Comparative Genomic Hybridization as the First-line Investigation for Neonates with Congenital Heart Disease: Experience in a Single Tertiary Center.
The purpose of the present study was to investigate the advantages and disadvantages of verifying genetic abnormalities using array comparative genomic hybridization (a-CGH) immediately after diagnosis of congenital heart disease (CHD). Among neonates under the age of 28 days who underwent echocardiography from January 1, 2014 to April 30, 2016, neonates whose chromosomal and genomic abnormalities were tested using a-CGH in cases of an abnormal finding on echocardiography were enrolled. Of the 166 patients diagnosed with CHD, 81 underwent a-CGH and 11 patients (11/81, 13.5%) had abnormal findings on a-CGH. 22q11.2 deletion syndrome was the most common (4/11, 36.4%). On the first a-CGH, 4 patients were negative (4/81, 5%). Three of them were finally diagnosed with Williams syndrome using fluorescent in situ hybridization (FISH), 1 patient was diagnosed with Noonan syndrome through exome sequencing. All of them exhibited diffuse pulmonary artery branch hypoplasia, as well as increased velocity of blood flow, on repeated echocardiography. Five patients started rehabilitation therapy at mean 6 months old age in outpatient clinics and epilepsy was diagnosed in 2 patients. Parents of 2 patients (22q11.2 deletion syndrome and Patau syndrome) refused treatment due to the anticipated prognosis. Screening tests for genetic abnormalities using a-CGH in neonates with CHD has the advantage of early diagnosis of genetic abnormality during the neonatal period in which there is no obvious symptom of genetic abnormality. However, there are disadvantages that some genetic abnormalities cannot be identified on a-CGH.


Application of Latent Growth Curve modeling to predict individual trajectories during neurofeedback treatment for tinnitus.
Tinnitus is a heterogeneous phenomenon indexed by various EEG oscillatory profiles. Applying neurofeedback (NFB) with the aim of changing these oscillatory patterns not only provides help for those who suffer from the phantom percept, but a promising foundation from which to probe influential factors. The reliable attribution of influential factors that potentially predict oscillatory changes during the course of NFB training may lead to the identification of subgroups of individuals that are more or less responsive to NFB training. The present study investigated oscillatory trajectories of delta (3-4Hz) and individual alpha (8.5-12Hz) during 15 NFB training sessions, based on a Latent Growth Curve framework. First, we found the desired enhancement of alpha, while delta was stable throughout the NFB training. Individual differences in tinnitus-specific variables and general-, as well as health-related quality of life predictors were largely unrelated to oscillatory change prior to and across the training. Only the predictors age and sex at baseline were clearly related to slow-wave delta, particularly so for older female individuals who showed higher delta power values from the start. Second, we confirmed a hierarchical cross-frequency association between the two frequency bands; however, in opposing directions to those anticipated in tinnitus. The establishment of individually tailored NFB protocols would boost this therapy's effectiveness in the treatment of tinnitus. In our analysis, we propose a conceptual groundwork toward this goal of developing more targeted treatment.


Substance P enhances cholinergic receptor desensitization in a clonal nerve cell line.
Substance P inhibits carbamylcholine-induced 22Na+ uptake in the clonal cell line PC12. This inhibition is noncompetitive with agonist but competitive with Na+. Octahydrohistrionicotoxin (H8-HTX) also exhibits this same pattern of inhibition. Moreover, both substance P and H8-HTX are very effective in enhancing agonist-induced receptor desensitization. Local anesthetics, such as QX222, also cause inhibition that is competitive with Na+, but they have only marginal effects on desensitization. Because substance P and H8-HTX cannot by themselves cause desensitization, their action is dependent on and synergistic with the action of agonist. Furthermore, substance P and H8-HTX do not appear to compete for the same site as QX222, which is thought to bind to the ion channel. Finally, substance P can stabilize the desensitized state of the receptor even when added subsequent to the actual desensitization and removal of agonist. Thus, substance P does not require open ion channels for binding and may modulate the activity of the receptor-ionophore complex by binding to a distinct regulatory site.


Moving forward together, stronger, and closer: An interpretative phenomenological analysis of marital benefits in infertile couples.
Some couples find in infertility the bonding opportunities that reinforce their relationship. Using an interpretative phenomenological analysis, this study examined marital benefits in three couples seeking fertility treatment. Interviews revealed five types of benefits: being engaged in a shared hardship, feeling closer to one another, feeling reassured in the relationship, developing a satisfying communication and support behaviors, and having faith in the couple's capacity to face adversity. A dyadic analysis also illustrated how marital benefits developed in each couple. Marital benefits nourished marital satisfaction, thus underscoring their importance to help couples cope through fertility treatment.


One-stage conversion of Roux-en-Y gastric bypass to a modified biliopancreatic diversion with duodenal switch using a hybrid sleeve concept.
Insufficient weight loss (percentage of excess weight loss [%EWL]<50%) is observed in approximately 20% of patients after Roux-en-Y gastric bypass (RYGB). Surgical revision can be performed by various procedures including malabsorptive techniques. Conversion to a biliopancreatic diversion with duodenal switch (BPD/DS) remains a complex technique which cannot always be performed as a one-stage procedure. This study evaluates the conversion of RYGB to BPD/DS using a novel gastric reconstruction technique based on a "hybrid sleeve" using the existing gastrojejunal anastomosis of the RYGB. All the procedures were performed at a private hospital. The consecutive patients who were eligible for conversion since 2010 were reviewed; eligibility included %EWL≤50% and normal gastric pouch. The gastrojejunal anastomosis of the RYGB was untouched and the gastric fundus was resected. The gastric continuity was restored by an anastomosis between a short segment of the alimentary limb and the gastric antrum. A standard BPD/DS was then performed without restoration of the jejunal continuity. Fourteen patients were converted to BPD/DS for a mean body mass index (BMI) of 44.3±6.0 kg/m2, a mean %EWL of 33.4%, and a percentage of total weight loss (%TWL) of 15.3±11.7%. The BMI before RYGB was 54.4±13.1 kg/m2, with half of the patients being super-obese. All but 3 conversions were completed as a single stage and laparoscopically in a mean of 177 minutes. The 30-day complication rate was 28.5%. No patient was lost to follow-up over a mean 25.8 months and the BMI of the 12 patients with a follow-up≥3 months is 33.2±7.2 kg/m2. With reference to the initial weight of the patients, the mean %EWL is 73.5% and %TWL is 37.6±16.0%. On average, patients benefited from a 21.1% TWL through the conversion of their RYGB. This procedure allows for an easier conversion of RYGB to BPD/DS and appears to be the most effective procedure for resuming weight loss. Nutritional consequences and weight loss are similar to the primary BPD/DS results. However, the benefits and risks must be carefully assessed according to the definition of weight loss failure.


Cardiovascular risk and hypertension control in Italy. Data from the 2015 World Hypertension Day.
Cardiovascular diseases (CVD) are the first cause of death and disability in western countries. Despite therapeutic advances, their prevalence is constantly increasing. Detailed assessment of modifiable CV risk factors could improve CVD prevention and management. to assess CV risk and hypertension control in a sample of the Italian population, individuals participating to the 2015 "World Hypertension Day" were interviewed in 62sites all over Italy. Blood pressure was measured with a validated auscultatory or oscillometric device and information on demography and prevalence of CVD risk factors was collected by an anonymous questionnaire. An ad-hoc modified version of the Systematic COronary Risk Evaluation (SCORE) system was then applied. 8657 recruited individuals (43%women, aged 56.68±16years) were subdivided into 3 age groups (40-49y, 50-59y, 60-69y) for analysis. CV risk was low in 62.4%, 18.0% and 0%; moderate in 26.0%, 66.0% and 62.5%; high/very high in 11.6%, 16% and 37.4%, respectively. Smoking was mainly responsible for increased CV risk among those aged 40-49y (26%smokers), while hypertension was the main factor in the whole sample and in subjects over 50y (36% and 42% respectively). Overall, BP control was unsatisfactory in 36% of individuals (28%, 48% and 31% of those who declared to be normotensive, hypertensive on treatment or unaware of their BP condition, respectively). In this sample of the Italian population, CV risk was alarmingly high, irrespectively of age, mostly due to presence of modifiable risk factors, including hypertension, which should thus be better addressed, especially in the youngsters.


Reduced Intracellular Drug Accumulation in Drug-Resistant Leukemia Cells is Not Only Solely Due to MDR-Mediated Efflux but also to Decreased Uptake.
Expression of ABC family transporter proteins that promote drug efflux from cancer cells is a widely observed mechanism of multi-drug resistance of cancer cells. Cell adaptation in long-term culture of HL60 leukemic cells in the presence of chemotherapy leads to induction and maintenance of the ABC transporters expression, preventing further accumulation of drugs. However, we found that decreased accumulation of drugs and fluorescent dyes also contributed by a reduced uptake by the resistant cells. Confocal time-lapse microscopy and flow cytometry revealed that fluid-phase endocytosis was diminished in drug-resistant cells compared to drug-sensitive cells. Drug uptake was increased by insulin co-treatment when cells were grown in methylcellulose and monitored under the microscope, but not when cultured in suspension. We propose that multi-drug resistance is not only solely achieved by enhanced efflux capacity but also by supressed intake of the drug, offering an alternative target to overcome drug resistance or potentiate chemotherapy.


In vitro cytocidal effect of novel lytic peptides on Plasmodium falciparum and Trypanosoma cruzi.
Plasmodium falciparum and Trypanosoma cruzi were killed by two novel lytic peptides (SB-37 and Shiva-1) in vitro. Human erythrocytes infected with P. falciparum, and Vero cells infected with T. cruzi, were exposed to these peptides. The result, in both cases, was a significant decrease in the level of parasite infection. Furthermore, the peptides had a marked cytocidal effect on trypomastigote stages of T. cruzi in media, whereas host eukaryotic cells were unaffected by the treatments. In view of the worldwide prevalence of these protozoan diseases and the lack of completely suitable treatments, lytic peptides may provide new and unique chemotherapeutic agents for the treatment of these infections.


[Progressive paralysis caused by radiation-induced cervical malignant peripheral nerve sheath tumor].
HISTORY AND DIAGNOSIS: A 59-year old engineer was admitted to the hospital because of pain in his right collar region and the onset of incomplete paresis of the right arm. Magnetic resonance tomography displayed an advanced tumour arising from the right paravertebral soft tissue. Histological examination revealed a malignant peripheral nerve sheath tumor (MPNST). Thirteen years before admission, the patient had a right-sided tumor-tonsillectomy of a squamous cell carcinoma and local radiation of a cystic squamous cell carcinoma in the ipsilateral cervical soft tissue. In the following course, progressive neurological symptoms occurred including beginning paraplegia, right phrenic paralysis and a severe concomitant pain syndrome. Due to the location and advanced tumor state, surgical treatment was not performed and palliative chemotherapy remained ineffective. Three months later the patient died due to rapidly progressive neurological failure. MPNST represents a rare entity which has been related to postoperative radiation. Unusual neurological symptoms in anatomical regions of former radiation should therefore include neurogenic secondary malignancies in the differential diagnosis for early surgical intervention.


Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate.
Bone resorption in balance with bone formation is vital for the maintenance of the skeleton and is mediated by osteoclasts. Cathepsin K is the predominant protease in osteoclasts that degrades the bulk of the major bone forming organic component, type I collagen. Although the potent collagenase activity of cathepsin K is well known, its mechanism of action remains elusive. Here, we report a cathepsin K-specific complex with chondroitin sulfate, which is essential for the collagenolytic activity of the enzyme. The complex is an oligomer consisting of five cathepsin K and five chondroitin sulfate molecules. Only the complex exhibits potent triple helical collagen-degrading activity, whereas monomeric cathepsin K has no collagenase activity. The primary substrate specificity of cathepsin K is not altered by complex formation, suggesting that the protease-chondroitin sulfate complex primarily facilitates the destabilization and/or the specific binding of the triple helical collagen structure. Inhibition of complex formation leads to the loss of collagenolytic activity but does not impair the proteolytic activity of cathepsin K toward noncollagenous substrates. The physiological relevance of cathepsin K complexes is supported by the findings that (i) the content of chondroitin sulfate present in bone and accessible to cathepsin K activity is sufficient for complex formation and (ii) Y212C, a cathepsin K mutant that causes pycnodysostosis (a bone sclerosing disorder) and that has no collagenase activity but remains potent as a gelatinase, is unable to form complexes. These findings reveal a novel mechanism of bone collagen degradation and suggest that targeting cathepsin K complex formation would be an effective and specific treatment for diseases with excessive bone resorption such as osteoporosis.


Bedside Drainage of Perianal Abscesses: Is It Safe and Effective?
Perianal abscesses require immediate incision and drainage (I&D). However, prompt bedside drainage is controversial as it may compromise exposure and thorough anal examination. To examine outcomes of bedside I&D of perianal abscesses in the emergency department (ED) vs. the operating room (OR). We conducted a retrospective review of all patients presented to the ED with a perianal abscesses between January 2018 and March 2020. Patients with Crohn's disease, horseshoe or recurrent abscesses were excluded. The study comprised 248 patients; 151 (60.89%) underwent I&D in the OR and 97 (39.11%) in the ED. Patients elected to bedside I&D had smaller abscess sizes (P = 0.01), presented with no fever, and had lower rates of inflammatory markers. The interval time from diagnosis to intervention was significantly shorter among the bedside I&D group 2.13 ± 2.34 hours vs. 10.41 ± 8.48 hours (P < 0.001). Of patients who underwent I&D in the OR, 7.3% had synchronous fistulas, whereas none at bedside had (P = 0.007). At median follow-up of 24 months, recurrence rate of abscess and fistula formation in patients treated in the ED were 11.3% and 6.2%, respectively, vs. 19.9% and 15.23% (P = 0.023, 0.006). Fever (OR 5.71, P = 0.005) and abscess size (OR 1.7, P = 0.026) at initial presentation were risk factors for late fistula formation. Bedside I&D significantly shortens waiting time and does not increase the rates of long-term complications in patients with small primary perianal abscesses.


Dental crowding in primary dentition and its relationship to arch and crown dimensions.
The purpose of this study was to compare dental arch size, mesiodistal and buccolingual crown widths, and crown shapes between 2 groups of children, 1 with anterior crowding in both dental arches and another with anterior spacing in both dental arches. Sixty-one sets (27 crowded and 34 spaced arches) of dental casts of normal occlusions were examined. For both lower and upper arches, crowded arches had statistically significantly smaller arch widths than did the spaced arches. The buccolingual width of the upper second primary molar of the crowded arches was statistically significantly larger than that of the spaced arches. However, there were little significant differences between crowded and spaced arches in arch length, mesiodistal crown width, and crown shape. It can be concluded that the factor that determines whether a primary dental arch is crowded is the absolute width of the arch.


The serrated neoplasia pathway of colorectal tumors: Identification of MUC5AC hypomethylation as an early marker of polyps with malignant potential.
The serrated neoplasia pathway accounts for 20-30% of colorectal cancers (CRC), which are characterized by extensive methylation (CpG island methylation phenotype, CIMP), frequent BRAF mutation and high microsatellite instability (MSI). We recently identified MUC5AC mucin gene hypomethylation as a specific marker of MSI CRC. The early identification of preneoplastic lesions among serrated polyps is currently challenging. Here, we performed a detailed pathological and molecular analysis of a large series of colorectal serrated polyps and evaluated the usefulness of mucin genes MUC2 and MUC5AC to differentiate serrated polyps and to identify lesions with malignant potential. A series of 330 colorectal polyps including 218 serrated polyps [42 goblet cell-rich hyperplastic polyps (GCHP), 68 microvesicular hyperplastic polyps (MVHP), 100 sessile serrated adenoma (SSA) and eight traditional serrated adenoma (TSA)] and 112 conventional adenomas was analyzed for BRAF/KRAS mutations, MSI, CIMP, MLH1 and MGMT methylation, and MUC2 and MUC5AC expression and methylation. We show that MUC5AC hypomethylation is an early event in the serrated neoplasia pathway, and specifically detects MVHP and SSA, arguing for a filiation between MVHP, SSA and CIMP-H/MSI CRC, whereas GCHP and TSA arise from a distinct pathway. Moreover, MUC5AC hypomethylation specifically identified serrated lesions with BRAF mutation, CIMP-H or MSI, suggesting that it may be useful to identify serrated neoplasia pathway-related precursor lesions. Our data suggest that MVHP should be recognized among HP and require particular attention.


Multiple arterial thromboemboli after COVID-19.
We present the case of a man in his fifties who presented with bilateral lower extremity ischaemia three weeks after COVID-19 infection. The patient had known. On arrival at the emergency department his left lower extremity had reduced sensation but preserved motor function. His right lower extremity had spontaneously improved on arrival. A CT angiogram showed thromboembolism in both popliteal arteries with extension down the tibiofibular trunk. An acute bilateral mechanical thromboembolectomy of the popliteal artery and tibiofibular trunk was performed. Postoperatively he was hypoxic and a CT thorax angiogram showed bilateral pulmonary embolism, a floating aortic thrombus and ground glass opacification changes typical after COVID-19 viral pneumonia. The patient was systemically anticoagulated. Echocardiography revealed an apical thrombus. There were no signs of cardiac arrhythmia. Haematological diagnostic tests were all negative. It is presumed that a previous COVID-19 infection contributed to the systemic thrombotic events. The patient was discharged after 9 days in good health and able to walk a normal distance.


Ketosis and brain handling of glutamate, glutamine, and GABA.
We hypothesize that one mechanism of the anti-epileptic effect of the ketogenic diet is to alter brain handling of glutamate. According to this formulation, in ketotic brain astrocyte metabolism is more active, resulting in enhanced conversion of glutamate to glutamine. This allows for: (a) more efficient removal of glutamate, the most important excitatory neurotransmitter; and (b) more efficient conversion of glutamine to GABA, the major inhibitory neurotransmitter.


Cardiac contractility modulation in patients with heart failure refractory to drug treatment.
Cardiac contractility modulation in patients with heart failure refractory to drug treatment aims to strengthen myocardial activity through transmission of nonexcitatory impulses to the heart. The present study reviewed a total of 251 patients from four studies; the results, however, showed a low level of evidence. Crossover analysis showed a strong placebo effect for patients with implants that were switched on after three months. The technology is still in the development stage and further studies are needed.


[Antibiotic sensitivity of Haemophilus influenzae isolated from patients with inflammatory lung diseases].
In 1980-1986 the sensitivity of 2,045 H. influenzae strains isolated from the bronchial contents of patients with inflammatory lung diseases were studied. This study revealed that 60-80% of H. influenzae cultures circulating in Leningrad were sensitive to tetracyclin, chloramphenicol and erythromycin. During the period of observation the tendency towards the decrease of the number of highly sensitive H. influenzae cultures and the increase of the number of strains resistant to all antibiotic preparations was followed. Most of H. influenzae strains isolated in Leningrad were sensitive to penicillin, oleandomycin and ampicillin. In 1983 the appearance of H. influenzae strains, multiresistant to antibiotics, was noted. In 1986 these strains constituted 4.5% of all isolated cultures.


[Clinical value of combined detection of serum tumor markers in lung cancer diagnosis].
To investigate the clinical significance of a combination of several serum tumor markers in the diagnosis of lung cancer. Serum CEA, CA125, CA199, CYFRA21-1 and NSE were measured with RIA, chromatometrychemoluminescence, ELISA and biochemoluminescence methods respectively in 340 patients with lung cancers at different TNM stages, 120 patients with benign lung diseases, and 45 healthy people. The sensitivities, specificities and accuracies of different combination of those markers for the diagnosis of lung cancers were compared. CYFRA21-1 had the highest sensitivity and accuracy (60.0% and 70.3%) and CA199 had the highest specificity (99.4%) for detecting lung cancers. CYFRA21-1 had the highest sensitivity (79.6%) for detecting squamous carcinoma. CEA had the highest sensitivity of (75.7%) for detecting adenocarcinoma. NSE had the highest sensitivity (76.2%) for detecting small cell lung cancers (SCLC). The combination of several serum tumor markers had higher sensitivities than the single marker for the diagnosis of lung cancers. With two markers, the combination of CYFRA21-1 and NSE had the highest sensitivity and accuracy (82.9% and 83.4%), while the combination of CA125 and CA199 had the highest specificity (94.5%). With three markers, the combination of CEA, NSE and CYFRA21-1 had the highest sensitivity and accuracy (89.1% and 85.1%), while the combination of CEA, CA125 and CA199 had the highest specificity (86.7%). The combination of CEA, CA125, CA199, CYFRA21-1 and NSE produced the best value, with a sensitivity of 93.8%, a specificity of 71.5%, and an accuracy of 86.5%. Serum CEA, CA125, CA199, CYFRA21-1 and NSE are helpful markers for the diagnosis of lung cancer. The combination of the markers can improve the sensitivity and accuracy of the diagnosis.


Stimulation of antibody production to the hapten 2,4-dinitrobenzene by affinity labeled murine lymphoid cells. I. Ability of affinity labeled murine lymphoid cells to activate the in vivo immune response.
The ability of meta-nitrobenzenediazonium fluoborate (m-NBDF)-labeled thymus and spleen (S) cells to transfer immunity to 2,4-dinitrophenyl (DNP) into irradiated syngeneic recipients was investigated. There was a significant increase in the number of anti-DNP plaque-forming cells (PFC) when m-NBDF-labeled thymus cells and normal spleen cells, or normal thymus cells and m-NBDF-labeled spleen cells were transferred, but not when both thymus- and S-cell populations were labeled and injected together into irradiated recipients. The ability of these cell populations to cooperate and enhance the in vivo immune response to DNP is discussed. The T cells seem to be actively involved in the development of this response; they participate beyond the mere role of carrying and presenting antigen to the B cells. It is suggested that cell to cell contact between T and B cells may be an important factor in the elicitation of an immune response. In addition, the cellular interaction is affected by irradiating the thymus cell preparation and the initiating interaction required for antibody synthesis probably occurs within 48 h after injecting the cell populations into the syngeneic irradiated recipients.


A Case Study of Sexual Abuse of a Minor.
Child Sexual Abuse (CSA) is a crime against children. It is largely underreported and commonly goes unpunished in our society as it is commonly perpetrated by close ones including family relations. Victims are left with the adverse sequelae associated with it sometimes for life. This report highlights the management of a case of PID in a child as a result of incest perpetrated by her father. It also brings to fore the problems and challenges of child sexual abuse in Nigeria. The patient was a 17 year old 100 level university student who lost her mother at the age of 14 and was living with her father alone. The father sexually abused her repeatedly for two years. She became pregnant and had the pregnancy illegally terminated at seven weeks gestation via dilatation and curettage. The procedure was complicated by Pelvic Inflammatory Disease (PID) which necessitated her presentation at the clinic where she was treated. The case brings to the fore the problem of child sexual abuse in Nigeria and its attendant sequelae. The health care providers should have a high index of suspicion for CSA when attending to minors and address sexual problems including CSA where present.


Usability Testing of a Web-Based Decision Aid for Breast Cancer Risk Assessment Among Multi-Ethnic Women.
Chemoprevention with antiestrogens could decrease the incidence of invasive breast cancer but uptake has been low among high-risk women in the United States. We have designed a web-based patient-facing decision aid, called RealRisks, to inform high-risk women about the risks and benefits of chemoprevention and facilitate shared decision-making with their primary care provider. We conducted two rounds of usability testing to determine how subjects engaged with and understood the information in RealRisks. A total of 7 English-speaking and 4 Spanish-speaking subjects completed testing. Using surveys, think-aloud protocols, and subject recordings, we identified several themes relating to the usability of RealRisks, specifically in the content, ease of use, and navigability of the application. By conducting studies in two languages with a diverse multi-ethnic population, we were able to implement interface changes to make RealRisks accessible to users with varying health literacy and acculturation.


Trypanin, a component of the flagellar Dynein regulatory complex, is essential in bloodstream form African trypanosomes.
The Trypanosoma brucei flagellum is a multifunctional organelle with critical roles in motility, cellular morphogenesis, and cell division. Although motility is thought to be important throughout the trypanosome lifecycle, most studies of flagellum structure and function have been restricted to the procyclic lifecycle stage, and our knowledge of the bloodstream form flagellum is limited. We have previously shown that trypanin functions as part of a flagellar dynein regulatory system that transmits regulatory signals from the central pair apparatus and radial spokes to axonemal dyneins. Here we investigate the requirement for this dynein regulatory system in bloodstream form trypanosomes. We demonstrate that trypanin is localized to the flagellum of bloodstream form trypanosomes, in a pattern identical to that seen in procyclic cells. Surprisingly, trypanin RNA interference is lethal in the bloodstream form. These knockdown mutants fail to initiate cytokinesis, but undergo multiple rounds of organelle replication, accumulating multiple flagella, nuclei, kinetoplasts, mitochondria, and flagellum attachment zone structures. These findings suggest that normal flagellar beat is essential in bloodstream form trypanosomes and underscore the emerging concept that there is a dichotomy between trypanosome lifecycle stages with respect to factors that contribute to cell division and cell morphogenesis. This is the first time that a defined dynein regulatory complex has been shown to be essential in any organism and implicates the dynein regulatory complex and other enzymatic regulators of flagellar motility as candidate drug targets for the treatment of African sleeping sickness.