The impact of the first 24 h of loop diuretic on kidney function in acute decompensated heart failure.
Because of the uncertainty in the appropriate initial loop diuretic dose in acute decompensated heart failure (ADHF), the risk of acute kidney injury (AKI) is believed to be increased with the high dose of initial intravenous (IV) loop diuretic. The purpose of this study is to examine the impact of the first 24-h IV diuretic on kidney function in ADHF. A retrospective cohort study included patients with ADHF. These patients were divided into two groups: the first group received an initial total IV diuretic dose that was equal to or 2.5 times less than the home dose in the first 24 h (low dose), while the second group received 2.5 times more than the home dose in the first 24 h (high dose). The primary outcome was the incidence of developing AKI within 48 h of first IV diuretic. The secondary outcomes were total hospital length of stay and all-cause 30-day readmission rates. A total of 252 patients were available for analysis; 172 patients received a low dose in the first 24 h, while 80 patients received a high dose. The incidence of AKI was higher in the high-dose group compared to that in the low-dose group (25% vs. 9.9%, P = 0.002). There was no significant difference between the two groups in terms of hospital stay and all-cause 30-day readmission. In patients with ADHF, the initial high dose of IV loop diuretics is associated with an increased risk of developing AKI.


Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity.
Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures. Sixteen molecules were purchased and subject to in vitro enzyme (FP-2 and FP-3) inhibition assays. Two compounds showed in vitro inhibition of FP-2 and FP-3 at low µM concentration. The selectivity of the inhibitors can be explained based on the predicted interactions of the molecule in the active site. Further, the inhibitors were evaluated in a functional assay and were found to induce morphological changes in line with their mode of action arresting Plasmodium development. Compound 15 was most potent inhibitor identified in this study.


Carbon dots derived from flax straw for highly sensitive and selective detections of cobalt, chromium, and ascorbic acid.
Fluorescent detections of cobalt, chromium, and ascorbic acid by carbon dots are of importance for human health and environment. Green synthesis of fluorescent carbon dots from biomass is essential for their sustainable applications. Herein, carbon dots were successfully prepared by a simple hydrothermal method using flax straw as carbon source. The obtained carbon dots possess a much higher quantum yield (20.7%) and excitation-dependent photoluminescence behavior. The "on-off" fluorescence principle, quenching of the fluorescence intensity of the carbon dots in the presence of Co2+ or Cr6+ based on static quenching effect and inner filter effect, is extended to "on-off-on" principle for detection of ascorbic acid based on the reduction of Cr6+ to Cr3+ by ascorbic acid. The linear ranges for detections of Co2+, Cr6+, and ascorbic acid are 0-500, 0.5-80, and 0-200 μM, and the limits of the corresponding detections are 0.38, 0.19, and 0.35 μM, respectively. Compared with most reported fluorescence detections, our linear ranges are significantly wider and our detection limits are much lower for the detections of Co2+, Cr6+, and ascorbic acid. This sensing platform is highly sensitive and selective to monitor Co2+ and Cr6+ in real water and ascorbic acid in vitamin C tablets with remarkable practicality.


Poor results after nerve grafting in the upper extremity: Quo vadis?
The clinical success of peripheral nerve grafting in the upper extremity was evaluated retrospectively in 41 patients. This study comprises a 10-year follow-up in a single institution. Donor and acceptor site morbidity as well as functional nerve recovery were evaluated. Thirty-one men and 10 women were included. Autologous nerve grafts were used for reconstruction of digital nerves in 17 patients, ulnar nerves in 12 patients, median nerves in 10 patients, radial nerve in 1 patient, and both the radial and median nerve in 1 patient. The length of nerve grafts ranged from 1-12.5 cm (mean, 4.8 cm). The follow-up period ranged from 18 months to 10 years. Acceptor site-related problems were noted in 51%% (n = 21) of patients. Donor-site morbidity was seen in 4 patients (10%%). The return of function was scored as "good" in 3 (7%%), "fair" in 11 (27%%), and "bad" in 27 (66%%) patients. The outcome of autologous nerve grafts in this small group of patients treated by several surgeons was unfavorable in terms of function. Recent experimental and clinical studies with biodegradable nerve guides for the repair of peripheral nerve gaps showed superior results in comparison to classic nerve grafts.


High-temperature etching of SiC in SF6/O2 inductively coupled plasma.
In this work, we demonstrate an effective way of deep (30 µm depth), highly oriented (90° sidewall angle) structures formation with sub-nanometer surface roughness (Rms = 0.7 nm) in silicon carbide (SiC). These structures were obtained by dry etching in SF6/O2 inductively coupled plasma (ICP) at increased substrate holder temperatures. It was shown that change in the temperature of the substrate holder in the range from 100 to 300 °C leads to a sharp decrease in the root mean square roughness from 153 to 0.7 nm. Along with this, it has been established that the etching rate of SiC also depends on the temperature of the substrate holder and reaches its maximum (1.28 µm/min) at temperatures close to 150 °C. Further temperature increase to 300 °C does not lead to the etching rate rising. The comparison of the results of the thermally stimulated process and the etching with a water-cooled substrate holder (15 °C) is carried out. Plasma optical emission spectroscopy was carried out at different temperatures of the substrate holder.


Health status and disease burden of unaccompanied asylum-seeking adolescents in Bielefeld, Germany: cross-sectional pilot study.
This exploratory pilot study aimed to investigate the physical and mental disease burden of unaccompanied asylum-seeking adolescents arriving in Bielefeld, a medium-size city in Germany. A cross-sectional survey with purposive sampling of 102 unaccompanied asylum-seeking adolescents aged 12-18 years was performed. Information on general health status, selected infectious and non-communicable diseases, iron deficiency anaemia and mental illness was collected during routine check-up medical examinations upon arrival in Bielefeld, Germany. The data were analysed using descriptive statistics. The analysis revealed a complex disease burden with a high prevalence of infections (58.8%), mental illness (13.7%) and iron deficiency anaemia (17.6%) and a very low prevalence of non-communicable diseases (<2.0%). One in five of the refugees were infected with parasites. Whilst sub-Saharan Africans showed the highest prevalence of infections (86.7%), including highest prevalences of parasites (46.7%), West Asians had the highest prevalence of mental disorders (20.0%). Overall, the disease burden in females was higher. A thorough medical and psychological screening after arrival is highly recommended to reduce the individual disease burden and the risk of infection for others. This promotes good physical and mental health, which is needed for successful integration into the receiving society. Barriers to health service access for unaccompanied asylum-seeking adolescents need to be lowered to allow need-specific health care and prevention.


Urinary excretion of aromatic acids in hyperphenylalaninemic states: response to a protein challenge.
A protein challenge (3g/kg) was given to 15 hyperphenylalaninemic patients for 4 days and urinary excretion of aromatic phenylalanine metabolites (e.g. phenylpyruvic acid; mandelic acid; ortho-hydroxy-phenylacetic acid) was studied by quantitative gas chromatographic analysis. Two groups of patients, different in their serum phenylalanine pattern, could be distinguished from the pattern of urinary aromatic acid excretion. In the first group, the aromatic acid excretion declined towards the end of the challenge whereas aromatic acid excretion increased throughout the challenge in the second group. The differences could be ascertained by statistical analysis.


The properties of goal-directed eye movements evoked by microstimulation of the cerebellar vermis in the cat.
The properties of eye movements evoked by microstimulation of the cerebellar vermis, lobules V VII, were investigated in encéphale isolé cats. The evoked eye movements tended to reach the same final goal in the orbit irrespective of initial eye position. The goal position depended on stimulus intensity. In contrast with the monkey, the goal of the eye movement lay within the oculomotor range. The goal position of the eye movements evoked by simultaneous stimuli delivered to two sites corresponded with the point which was obtained by the vectorial addition of the two eye movements evoked by the stimulation of each site. These findings suggest that the cat vermal lobules V VII play an important role in the control of horizontal and vertical eye position in the orbit.


Clients' Emotional Experiences Tied to Therapist-Led (but Not Client-Led) Physiological Synchrony during Imagery Rescripting.
Imagery rescripting (IR), an effective intervention technique, may achieve its benefits through various change mechanisms. Previous work has indicated that client-therapist physiological synchrony during IR may serve as one such mechanism. The present work explores the possibility that therapist-led vs. client-led synchrony may be differentially tied to clients' emotional experiences in therapy. The analyses were conducted with data taken from an open trial of a brief protocol for treating test anxiety (86 IR sessions from 50 client-therapist dyads). Physiological synchrony in electrodermal activity was indexed using two cross-correlation functions per session: once for client leading and again for therapist leading (in both cases, with lags up to 10 s). The clients' and therapists' in-session emotions were assessed with the Profile of Mood States. Actor-partner interdependence models showed that certain client (but not therapist) in-session emotions, namely higher contentment and lower anxiety and depression, were tied to therapist-led (but not client-led) physiological synchrony. The results suggest that therapist-led synchrony (i.e., clients' arousal tracking therapists' earlier arousal) is tied to more positive and less negative emotional experiences for clients.


Chromatin: Liquid or Solid?
In this issue of Cell, Strickfaden et al. reveal that condensed chromatin shows a solid-like behavior at mesoscales both in vitro and in living cells. Using fluorescent microscopy, fluorescent recovery after photobleaching, and transmission electron microscopy, this work investigates chromatin condensates, providing new insights into the physical organization of the genome.


Creation of a neonatal end-of-life palliative care protocol.
To create a protocol delineating the needs of patients, families, and staff necessary to provide a pain-free, dignified, family-, and staff-supported death for newborns who cannot benefit from intensive, life-extending, technological support. Using Internet e-mail, a Delphi study with sequential questionnaires soliciting participant response, investigator analysis, and follow-up responses from participants was conducted to build a consensus document. Institutional review was granted and respondents gave consent. Recruitment was conducted at medical, ethics, nursing, and multidisciplinary organization meetings. Synthesis of 16 palliative care/end-of-life protocols developed by regional, institutional, and parent organizations was included. Participants from 93 locations in the US and 4 abroad gave feedback to 13 questions derived from clinical experience and the literature. The data underwent four rounds of analysis with 95% retention of the 101 participants over an 18-month period. Specific consensus-based recommendations are presented with a description of palliative care; categories of candidates; planning and education needed to begin palliative care services; relationships between community and tertiary centers; components of optimally supported neonatal death; family care, including cultural, spiritual, and practical needs; ventilator withdrawal, including pain and symptom management; recommendations when death does not occur after cessation of life-extending interventions; family follow-up care; and necessary ongoing staff support.


Philadelphia chromosome-negative myeloproliferative neoplasms: clinical aspects and treatment options.
Clinical studies of Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) have progressed greatly with the discovery of mutations in three driver genes: JAK2, MPL, and calreticulin. Other genes that may play important roles in pathogenesis and progression of MPN have also been identified. Several prognostic prediction systems based on various risk factors including these genetic factors have been developed and utilized in clinical practice. All mutations of the three driver genes result in JAK2 activation, and JAK inhibitors have indeed improved clinical outcomes for primary myelofibrosis and polycythemia vera. However, they have minimal ability to inhibit clonogenic growth, far below that of ABL tyrosine kinase inhibitors in chronic myeloid leukemia. Therefore, hematopoietic stem cell transplantation (HSCT), which still has a high mortality rate, remains the only curative treatment for MPN. Efforts are being made to advance the treatment of MPN by refining HSCT methods, combining JAK inhibitors with other molecularly targeted agents, and reviewing the safety and clonogenic inhibitory effects of interferon-alfa.


Combining Single Molecule Super-Resolution Imaging Techniques to Unravel the Nanoscale Organization of the Presynapse.
The fusion of synaptic vesicles with the plasma membrane underpins neurotransmission. A number of presynaptic proteins play a critical role in overcoming the energy barrier inherent to the fusion of the negatively charged vesicular and plasma membranes. Emerging concepts suggest that this process is hierarchical and dependent on rapid and transient reorganization of proteins in and out of small nanoclusters located in the active zones of nerve terminals. Examining the nanoscale organization of presynaptic molecules requires super-resolution microscopy to overcome the limits of conventional light microscopy. In this chapter, we describe three super-resolution techniques that allow for the examination of the nanoscale organization of proteins within live hippocampal nerve terminals. We used (1) single-particle tracking photoactivated localization microscopy (sptPALM) to resolve the mobility and clustering of syntaxin1A (STX1A), (2) universal Point Accumulation Imaging in Nanoscale Topography (uPAINT) to study the mobility of a pool of vesicular-associated membrane protein 2 (VAMP2) transiting on the plasma membrane, and (3) subdiffractional Tracking of Internalized Molecules (sdTIM) to track VAMP2-positive recycling synaptic vesicles in conjunction with Cholera Toxin subunit B (CTB), which has recently been shown to be trafficked retrogradely from the presynapse to the cell body via signaling endosomes.


Sex-related differences in symptomatic patients with hypertrophic obstructive cardiomyopathy - Time for a new definition?
Sex-related differences in diagnosis and treatment of hypertrophic obstructive cardiomyopathy (HOCM) are still unclear. Therefore, we analyzed baseline characteristics of symptomatic patients with indication for alcohol septal ablation (PTSMA) with respect to gender. Between 05/2000 and 06/2017 indication for PTSMA was seen in 1014 patients (420 (41.4%) women and 594 (58.6%) men). Women were older (61.4 ± 15.0 vs. 51.8 ± 13.6 years; p < 0.00001) and suffered more often from dyspnea NYHA III/IV (81.4% vs. 67.7%; p < 0.001), whereas angina pectoris and syncopes were comparable. Echocardiographic gradients were comparable in women (66.4 ± 39.1 mmHg at rest and 106.5 ± 46.6 mmHg at Valsalva) and men (62.7 ± 38.8 mmHg at rest and 103.7 ± 42.7 mmHg at Valsalva). Women had smaller absolute diameter of the left atrium (LA) (44.4 ± 6.9 vs. 47.2 ± 6.5 mm; p < 0.0001), septal thickness (IVS) (20.5 ± 4.1 vs. 21.4 ± 4.5 mm; p < 0.01), and left ventricular posterior wall thickness (LVPW) (12.7 ± 2.8 vs. 13.6 ± 2.9 mm; p < 0.0001). But, indexed for BSA the relationship reversed in LA (25.2 ± 4.3 mm/m2 in women vs. 23.1 ± 3.4 mm/m2), IVS (11.7 ± 2.7 mm/m2 in women vs. 10.6 ± 2.5 mm/m2) and LVPW (7.3 ± 1.7 mm/m2 in women vs. 6.7 ± 1.6 mm/m2), p < 0.00001 each. Women with HOCM and indication for PTSMA are older and more symptomatic with advanced disease progression. Reconsideration of disease definition and awareness maybe necessary in order to avoid delayed diagnosis and treatment of HOCM in women.


Assessment of the antifungal activity of Lactobacillus and Pediococcus spp. for use as bioprotective cultures in dairy products.
Fungi are commonly involved in dairy product spoilage and the use of bioprotective cultures can be a complementary approach to reduce food waste and economic losses. In this study, the antifungal activity of 89 Lactobacillus and 23 Pediococcus spp. isolates against three spoilage species, e.g., Yarrowia lipolytica, Rhodotorula mucilaginosa and Penicillium brevicompactum, was first evaluated in milk agar. None of the tested pediococci showed antifungal activity while 3, 23 and 43 lactobacilli isolates showed strong antifungal activity or total inhibition against Y. lipolytica, R. mucilaginosa and P. brevicompactum, respectively. Then, the three most promising strains, Lactobacillus paracasei SYR90, Lactobacillus plantarum OVI9 and Lactobacillus rhamnosus BIOIII28 at initial concentrations of 105 and 107 CFU/ml were tested as bioprotective cultures against the same fungal targets in a yogurt model during a 5-week storage period at 10 °C. While limited effects were observed at 105 CFU/ml inoculum level, L. paracasei SYR90 and L. rhamnosus BIOIII28 at 107 CFU/ml respectively retarded the growth of R. mucilaginosa and P. brevicompactum as compared to a control without selected cultures. In contrast, growth of Y. lipolytica was only slightly affected. In conclusion, these selected strains may be good candidates for bioprotection of fermented dairy products.


Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance.
Outcome data from a prospective study of active surveillance of localised prostate cancer were analysed to identify factors, present at the time of diagnosis, that predict subsequent radical treatment. Eligible patients had clinical stage T1-T2a, N0-Nx, M0-Mx adenocarcinoma of the prostate with serum PSA<15 ng/ml, Gleason score <or= 7, primary Gleason grade <or= 3, and % positive biopsy cores (pbc) <or= 50%. Monitoring included serial PSA measurement and repeat prostate biopsies. Radical treatment was initiated in the event of biochemical progression (PSA velocity > 1 ng/ml/yr) or histological progression (primary Gleason grade >or= 4, or %pbc > 50%). Multivariate Cox regression analysis of baseline variables was performed with respect to time to radical treatment. The 326 men recruited from 2002 to 2006 have been followed for a median of 22 mo. Median age was 67 yr, and median initial PSA (iPSA) 6.4 ng/ml. Sixty-five patients (20%) had deferred radical treatment, 16 (5%) changed to watchful waiting because of increasing comorbidity, 7 (2%) died of other causes, and 238 (73%) remain on surveillance. On multivariate Cox regression analysis, the free/total PSA ratio (p<0.001) and clinical T stage (p=0.006) were independent determinants of time to radical treatment. In addition to established prognostic factors, the free/total PSA ratio may predict time to radical treatment in patients with untreated, localised prostate cancer managed by active surveillance. This possibility warrants further study.


Successful treatment of osteonecrosis-induced fractured mandible with teriparatide therapy: A case report.
The management of medication-related osteonecrosis of the jaw (MRONJ) is controversial. To date, there is no established treatment for cases of advanced stage 3 MRONJ osteoporosis in elderly patients. An 87-year-old osteoporotic woman with osteonecrosis-induced left mandible fracture related to minodronate therapy was referred to us for treatment. She had a vertebral compression fracture concurrently and had started subcutaneous injection of teriparatide. After 18 months of treatment with teriparatide the pathological mandible fracture was healed and functional recovery of the occlusion was obtained by complete dentures. Teriparatide may have a powerful anabolic effect on bone, and promote bone regeneration against pathologic mandible fracture induced by MRONJ. Based upon these findings, teriparatide might be beneficial for advanced stage 3 MRONJ osteoporosis in elderly patients.


Impact of the Frozen Elephant Trunk Technique on Total Aortic Arch Replacement.
The frozen elephant trunk (FET) technique can facilitate the distal anastomosis of total arch replacement (TAR); therefore, the technique is increasingly being used in TAR cases. However, identifying suitable patients remains controversial. This study analyzes the outcome of TAR using FET and clarifies the indications for using FET. Patients who underwent TAR between January 2008 and December 2018 were enrolled and divided into 2 groups: that is, patients treated with conventional TAR (cTAR group, n = 39) and those treated with TAR using FET (TAR-FET group, n = 76). Early and late outcomes were compared. The mean operation time was significantly shorter in the TAR-FET group (447.0 ± 82.1 min) than in the cTAR group (509.4 ± 123.9 min) (P < 0.01). Likewise, circulatory arrest time was significantly shorter in the TAR-FET group (29.0 ± 7.8 min) than in the cTAR group (64.2 ± 20.2 min) (P < 0.001). Postoperative renal function tended to be preserved in the TAR-FET group. Recurrent nerve palsy was less frequent in the TAR-FET group (9.2%) compared with the cTAR group (25.6%) (P < 0.05). Patients with chronic aortic dissection tended to undergo reintervention more frequently following TAR using the FET technique. The FET technique contributed to save operation and circulatory arrest times during TAR and seemed less invasive in terms of renal function and less-frequent recurrent nerve palsy. Considering posttreatment reintervention, however, care should be taken in its application to chronic aortic dissection.


Are NSAIDs Safe? Assessing the Risk-Benefit Profile of Nonsteroidal Anti-inflammatory Drug Use in Postoperative Pain Management.
In this article, we review controversies in assessing the risk of serious adverse effects caused by administration of nonsteroidal anti-inflammatory drugs (NSAIDs). Our focus is upon NSAIDs used in short courses for the management of acute postoperative pain. In our review of the literature, we found that the risks of short-term NSAID use may be overemphasized. Specifically, that the likelihood of renal dysfunction, bleeding, nonunion of bone, gastric complications, and finally, cardiac dysfunction do not appear to be significantly increased when NSAIDs are used appropriately after surgery. The importance of this finding is that in light of the opioid epidemic, it is crucial to be aware of alternative analgesic options that are safe for postoperative pain control.


Correction to "Immunohistochemical localization of d-β-aspartic acid in congenital and acquired middle ear cholesteatoma".
[This corrects the article DOI: 10.1002/lio2.856.].


A retrospective review of the real-world experience of the Pegfilgrastim biosimilar (Lapelga®) to the reference biologic (Neulasta®).
Cancer patients receiving myelosuppressive chemotherapy are vulnerable to febrile neutropenia (FN) which contributes to poor treatment outcomes. The use of granulocyte colony-stimulating factors is administered to prevent chemotherapy-induced neutropenia. The introduction of biosimilars has allowed for greater cost-savings while maintaining safety and efficacy. This retrospective study assessed the incidence of FN and related treatment outcomes and the cost minimization of a pegfilgrastim biosimilar and its reference. A retrospective chart review of breast cancer patients receiving (neo) adjuvant chemotherapy from February 2017 to May 2020 was conducted. The endpoints included the incidence of FN, the occurrence of dose reduction (DR), dose delay (DD) and pain. A cost minimization analysis was performed from a third-party payer perspective. One hundred Neulasta® and 74 Lapelga® patients were included in the first-cycle analysis. The rate of FN in cycle 1 for Neulasta® and Lapelga® was 2/100 and 4/74, respectively; risk difference (RD) = 3.4%; 95% CI: -2.4 to 9.2%. Eighty-three Neulasta® and 59 Lapelga® patients were included in the all-cycle analyses, where DR was reported in 76 (15%) Neulasta® cycles vs 33 (10%) Lapelga® cycles (RD = -3.6, 95% CI: -10.2 to 2.9). DD was reported in 20 (4%) Neulasta® cycles vs. 11 (3.5%) Lapelga® cycles (RD = -0.3; 95% CI: -2.7 to 2.0). Adverse events were similar between groups. Cost minimization using a cohort of 20,000 patients translated into an incremental savings of $21,606,800 CAD for each cycle. The biosimilar pegfilgrastim was non-inferior to the reference biologic based on FN incidence in addition to related outcomes including DR and DD.


Axon and Schwann cell partnership during nerve regrowth.
Regeneration of peripheral nerve involves an essential contribution by Schwann cells (SCs) in collaboration with regrowing axons. We examined such collaboration between new axons and Schwann cells destined to reform peripheral nerve trucks in a regeneration chamber bridging transected rat sciatic nerves. There was a highly intimate "dance" between axons that followed outgrowing and proliferating SCs. Axons without SCs only grew short distances and almost all axon processes had associated SC processes. When regeneration chambers were infused through an external access port with local mitomycin, a mitosis inhibitor, SC proliferation, migration and subsequent axon regrowth were dramatically reduced. Adding laminin to mitomycin did not reverse this regenerative lag and indicated that SCs provide more than laminin synthesis alone. Laminin infused alone supplemented endogenous laminin and facilitated first SC then axon regrowth. "Wrong way" misdirected axons were associated with misdirected SC processes and were more numerous in bridges exposed to mitomycin, but were fewer in laminin supplemented bridges. Later, by 21 days, there was myelinated axon repopulation of regenerative bridges but those exposed to mitomycin alone at early time points had substantial impairments in axon investment. Reforming peripheral nerve trucks involves a very close and intimate relationship between axons and SCs that must proliferate and migrate, facilitated by laminin.


Protective Effects of ShcA Protein Silencing for Photothrombotic Cerebral Infarction.
Reactive oxygen species (ROS) exacerbate stroke-induced cell damage. We found that ShcA, a protein that regulates ROS, is highly expressed in a Rose Bengal photothrombosis model. We investigated whether ShcA is essential for mitophagy in ROS-induced cellular damage and determined whether ROS exacerbate mitochondrial dysfunction via ShcA protein expression. Ischemic stroke was generated by Rose Bengal photothrombosis in mice. To silence ShcA protein expression in the mouse brain, ShcA-targeting siRNA-encapsulated nanoparticles were intrathecally injected into the cisterna magna. Upon staining with antibodies against ShcA counterpart caspase-3 or NeuN, we found that the ShcA protein expression was increased in apoptotic neurons. In addition, mitochondrial dysfunction and excessive mitophagy were evident in photothrombotic stroke tissue. Infarct volumes were significantly reduced, and neurological deficits were diminished in the ShcA siRNA nanoparticle-treated group, compared with the negative control siRNA nanoparticle-treated group. We confirmed that the reduction of ShcA expression by nanoparticle treatment rescued the expression of genes, associated with mitochondrial dynamics and mitophagy mediation in a stroke model. This study suggests that the regulation of ShcA protein expression can be a therapeutic target for reducing brain damage with mitochondrial dysfunction caused by thrombotic infarction.


Opioid receptor-mediated inhibition of 3H-dopamine and 14C-acetylcholine release from rat nucleus accumbens slices. A study on the possible involvement of K+ channels and adenylate cyclase.
The release of 14C-ACh from rat nucleus accumbens slices, induced by 15 mM [K+], was inhibited by the mu- and delta-opioid agonists DAMGO and DPDPE, respectively, whereas only the kappa agonist U50,488 reduced the release of 3H-DA. The opioid receptors involved appear to be localized on nerve terminals, since blockade of action potential propagation by 1 microM TTX did not diminish the inhibitory effects of DAMGO, DPDPE or U50,488. Enhancement of the potassium concentration in the superfusion medium to 56 mM with simultaneous reduction of the Ca2+ concentration from 1.2 mM to 0.12 mM induced a release similar to that caused by 15 mM K+ and 1.2 mM Ca+. Under this conditions, the inhibitory effects of both DAMGO and DPDPE on stimulated 14C-ACh release were reduced, whereas the inhibition of evoked 3H-DA release caused by U50,488 was not affected. Activation of mu- as well as delta-opioid receptors by DAMGO and DPDPE, respectively, inhibited forskolin-stimulated adenylate cyclase activity. However, increasing the intracellular cAMP levels with 0.3 mM 8-bromo-cAMP affected neither the depolarization-induced release of 14C-ACh or 3H-DA from accumbens slices nor the inhibitory effects of opioid receptor activation thereon. The results indicate that the mechanism by which functional mu and delta receptors presynaptically inhibit the depolarization-induced 14C-ACh release from nucleus accumbens slices is likely to involve an increase of potassium channel conductance. In contrast, activation of kappa-opioid receptors, which inhibits depolarization-evoked 3H-DA release, apparently does not result in a hyperpolarization of (dopaminergic) nerve terminals. In none of these inhibitory effects presynaptic adenylate cyclase appears to be involved.


Diagnosis of glomus tumor of the elbow: A case report.
Glomus tumors are rare and often benign vascular lesions that present classically in the subungual region of the hand. Nonetheless, presentations in atypical sites have been reported over the years. However, the classic symptoms of typical glomus tumors are often absent in tumors of atypical sites. We present a case of an extradigital glomus tumor with a 3-year history of pain in the lateral aspect of the elbow. The case we present took three years and multiple visits to different clinics and specialties to reach the final diagnosis and management. It often takes longer to diagnose Glomus tumors of atypical sites and presentations. The causes could be related to the rare incidence, the atypical presentation in site and symptoms, or the diagnostic methods. This case report discusses the possible causes behind the diagnostic delay in extradigital glomus tumors, aiming to raise clinical awareness among primary health care physicians.


[The study of developmental pharmacology (I). Effect of pentazocine HCl on the physiology of rats given the drug during perinatal and postnatal periods (author's transl)].
The effects of drug administration on the dams (F0) and their offspring (F1), particularly on the central nervous and reproductive functions of F1, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F0 at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F1, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the open-field test.


Effects of ML-9 on insulin stimulation of glucose transport in 3T3-L1 adipocytes.
Treatment of 3T3-L1 adipocytes with insulin resulted in activation of 2-deoxyglucose transport activity and translocation of glucose transporters (GLUT4 and GLUT1) from the cytoplasmic space to the plasma membrane. ML-9 (a myosin light chain kinase inhibitor) inhibited insulin stimulation of 2-deoxyglucose transport activity by 80% at 100 microM (IC50 = 27 microM) without affecting 2-deoxyglucose transport activity in the basal state. The inhibition was independent of extracellular Ca2+ concentration and almost fully reversible at 40 microM ML-9. ML-9 did not inhibit insulin-stimulated tyrosine phosphorylation of 95-kDa protein in the wheat germ agglutinin-purified preparation and of 95- and 160-kDa proteins in intact cells. However, ML-9 inhibited insulin-induced translocation of both GLUT4 and GLUT1 in a dose-dependent manner. The dose-response curves were similar to those observed for the inhibition of insulin stimulation of 2-deoxyglucose transport activity. Neither insulin nor ML-9 affected the phosphorylation state of both heavy and light chains of myosin. Therefore, it seems likely that ML-9 inhibits the insulin-induced translocation of glucose transporters at a step beyond the insulin receptor kinase activity by a mechanism different from that affecting phosphorylation of the myosin light chain. Phosphorylating activity of microtubule-associated protein 2 and myelin basic protein was stimulated by insulin, and this stimulation was not affected by ML-9. ML-9, however, inhibited the phosphorylating activity in vitro and insulin stimulation of the phosphorylating activity of ribosomal protein S6 in intact cells in a dose-dependent manner similar to that observed for the inhibition of insulin stimulation of glucose transport. These results suggest that mitogen-activated protein kinase may be one of the constituents in intracellular insulin signaling to the glucose transport system.


Bayesian-network-based safety risk assessment for steel construction projects.
There are four primary accident types at steel building construction (SC) projects: falls (tumbles), object falls, object collapse, and electrocution. Several systematic safety risk assessment approaches, such as fault tree analysis (FTA) and failure mode and effect criticality analysis (FMECA), have been used to evaluate safety risks at SC projects. However, these traditional methods ineffectively address dependencies among safety factors at various levels that fail to provide early warnings to prevent occupational accidents. To overcome the limitations of traditional approaches, this study addresses the development of a safety risk-assessment model for SC projects by establishing the Bayesian networks (BN) based on fault tree (FT) transformation. The BN-based safety risk-assessment model was validated against the safety inspection records of six SC building projects and nine projects in which site accidents occurred. The ranks of posterior probabilities from the BN model were highly consistent with the accidents that occurred at each project site. The model accurately provides site safety-management abilities by calculating the probabilities of safety risks and further analyzing the causes of accidents based on their relationships in BNs. In practice, based on the analysis of accident risks and significant safety factors, proper preventive safety management strategies can be established to reduce the occurrence of accidents on SC sites.


Endovascular treatment of intracranial vertebral artery dissecting aneurysm, a case series study with two years follow up on complications.
This study is aimed to analyze the clinical outcomes of endovascular treatments for patients with intracranial vertebral artery dissecting aneurysms. Clinical data of 32 patients with vertebral artery dissecting aneurysms who underwent endovascular procedures in the Department of Neurosurgery of our University from January 2016 to December 2019 were retrospectively analyzed. Nine cases were treated with endovascular occlusion; 23 cases received reconstructive treatment, including 20 cases of stent combined with coil embolization, and 3 cases of stent implantation. The angiography taken at 3-22 months after surgery was reviewed. The endovascular treatments for all 32 cases were successful. Thirty-one cases had no postoperative complications during index hospital. Mid-term follow-up showed that: 27 cases (84%) had embolism; 5 cases (16%) had recurrence, of which 4 cases were treated again with endovascular procedures followed with no further complications and no recurrence, and 1 case received closely monitor but no reoperation. During an average follow-up of 10.5 months, except for one case that was self-discharged due to end-stage brainstem compression and respiratory failure, the rest of the patients were in stable conditions without bleeding or infarction. Endovascular treatment of intracranial vertebral artery dissecting aneurysms is safe and effective. Recurrent vertebral artery dissecting aneurysms can be treated with endovascular reoperations with satisfactory outcomes.


Novel, druglike 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine-based selective inhibitors of human neuronal nitric oxide synthase (nNOS).
A novel class of 1,7-disubstituted 2,3,4,5-tetrahydro-1H-benzo[b]azepine derivatives was designed, synthesized and evaluated as human nitric oxide synthase (NOS) inhibitors. Structure-activity relationship studies based on various basic amine side chains attached at the 1-position of the 2,3,4,5-tetrahydro-1H-benzo[b]azepine ring led to the identification of several potent and highly selective inhibitors (17, 18, 25, (±)-39, and (±)-40) of human neuronal NOS. The potential therapeutic application of one of these new selective nNOS inhibitors (17) was demonstrated in an in vivo spinal nerve ligation model of neuropathic pain, and various in vitro safety pharmacology studies such as the hERG K(+) channel inhibition assay and high throughput broad screen (minimal activity at 79 receptors/transporters/ion channels).


Mechanisms of mechanosensing - mechanosensitive channels, function and re-engineering.
Sensing and responding to mechanical stimuli is an ancient behavior and ubiquitous to all forms of life. One of its players 'mechanosensitive ion channels' are involved in processes from osmosensing in bacteria to pain in humans. However, the mechanism of mechanosensing is yet to be elucidated. This review describes recent developments in the understanding of a bacterial mechanosensitive channel. Force from the lipid principle of mechanosensation, new methods to understand protein-lipid interactions, the role of water in the gating, the use of engineered mechanosensitive channels in the understanding of the gating mechanism and application of the accumulated knowledge in the field of drug delivery, drug design and sensor technologies are discussed.


Scanning-electron microscopy of chromosome aberrations.
This study is the first report of scanning-electron microscopy of isolated and purified metaphase chromosomes containing drug-induced aberrations. The technique reported allows high resolution topological examination of chromosomal aberrations which may pass undetected with conventional techniques.


Acute renal effects of oral felodipine in normal man.
The acute renal effects of a single oral dose of felodipine 0.15 mg/kg were studied in 8 healthy males. Thirty minutes after administration the mean plasma concentration was 25.7 nmol/l. There was a significant reduction in diastolic blood pressure (24%) and a concomitant rise in heart rate (38%), leaving the systolic pressure unchanged. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were measured by the constant infusion technique using the clearance of 125I-iothalamate and 131I-hippuran respectively. GFR was unchanged and the filtration fraction (FF) was reduced, whilst there was a decrease in renal vascular resistance (RVR). The glomerular filter characteristics were unchanged, as estimated by the unchanged excretion rate of albumin. There was a significant rise in the clearance of sodium (176%) but only a small and insignificant increase in urine volume. Clearance of potassium was decreased. An increase in the clearance of uric acid and a rise in the beta-2-microglobulin excretion rate were found, both suggesting a proximal tubular effect of felodipine. The excretion rate of calcium was increased.


Gynaecological tuberculosis: analysis of a personal series of 710 cases.
A study has been made of 710 patients with proved gynaecological tuberculosis investigated between January 1, 1951 and March 31, 1985. The main presenting symptoms in order of frequency were infertility, pelvic pain, excessive menstrual loss and amenorrhoea. The average age was 31 years at first attendance, only 16% of married women had been pregnant and palpable adnexal masses were found in 47%. Seven drug programmes have been used, the best results being obtained with the current regimen employing rifampicin, ethambutol and isoniazid. Where drug treatment failed, surgery under further drug cover was successfully employed. Toxic drug reactions occurred in 114 patients.


The influence of the major histocompatibility complex (H-2) on experimental diabetes in mice.
Mice with different histocompatibility loci on an identical background genome (congenic resistant lines of mice) were used to study the possible influence of the histocompatibility complex on experimental diabetes. The major histocompatibility complex (H-2) was not found to influence the diabetogenic effect of encephalomyocarditis (EMC) virus. In contrast the glucose intolerance following heterologous and homologous immunization with pancreatic antigens appeared H-2 influenced. Antibodies against cell surface components on viable B-cells were present in serum from mice with glucose intolerance induced by homologous immunization. The results suggest that the susceptibility to experimental autoimmune diabetes in mice is influenced by the H-2 complex.


Hydrogen sulfide biosynthesis is impaired in the osteoarthritic joint.
Osteoarthritis (OA) is the most common form of arthritis and it is a leading cause of disability in the elderly. Its complete etiology is not known although there are several metabolic, genetic, epigenetic, and local contributing factors involved. At the moment, there is no cure for this pathology and treatment alternatives to retard or stop its progression are intensively being sought. Hydrogen sulfide (H2S) is a small gaseous molecule and is present in sulfurous mineral waters as its active component. Data from recent clinical trials shows that balneotherapy (immersion in mineral and/or thermal waters from natural springs) in sulfurous waters can improve OA symptoms, in particular, pain and function. Yet, the underlying mechanisms are poorly known. Hydrogen sulfide is also considered, with NO and CO, an endogenous signaling gasotransmitter. It is synthesized endogenously with the help of three enzymes, cystathionine gamma-lyase (CTH), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST). Here, the expression of these three enzymes was demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and their protein abundance [by immunohistochemistry and Western blot (WB)] in human articular cartilage. No significant differences were found in CBS or CTH expression or abundance, but mRNA and protein levels of 3-MPST were significantly reduced in cartilage form OA donors. Also, the biosynthesis of H2S from OA cartilage, measured with a specific microelectrode, was significantly lower than in OA-free tissue. Yet, no differences were found in H2S concentration in serum from OA patients and OA-free donors. The current results suggest that reduced levels of the mitochondrial enzyme 3-MPST in OA cartilage might be, at least in part, responsible for a reduction in H2S biosynthesis in this tissue and that impaired H2S biosynthesis in the joint might be a contributing factor to OA. This could contribute to explain why exogenous supplementation of H2S, for instance with sulfurous thermal water, has positive effects in OA patients.


Fusion of mouse alveolar macrophages induced by 1 alpha,25-dihydroxyvitamin D3 involves extracellular, but not intracellular, calcium.
We have reported that the active form of vitamin D3, 1 alpha, 25-dihydroxy-vitamin D3 [1 alpha, 25(OH)2D3], directly induces the fusion of mouse alveolar macrophages (Abe et al: Proc. Natl. Acad. Sci. USA 80:5583-5587, 1983). The fusion process can be divided into two phases: the 1 alpha,25(OH)2D3-dependent priming phase (0-18 hr) and the calcium-dependent progression phase (18-72 hr) (Jin et al: J. Cell. Physiol. 137:110-116, 1988). In the present study, we examined the role of calcium in the progression phase of macrophage fusion induced by 1 alpha,25(OH)2D3. Macrophages pretreated with 1 alpha,25(OH)2D3 for 48 hr in a low-calcium (0.13 mM) medium began to fuse quickly 30 min after the culture medium was switched to a normal calcium (1.85 mM) medium. Of various cations tested, calcium was the most effective in inducing fusion, followed by strontium and manganese. Magnesium, potassium, and sodium had no effect. Calcium ionophores such as A23187 and ionomycin did not induce fusion in the low-calcium medium, nor did they potentiate fusion in the media containing higher concentrations of calcium. The intracellular concentration of free Ca2+, measured by a fluorescent method using fura-2 AM, was 116 +/- 1 nM in the macrophages pretreated with 1 alpha,25(OH)2D3 for 48 hr in the low-calcium medium. When calcium chloride was added to the assay system at a final concentration of 1.85 mM, the cytosolic free Ca2+ concentration did not increase appreciably (from 116 to 144 nM). But the macrophages began to fuse quickly when CaCl2 was added. In contrast, adding ionomycin increased cytosolic free Ca2+ from 116 to 440 nM, but no fusion occurred. These results clearly indicate that the extracellular, but not the intracellular, calcium is involved in the progression phase of the fusion of mouse alveolar macrophages primed by 1 alpha,25(OH)2D3.


The Emperor Dom Pedro II: his convulsive seizures when a boy.
Dom Pedro II, the Prince Heir and Emperor under regency, in a delicate period of the construction of the Brazilian nation, had convulsive seizures. To investigate the convulsive seizures and related syndromes of Dom Pedro II and his family, besides the physicians in charge of the health care. Narrative review based on primary and secondary sources. The scattered and self-limited convulsive seizures associated with physical and mental integrity favored a benign prognosis. Dom Pedro and his family presented rich history of epileptic seizures and febrile convulsion. This variety resembles the diagnosis of generalized epilepsy with febrile seizures plus that seems to be a combination of several syndromes with shared genetic susceptibility.


Porous graphitic carbon nitride with nitrogen defects and cobalt-nitrogen (CoN) bonds for efficient broad spectrum (visible and near-infrared) photocatalytic H2 production.
The porous graphitic carbon nitride (g-C3N4) with nitrogen defects and cobalt-nitrogen (CoN) bonds (g-C3N4-Co-K) is prepared by controllable copolymerization of melamine with KOH and Co(NO3)2·6H2O. The method not only provides g-C3N4 with porous structure and CoN bonds that accelerate photoexcited carrier transfer and endow numerous active sites, but also redshifts the g-C3N4 absorption edge into near-infrared (NIR) light region through the introduction of nitrogen defects and thus is suitable for H2 evolution. The g-C3N4-Co-K exhibits significantly superior photocatalytic hydrogen generation performance (808 µmol h-1 g-1) under simulated solar light irradiation, about 15.5 times higher than pure g-C3N4, about 5.2 times higher than g-C3N4 with CoN bonds (g-C3N4-Co), and about 2.1 times higher than g-C3N4 with nitrogen defects (g-C3N4-K). Interestingly, it is for the first time revealed that the synergistic effect of nitrogen defects and CoN bonds result in enhanced H2 generation activity (470 µmol h-1 g-1) under NIR light irradiation.


Hyperpolarized 13 C spectroscopic imaging using single-shot 3D sequences with unpaired adiabatic refocusing pulses.
Hyperpolarized MRI with 13 C-labeled metabolites has enabled metabolic imaging of tumors in vivo. The heterogeneous nature of tumors and the limited lifetime of the hyperpolarization require high resolution, both temporally and spatially. We describe two sequences that make more efficient use of the 13 C polarization than previously described single-shot 3D sequences. With these sequences, the target metabolite resonances were excited using spectral-spatial pulses and the data acquired using spiral readouts from a series of echoes created using a fast-spin-echo sequence employing adiabatic 180° pulses. The third dimension was encoded with blipped gradients applied in an interleaved order to the echo train. Adiabatic inversion pulses applied in the absence of slice selection gradients allowed acquisition of signal from odd echoes, formed by unpaired adiabatic pulses, as well as from even echoes. The sequences were tested on tumor-bearing mice following intravenous injection of hyperpolarized [1-13 C]pyruvate. [1-13 C] pyruvate and [1-13 C] lactate images were acquired in vivo with a 4 × 4 × 2 cm3 field of view and a 32 × 32 × 16 matrix, leading to a nominal resolution of 1.25 × 1.25 × 1.25 mm3 and an effective resolution of 1.25 × 1.25 × 4.5 mm3 when the z-direction point spread function was taken into account. The acquisition of signal from more echoes also allowed for an improvement in the signal-to-noise ratio for resonances with longer T2 relaxation times. The pulse sequences described here produced hyperpolarized 13 C images with improved resolution and signal-to-noise ratio when compared with similar sequences described previously.


Ionic liquids showing phase separation with water prepared by mixing hydrophilic and polar amino acid ionic liquids.
Both water soluble lysine- and aspartic acid-based amino acid ionic liquids (AAILs) were mixed to prepare polar AAILs showing phase separation with water.


Metabolism drives macrophage heterogeneity in the tumor microenvironment.
Tumor-associated macrophages (TAMs) are a major cellular component in the tumor microenvironment (TME). However, the relationship between the phenotype and metabolic pattern of TAMs remains poorly understood. We performed single-cell transcriptome profiling on hepatic TAMs from mice bearing liver metastatic tumors. We find that TAMs manifest high heterogeneity at the levels of transcription, development, metabolism, and function. Integrative analyses and validation experiments indicate that increased purine metabolism is a feature of TAMs with pro-tumor and terminal differentiation phenotypes. Like mouse TAMs, human TAMs are highly heterogeneous. Human TAMs with increased purine metabolism exhibit a pro-tumor phenotype and correlate with poor therapeutic efficacy to immune checkpoint blockade. Altogether, our work demonstrates that TAMs are developmentally, metabolically, and functionally heterogeneous and purine metabolism may be a key metabolic feature of a pro-tumor macrophage population.


Patient-Controlled Remifentanil Analgesia as Alternative for Pethidine with Midazolam During Oocyte Retrieval in IVF/ICSI Procedures: A Randomized Controlled Trial.
Pethidine with midazolam-induced conscious sedation for pain relief during transvaginal oocyte retrieval for in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) procedures is associated with residual pain and oversedation. Patient-controlled analgesia (PCA) with remifentanil may serve as an alternative for pethidine. We investigated whether PCA remifentanil with diclofenac was associated with improved periprocedural pain relief than pethidine analgesia during IVF/ICSI procedures, with sedation scores, safety profiles, and patient satisfaction as secondary endpoints. Seventy-six women were randomized to receive pethidine (2 mg/kg i.m.) and midazolam (7.5 mg)-induced conscious sedation (n = 40) or PCA with remifentanil and diclofenac (50 mg; n = 36). The Numeric Rating Scale, McGill Pain Questionnaire (MPQ), Ramsey Sedation Scale, and a 5-day pain-and-discomfort diary were used to evaluate pain and sedation levels. There were no differences in baseline characteristics and reproductive outcomes between both groups. Periprocedural pain scores were comparable for remifentanil and pethidine groups (4 [3 to 7] vs. 6 [4 to 8]; P = 0.13). Pain scores in the pethidine group were significantly lower at 30 minutes after the procedure (1 [0 to 3] vs. 2 [1 to 5]; P = 0.016), but at cost of higher sedation levels when compared to remifentanil (4 [2 to 4] vs. 2 [2 to 2]; P < 0.001). Patient satisfaction was higher, and MPQ scores were lower in the remifentanil group. There were no differences in safety profiles between both analgesics. Patient-controlled analgesia with remifentanil showed a similar reduction in pain scores than pethidine with midazolam during oocyte retrieval, while pethidine induced the highest pain relief after the procedure. However, PCA remifentanil was associated with less sedation and a better patient satisfaction profile than pethidine.


Building a Successful Endoscopic Skull Base and Pituitary Surgery Practice.
Building an endoscopic cranial base practice can be challenging and is predicated on the right team. Successful outcomes stem from an efficient and talented team that improves its skills experientially in a supportive environment. As with most new endeavors that are beyond the traditional approach, there is a great deal of up-front effort and investment required. This article explores some of the key building blocks necessary for a successful endoscopic cranial base and pituitary program and highlights some of the lessons learned during the authors' journey at the Cleveland Clinic.


Identification of multicomponent histidine-aspartate phosphorelay system controlling flagellar and motility gene expression in Geobacter species.
Geobacter species play an important role in the natural biogeochemical cycles of aquatic sediments and subsurface environments as well as in subsurface bioremediation by oxidizing organic compounds with the reduction of insoluble Fe(III) oxides. Flagellum-based motility is considered to be critical for Geobacter species to locate fresh sources of Fe(III) oxides. Functional and comparative genomic approaches, coupled with genetic and biochemical methods, identified key regulators for flagellar gene expression in Geobacter species. A master transcriptional regulator, designated FgrM, is a member of the enhancer-binding protein family. The fgrM gene in the most studied strain of Geobacter species, Geobacter sulfurreducens strain DL-1, is truncated by a transposase gene, preventing flagellar biosynthesis. Integrating a functional FgrM homolog restored flagellar biosynthesis and motility in G. sulfurreducens DL-1 and enhanced the ability to reduce insoluble Fe(III) oxide. Interrupting the fgrM gene in G. sulfurreducens strain KN400, which is motile, removed the capacity for flagellar production and inhibited Fe(III) oxide reduction. FgrM, which is also a response regulator of the two-component His-Asp phosphorelay system, was phosphorylated by histidine kinase GHK4, which was essential for flagellar production and motility. GHK4, which is a hybrid kinase with a receiver domain at the N terminus, was phosphorylated by another histidine kinase, GHK3. Therefore, the multicomponent His-Asp phosphorelay system appears to control flagellar gene expression in Geobacter species.


Refractive changes after pediatric intraocular lens implantation.
To report refractive changes after cataract surgery and intraocular lens implantation in infants and children. In an ongoing prospective study, the refractive errors of all patients younger than 18 years undergoing intraocular lens implantation were determined at 6 weeks, 3 months, 6 months, and 1 year, and at least yearly thereafter. All patients with greater than 6 months of follow-up were included in the study. Eighty-three eyes of 81 patients were identified. Cataracts were traumatic in 32 eyes (38%) and developmental in 42 eyes (50%). At implantation, the mean (+/-SD) age was 6.3 +/- 4.6 years (range, 9 months to 17 years). The mean follow-up was 26.6 months (range, 6 months to 6.6 years). Patients 0 to 2 years old at the time of implantation demonstrated a mean myopic shift of -3.00 diopters during a mean follow-up period of 2.5 years. Patients 2 to 6 years old at the time of implantation demonstrated a mean myopic shift of -1.50 diopters in a similar follow-up period. Children aged 6 to 8 years experienced a mean myopic shift of -1.80 diopters during a mean follow-up period of 3.0 years, while children older than 8 years at the time of intraocular lens implantation experienced a mean myopic shift of -0.38 diopters during a mean follow-up period of 1.8 years. On average, the operated-on eye showed a greater mean myopic shift than the fellow eye. No statistically significant differences in refractive change were found in comparing amblyopic to nonamblyopic eyes, traumatic to nontraumatic cataracts, or primary to secondary intraocular lenses. Our data demonstrate a trend toward increasing postoperative myopia in pediatric patients undergoing intraocular lens implantation. This myopic shift is greatest in the younger age groups and persists until at least 8 years of age. There is much variability in the postoperative refractive changes, and predicting exactly when and where the refraction will stabilize for an individual patient is difficult.


Trends and Pattern of Diseases Under Integrated Disease Surveillance Project in Jodhpur, Rajasthan: A Retrospective Observational Study.
Progress of the Integrated Disease Surveillance (IDSP) is of utmost importance to ensure optimal performance in Jodhpur, Rajasthan, India. The purpose of the study was to document the physical performance of the surveillance system on its core and support functions. Mixed method study was conducted between September 2020 to October 2020. Quantitative data was collected from the district IDSP unit of the Chief Medical and Health Office (CMHO) for various blocks of Rajasthan using syndromic, presumptive, and laboratory-confirmed reporting formats. Ethical clearance was obtained from the Institutional Ethical Committee of AIIMS, Jodhpur. Rajasthan reported outbreaks between 0.55 to 1.2% of the national average between 2015-2019. Acute respiratory infections, fever of unknown origin, and acute diarrhea were the leading diseases under the presumptive reporting format. Major syndromic cases reported were cough with/without fever (more than three weeks) and fever less than seven days with the rash. Laboratory-confirmed Dengue, Malaria, and hepatitis were reported more in urban Jodhpur. Despite some pitfalls, IDSP has made satisfactory improvements in its core and support functions in the Jodhpur district of Rajasthan. The number of preventable morbidity and mortality cases associated with notifiable infectious diseases in our country can be effectively countered by strengthening the IDSP reporting system.


Degrees of separation: a quantitative neuroimaging meta-analysis investigating self-specificity and shared neural activation between self- and other-reflection.
In functional neuroimaging studies, self-specificity has been investigated by contrasting other-relevant processing against the self. Our meta-analysis investigates self-specificity with respect to degrees of self-relatedness (SR) of the other (i.e. close and public other). Literature suggests a dorsal-ventral component of self- and other-reflection within the MPFC, which has yet to be analyzed according to varying SR, nor has it been quantified statistically. In the present meta-analysis, we pursued three main objectives. First, we conducted whole-brain ALE meta-analyses using contemporary literature analyzing self>close other and self>public other contrasts to determine self-specific regions sensitive to SR. Next, we conducted ALE and conjunction analyses of studies employing self>control, close other>control, or public other>control contrasts to determine shared regions of activation. Third, we conducted post hoc analyses to quantify any observed dorsal-ventral distinction, employing novel methodology using a surface-based coordinates system. We observed significant activation in the dACC and vACC for self>close other and self>public other, whereas anterior insula was observed only for self>public other. An MPFC dorsal-ventral distinction was observed and quantified whereby public other>control was significantly more dorsal than self>control and close other>control. Our results are discussed with regards to SR. Prospective avenues of research exploiting our methodology are proposed.


Effect of fast positive ions incident on caesiated plasma grid of negative ion source.
This paper describes the effect on negative ion formation on a caesiated surface of the backscattering of positive ions approaching it with energy of a few tens of eV. For a positive ion energy of 45 eV, the surface produced negative ion current density due to these fast positive ions is 12 times larger than that due to thermal atoms, thus dominating the negative ion surface production instead of the thermal atoms, as considered until now.


Deoxynivalenol accumulation and other scab symptoms in six romanian wheat genotypes inoculated withFusarium graminearum.
At anthesis, under field conditions at Fundulea, each of 6 Romanian winter wheat genotypes was inoculated with 3Fusarium graminearum isolates used individually.Fusarium head blight (FHB) was assessed according to the following traits: relative weight of spikes (RWS), percentage of Fusarium damaged kernels (FDK), relative weight of kernels per head (RWKH), area under the disease progress curve (AUDPC) and deoxynivalenol (DON) content in total sample of kernels. Correlations between these traits and parameters revealed important differences between examined wheat genotypes in: DON accumulation, progress of FHB development, yield reduction, and models of host - pathogen interactions in theTriticum - Fusarium pathosystem. Significant correlations between different attributes of FHB were found forFusarium isolate 1 which is a moderate producer of DON (0.89 µg g(-1)). Weight of spike was significantly correlated with weight of kernels per spike (r = 0.93**) and with percentage of damaged kernels (r = - 0.87**), while FDK was highly correlated with RWKH (r = - 0.85*) and with DON content (r = 0.82*). Area under the disease progress curve was also found to be significantly correlated with DON content (r = 0.86*).


Thyroglobulin assay 4 weeks after thyroidectomy predicts outcome in low-risk papillary thyroid carcinoma.
Thyroidectomy followed by administration of large activities of 131I is the treatment of choice for differentiated thyroid carcinomas. Due to its good prognosis, some authors argue that papillary thyroid cancer with a diameter of up to 10 mm can be treated by surgery alone. In the new TNM classification started in 2002, the T1 group now encompasses all tumours with a diameter up to 20 mm, which widens the indications for a conservative approach. In this instance, prognostic markers are needed to better select patients before planning non-aggressive treatment. Serum thyroglobulin plays a pivotal role in thyroid carcinoma management after thyroid ablation (i.e., surgery and radioiodine) but is of limited value before these treatments. However, thyroglobulin assay performed after surgery but before radioiodine treatment has been proven to be useful in predicting the presence/absence of distant metastasis. Our study was undertaken in patients affected by pT1 papillary thyroid carcinoma to evaluate the predictive value of post-surgery thyroglobulin assay on 1) restaging immediately after radioiodine treatment and 2) restaging at 12 months. We selected 156 patients affected by pT1 histologically proven papillary thyroid carcinoma, submitted to total thyroidectomy. Serum thyroglobulin was assayed by a specific immunoradiometric method 4 weeks after surgery, just before radioiodine administration. Cut-off levels were selected by receiver operating characteristic curve analysis. Thyroglobulin levels were compared to the results of a post-radioiodine treatment scan and 12-month restaging. Globally, 23 out of 156 patients showed persistent/recurrent disease (15%). Post-surgery thyroglobulin levels above 4.50 microg/L identified 94% of patients with metastasis at post-dose scan, and a level below 3.20 microg/L identified 86% and 93% of relapsed and disease-free patients at 12-month restaging, respectively. Multivariate analysis and Spearman rank correlation showed that the N-status and post-surgery thyroglobulin level are independent prognostic factors. The post-surgery thyroglobulin level could be systematically assayed in patients with pT1-papillary thyroid carcinoma and taken into account in planning treatment.


Let us be careful with the evidence on mentalizing, cognitive biases, and religious beliefs.
Norenzayan et al.'s theoretical synthesis is highly plausible and commendable. However, the empirical evidence for the arguments on mentalizing, cognitive biases, and religious belief is currently not as strong as the writers suggest. Although certainly abundant and compelling, this evidence is indirect, contradictory, and weak and must be acknowledged as such. More direct studies are needed to support the theory.


Formic acid induces hypertension-related hemorrhage in hSSAOTG in mice and human.
Hypertension is a confirmed risk factor for cerebral hemorrhage in humans. Which endogenous factor directly induces hypertension-related hemorrhage is unclear. In this study, 42 hemorrhagic patients with hypertension and hyperlipidemia and 42 age-matched healthy controls were enrolled. The contents of serum semicarbazide-sensitive amine oxidase (SSAO) and formic acid (FC, FC is a final product of SSAO through the oxidation of endogenous formaldehyde, which results from the enzymatic oxidative deamination of the SSAO substrate, methylamine) were examined in the patients after stroke. Hemorrhagic areas were quantified by computer tomography. In the animal study, hemorrhagic degree was assessed by hemotoxylin & eosin or tissue hemoglobin kits. The relationship between FC and blood pressure/hemorrhagic degree was examined in wild-type mice and hSSAOTG mice fed with high-fat diets or high-fat and -salt diets. The results showed that the levels of serum FC were positively correlated with blood pressure and hemorrhagic areas in hemorrhagic patients. Transfection of microRNA-134 could enhance SSAO expression in human vascular smooth muscle cells. Consistently, after treatment with high-fat and -salt diets, hSSAOTG mice exhibited higher levels of miR134 and FC, higher blood pressure, and more severe hemorrhage than wild-type mice. Interestingly, folic acid reduced hypertension and hemorrhage in hSSAOTG mice fed with high-fat diets. These findings suggest that FC is a crucial endogenous factor for hypertension and hemorrhage.


Dental and Dentoalveolar Injuries in the Pediatric Patient.
Dental and dentoalveolar injuries are common in the pediatric population. Management is predicated on the type of tooth injured (primary or permanent), extent of injury, the dental and behavioral age of the patient, and ability of the patient to tolerate treatment. Although many dental injuries occur in isolation, a systematic evaluation of the patient is mandatory to confirm the absence of basal bone fractures of the maxilla or mandible, traumatic brain injury, cervical spine injury, and/or facial soft tissue injury. Long-term follow-up is paramount to achieving a functional occlusion and optimal dental health following injury.


Pelvic Organ Preservation in Non-muscle-invasive Bladder Cancer: Less Is More.
Radical cystectomy (RC) is a treatment option for high-risk non-muscle-invasive bladder cancer (NMIBC) but is associated with high morbidity and a negative impact on quality of life. Reproductive or pelvic organ-sparing cystectomy (ROSC) techniques have emerged as a potential strategy to mitigate some potential effects of standard RC. Here we discuss current knowledge regarding oncological, functional, and sexual function outcomes associated with ROSC and their applicability in NMIBC. These outcomes can be used to make informed clinical decisions regarding cystectomy technique in appropriately staged and selected patients with NMIBC. PATIENT SUMMARY: We reviewed results for bladder cancer control, urinary function, and sexual function after removal of the bladder with and without techniques to spare reproductive or pelvic organs. We found evidence of better sexual function outcomes with a sparing approach without compromise of cancer control. Further studies are needed to assess urinary function and pelvic floor-related outcomes.


Gamma radiation dose rate in high-altitude areas in the Bageshwar, Champawat and Pithoragarh districts of Uttarakhand, India.
Radiation has a deteriorating effect on humans as well as on the environment depending on its level, although we have all been exposed to natural gamma radiation from birth. The presence of radionuclides in rocks, soil, plants, and water is a major factor behind the natural gamma radiation. The present study deals with the study of natural gamma radiation at Bageshwar, Champawat and Pithoragarh districts of Uttarakhand. It also consists of seasonal variations in gamma radiation and its relationship with altitude and geology. The purpose of this study was to investigate the influence of altitude and geology on natural gamma radiation dose rate data in high-altitude areas of India. The highest gamma radiation value was 444 nSv/h in the summer and 342 nSv/h in the winter. The investigation recorded the gamma radiation up to 2542.20 m altitude, indicating that the geology of the areas is more relevant than the altitude. Few sites in such a high-altitude zone were found to exceed the value of 200 nSv/h, as reported by UNSCEAR. This research is necessary in order to consider the human health and climate changes, both of which are part of the action plan for the United Nation's Sustainable Development Goals (SDG 3, SDG 13).


Time in Range Estimation in Patients with Type 2 Diabetes is Improved by Incorporating Fasting and Postprandial Glucose Levels.
Time in range (TIR) as assessed by continuous glucose monitoring (CGM) measures an individual's glucose fluctuations within set limits in a time period and is increasingly used together with HbA1c in patients with diabetes. HbA1c indicates the average glucose concentration but provides no information on glucose fluctuation. However, before CGM becomes available for patients with type 2 diabetes (T2D) worldwide, especially in developing nations, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) are still the common biomarkers used for monitoring diabetes conditions. We investigated the importance of FPG and PPG to glucose fluctuation in patients with T2D. We used machine learning to provide a new estimate of TIR based on the HbA1c, together with FPG and PPG. This study included 399 patients with T2D. (1) Univariate and (2) multivariate linear regression models and (3) random forest regression models were developed to predict the TIR. Subgroup analysis was performed in the newly diagnosed T2D population to explore and optimize the prediction model for patients with different disease history. Regression analysis suggests that FPG was strongly linked to minimum glucose, while PPG was strongly correlated with maximum glucose. After FPG and PPG were incorporated into the multivariate linear regression model, the prediction performance of TIR was improved compared with the univariate correlation between HbA1c and TIR, and the correlation coefficient (95% CI) increased from 0.62 (0.59, 0.65) to 0.73 (0.72, 0.75) (p < 0.001). The random forest model significantly outperformed the linear model (p < 0.001) in predicting TIR through FPG, PPG and HbA1c, with a stronger correlation coefficient 0.79 (0.79, 0.80). The results offered a comprehensive understanding of glucose fluctuations through FPG and PPG compared to HbA1c alone. Our novel TIR prediction model based on random forest regression with FPG, PPG, and HbA1c provides a better prediction performance than the univariate model with solely HbA1c. The results indicate a nonlinear relationship between TIR and glycaemic parameters. Our results suggest that machine learning may have the potential to be used in developing better models for understanding patients' disease status and providing necessary interventions for glycaemic control.


[Surgical management of patent ductus arteriosus in low body weight infants].
Between January 1980 and December 1994, seventeen premature infants weighing less than 2500 g underwent surgical management for the isolated patent ductus arteriosus (PDA). Indometacine therapy for closure of PDA was not effective for all these patients. In terms of the body weight at birth, they were divided into two groups; Group I (G-I) consisted of ten patients with birth weight less than 1000 g and Group II (G-II) of seven patients weighing more than 1000 g. The age at operation was 22.1 +/- 15.4 days in the G-I and 14.3 +/- 11.4 days in the G-II. The ductus was ligated in all patients but one of the G-II, in whom it was divided. There were five (50%) hospital deaths in the G-I and none in the G-II. The causes of death in the G-I were related to necrotizing enterocolitis (NEC) in two and infant respiratory distress syndrome (IRDS), acute renal failure, and broncho-esophagial fistula in each. The age at operation tended to be older in nonsurvivors rather than in survivors in the G-I (28.0 +/- 16.8 days vs. 16.2 +/- 14.0 days, respectively, but the difference did not reach significance). Before surgery, all patients in the G-I required mechanical ventilator support and nine of them were associated with IRDS. In contrast, only two patients in the G-II needed mechanical ventilation preoperatively. The postoperative period of intubation was also significantly longer in the G-I than in the G-II (51.6 +/- 35.2 days vs. 2.2 +/- 1.5 days, respectively, p < 0.05). In conclusions, the surgery for PDA can be safely performed even in small premature babies weighing less than 1000 g. When medical therapy for PDA is not effective in the premature patients, the surgical management should be considered as early as possible before their conditions become worse due to such critical complications as NEC, IRDS, and renal failure.


The optimal timing and courses of bevacizumab added to chemotherapy for non-squamous non-small cell lung cancer: revelations from the real-world experience in a single Chinese cancer center.
Bevacizumab combined with platinum-based chemotherapy has been approved in the first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC) without driver genes, but this regimen for second-line or later-line treatment of non-squamous NSCLC remains to be further tested. Our study aimed to provide data on the safety and effectiveness of bevacizumab (Bev)-containing chemotherapy in different-line settings for patients with NSCLC in the Chinese real-world clinical routine practice and to explore predictors for progression-free survival (PFS) and overall survival (OS). We reviewed the medical records of 194 patients with non-squamous NSCLC who received Bev plus chemotherapy as the first-, second- or third- or later-line treatment between December 2009 and January 2020 at Fudan University, Shanghai Cancer Center. Clinical characteristics, treatment history, clinical evaluation, and adverse effects of each patient were deeply analyzed. PFS and OS were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were conducted to find predictors of longer PFS and OS. One hundred ninety-four patients were enrolled in this study, including 102 (52.6%), 58 (29.9%) and 34 (17.5%) patients received Bev in combination with the first-line chemotherapy (Bev + Che1), second-line chemotherapy (Bev + Che2) and third-/later-line chemotherapy (Bev + Che3), respectively. Administration of Bev in combination with the first-line chemotherapy and >6 courses were independent predictors of significantly prolonged PFS. Whereas, patients older than 65 years or with ECOG PS ≥2 may not benefit more from Bev added to the first-line chemotherapy compared to second-/later-line chemotherapy. PFS of patients received treatment with/without chemotherapy as maintenance therapy showed no significant difference (P=0.354) in >6 courses Bev cohort. As for OS, Bev plus the first-line chemotherapy and number of metastatic sites <3 were independent predictors. The most common adverse effects (AE) were leukopenia, neutropenia, hypertension, and proteinuria. Twenty patients suffered from AE ≥ Grade 3. Bev, in combination with the front-line chemotherapy, is proven beneficial for survival well-tolerated.


Congenital lipodystrophy: An endocrine study in three siblings. I. Disorders of carbohydrate metabolism.
Three siblings with congenital lipodystrophy were studied extensively for endocrine abnormalities. A severe disturbance in carbohydrate metabolism was observed. Plasma concentrations of glucagon and insulin were markedly elevated both in the basal state and in response to provocative stimuli. In addition, marked resistance to exogenous insulin and a diabetic oral glucose tolerance test were demonstrated. Lipid metabolism, GH, and ACTH secretion were normal...


Sodium nitroprusside-induced hypotension and renal blood flow.
Hypotension produced by sodium nitroprusside during halothane anaesthesia in a series of experiments in dogs was accompanied by the maintenance of renal blood flow. Renal blood flow was maintained at levels of systemic pressure at which flow is customarily reduced in man and experimental animals. The significance of this observation is the possibility that sodium nitroprusside has a protective effect on the kidney, not only in states of deliberate hypotension, but in other low flow states where renal perfusion and function may be compromised.


From scarcity to solutions: Therapeutic strategies to restore adipose tissue functionality in rare disorders of lipodystrophy.
Lipodystrophy is a rare disorder characterised by abnormal or deficient adipose tissue formation and distribution. It poses significant challenges to affected individuals, including the development of severe metabolic complications like diabetes and fatty liver disease. These conditions are often chronic, debilitating and life-threatening, with limited treatment options and a lack of specialised expertise. This review aims to raise awareness of lipodystrophy disorders and highlights therapeutic strategies to restore adipose tissue functionality. Extensive research has been conducted, including both historical and recent advances. We have examined and summarised the literature to provide an overview of potential strategies to restore adipose tissue functionality and treat/reverse metabolic complications in lipodystrophy disorders. A wealth of basic and clinical research has investigated various therapeutic approaches for lipodystrophy. These include ground-breaking methods such as adipose tissue transplantation, innovative leptin replacement therapy, targeted inhibition of lipolysis and cutting-edge gene and cell therapies. Each approach shows great potential in addressing the complex challenges posed by lipodystrophy. Lipodystrophy disorders require urgent attention and innovative treatments. Through rigorous basic and clinical research, several promising therapeutic strategies have emerged that could restore adipose tissue functionality and reverse the severe metabolic complications associated with this condition. However, further research and collaboration between academics, clinicians, patient advocacy groups and pharmaceutical companies will be crucial in transforming these scientific breakthroughs into effective and viable treatment options for individuals and families affected by lipodystrophy. Fostering such interdisciplinary partnerships could pave the way for a brighter future for those battling this debilitating disorder.


Evaluation of the potential of PET-MRI fusion for detection of liver metastases in patients with neuroendocrine tumours.
This study was performed to assess the role of retrospective PET-MRI fusion with Ga-68-DOTA(0)-Phe(1)-Tyr(3)-octreotide (Ga-68-DOTATOC) PET and Gd-EOB-DTPA MRI in the detection of hepatic metastases from neuroendocrine tumours (NET). Twenty-two consecutive patients with suspected liver metastases from histopathologically proven NET were examined with Gd-EOB-DTPA MRI and multiphase contrast-enhanced Ga-68-DOTATOC PET/CT. PET and MRI images were retrospectively fused using commercially available software. Two physicians experienced in nuclear medicine and radiology analysed the images to assess diagnostic confidence and characterise liver lesions. A total of 181 lesions were detected. PET-MRI showed a sensitivity of 91.2% (significantly superior to PET/CT; P < 0.05) and a specificity of 95.6% (significantly superior to MRI; P < 0.05). PET/CT had a sensitivity of 73.5% and a specificity of 88.2%. MRI had a sensitivity of 87.6% and a specificity of 86.8%. The area under the curve was 0.98 for PET-MRI, 0.96 for MRI, and 0.89 for PET/CT (P < 0.05). Retrospectively fused PET-MRI was superior to multiphase contrast-enhanced Ga-68-DOTATOC PET/CT and Gd-EOB-DTPA MRI in the detection of NET liver metastases. It was more sensitive than PET/CT and more specific than MRI. Fused PET-MRI therefore seems well suited for surgical and interventional treatment planning of NET liver metastases. • Ga-68-DOTATOC PET-Gd-EOB-DTPA MRI fusion can improve imaging of liver metastases of neuroendocrine tumours. • This technique appears more sensitive than PET/CT for staging NET hepatic metastases. • Ga-68-DOTATOC PET-Gd-EOB-DTPA MRI fusion is more specific than MRI alone.


Lactobacillus-fermented milk products attenuate bone loss in an experimental rat model of ovariectomy-induced post-menopausal primary osteoporosis.
In this study, we investigated the anti-osteoporotic effect of two fermented milk products (FMPs) fermented by Lactobacillus plantarum A41 and Lactobacillus fermentum SRK414 on a rat model of ovariectomy-induced post-menopausal primary osteoporosis. The two Lactobacillus FMPs increased the bone volume and bone mineral density (BMD) in ovariectomized (OVX) rats, and normalized the bone biomarkers in the serum. Additionally, they altered the gene expression levels of bone-metabolism-related markers. Furthermore, the two Lactobacillus FMPs downregulated bone-apoptosis-related genes stimulated by ovariectomy. Interestingly, the Lactobacillus FMPs decreased the levels of inflammation markers in the serum, bone, ileum and colon of the rats. Gut bacterial populations were also affected upon FMP treatment due to increase in the abundance of the genus Lactobacillus and Faecalibacterium prausnitzii. Milk products fermented by L. plantarum A41 and L. fermentum SRK414 can exhibit anti-osteoporotic effects on post-menopausal osteoporosis via regulating the expression of bone-metabolism-related markers. The two Lactobacillus FMPs used in the study can be an ideal method that has its potential of treating post-menopausal osteoporosis instead of drug treatments.


Macrolides for better resolution of community-acquired pneumonia: A global meta-analysis of clinical outcomes with focus on microbial aetiology.
This meta-analysis examined the effect of macrolides on resolution of community-acquired pneumonia (CAP) and interpretation of clinical benefit according to microbiology; emphasis is given to data under-reported countries (URCs). This meta-analysis included 47 publications published between 1994 and 2022. Publications were analysed for 30-d mortality (58 759 patients) and resolution of CAP (6465 patients). A separate meta-analysis was done for the prevalence of respiratory pathogens in URCs. Mortality after 30 d was reduced by the addition of macrolides (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.51-0.82). The OR for CAP resolution when macrolides were added to the treatment regimen was 1.23 (95% CI 1.00-1.52). In the CAP resolution analysis, the most prevalent pathogen was Streptococcus pneumoniae (12.68%; 95% CI 9.36-16.95%). Analysis of the pathogen epidemiology from the URCs included 12 publications. The most prevalent pathogens were S. pneumoniae (24.91%) and Klebsiella pneumoniae (12.90%). The addition of macrolides to the treatment regimen led to 35% relative decrease of 30-d mortality and to 23% relative increase in resolution of CAP.


[A focus on the diagnosis of early rheumatoid arthritis].
The need for early initiation of treatment in rheumatoid arthritis (RA) has been established. The 1987 RA classification criteria are not suitable for this strategy. Therefore, as a collaboration of ACR and EULAR, new classification criteria for RA were published in 2010. Several studies assessed agreement between 1987 and 2010 criteria and the potential source of discordance. This review will describe the current evidence evaluating the 2010 criteria, and show some important questions regarding the criteria.


Quality of life and outcomes after rubber band ligation for haemorrhoidal disease.
The main objective of this study was to assess the impact on quality of life after rubber band ligation (RBL) in patients with symptomatic grade II-III haemorrhoids who did not improve after 6 months of conservative treatment, using quality of life scores. This was a prospective cohort observational study where patients with haemorrhoidal disease and indication for RBL were included between December 2019 and December 2020. RBL was offered as first-line treatment in this group. Patient´s quality of life was assessed by scores: HDSS (Hemorrhoidal Disease Symptom Score) and SHS (Short Health Scale).Secondary objectives were: to evaluate the rate of patients requiring one or more RBL procedures, to establish the overall success rate of RBL and to analyse complications. A total of 100 patients were finally included. Regarding the impact on quality of life after RBL, a significant reduction was found in the HDSS and SHS scores (p < 0.001). The main improvement was found in the first month and it was maintained until the sixth month. A high degree of satisfaction with the procedure was reported by 76% of patients. The overall success rate of banding was 89%. A 12% complication rate was detected, the most frequent complication was severe anal pain (58.3%) and self-limiting bleeding (41.7%). Rubber band ligation, as a treatment for symptomatic grade II-III haemorrhoids that do not respond to medical treatment, leads to a significant improvement in patients' symptoms and quality of life. It also has a high degree of satisfaction between patients.


ABO incompatible high-titer renal transplantation without splenectomy or anti-CD20 treatment.
Most successful protocols for renal transplantation across ABO incompatible (ABOi) barriers have utilized splenectomy as part of the pre-conditioning process. We recently described successful ABOi transplantation using anti-CD20 monoclonal antibody in lieu of splenectomy. In the current study, we hypothesized that plasmapheresis (PP) and low dose CMV hyper-immunoglobulin (CMVIg) alone would be sufficient to achieve successful engraftment of ABOi kidneys. We describe four blood type incompatible patients who received live donor renal transplants from A1 (two patients), A2 (one patient), and B (one patient) donors. All patients started with antihuman globulin (AHG) phase titers of 64 or higher and were pre-conditioned with PP/CMVIg but not splenectomy or anti-CD20. All 4 patients underwent successful transplantation and have a mean current serum creatinine of 1.1 (range: 0.9-1.2). There were no episodes of antibody mediated rejection. Rapid allograft accommodation may limit the need for long-term antibody suppression provided by splenectomy or anti-CD20, thereby eliminating the added infectious risk of these modalities and removing another disincentive to ABOi transplantation.


[Plasma cortisol response to intravenous beta 1-24 corticotropin as related to the fat mass and its topographic localisation (author's transl)].
Plasma cortisol response induced by 2.5 microgram/kg beta 1-24 corticotropin (1 hour infusion) in obese females was not related to fat mass. The response was increasingly pronounced as fat predominated in the upper body segment, i.e. android obesity. This phenomenon may be interpreted as indicating an increased adrenal capacity to secrete cortisol in such obese patients. Low level but longstanding excess cortisol secretion is probably the cause of the android features of obesity.


Double-level posterior spinal shortening for paralytic osteoporotic vertebral collapse of two vertebral bodies with a normal vertebra in between: a case report.
Spinal shortening is indicated for osteoporotic vertebral collapse. However, this surgical procedure has not been indicated for more than two vertebral levels that are not adjacent. We experienced a rare case of paraparesis due to osteoporotic vertebral collapse of two vertebral bodies with a normal vertebra in between and treated successfully by the double-level posterior shortening procedure. A 79-year-old woman suffered from delayed paraparesis 2 years after L1 and Th11 vertebral body compression fracture. Plain X-ray photographs showed Th11 and L1 vertebral body collapse, Th7 compression fracture and a kyphosis angle of 30 degrees from Th10 to L2. Plain magnetic resonance imaging showed spinal canal stenosis at Th11 and L1 vertebral body levels. She was treated by double-level posterior spinal shortening using pedicle screw and hook systems. After the procedure, the patient's kyphosis angle decreased to 10 degrees and her back pain, leg pain, and sensory deficits improved. She was able to walk by herself. Although new vertebral compression fractures occurred at L4 and L5 in the follow-up period, there has been no deterioration of the neurological symptoms 5 years after the operation. Delayed paraparesis after double-level thoracolumbar vertebral collapse due to osteoporosis was treated successfully by double-level posterior spinal shortening using a pedicle screw and hook system.


Periacinar retraction clefting in the prostatic needle core biopsies: an important diagnostic criterion or a simple artifact?
The diagnosis of prostatic adenocarcinoma in needle core biopsy is based on major and supportive criteria. One of the supportive criteria is the presence of retraction clefting around neoplastic glands. We analyzed a series of 137 prostatic cancer cases diagnosed by needle core biopsy to determine the frequency, extent and criteria for periacinar retraction clefting. Clefting was analyzed on ten neoplastic and ten normal glands in three different high power fields. One-third or more glands with clefts affecting more than 50% of circumference were significantly more common in tumors (51.8%) than in benign glands (8%) (P<0.0001). A stricter criterion that designated as positive the cases with at least 50% of neoplastic glands (15 of 30) with clefts that affected more than 50% of circumference revealed clefts in only 15.3% of the malignant cases but none in benign cases (0%) (P<0.0001). Regardless of their extension, 15 or more glands with clefts were also more prominent in malignant cases (86.9%) than in benign cases (20.4%) (P<0.0001). We conclude that periacinar retraction clefting represents a reliable criterion for diagnosis of the prostatic adenocarcinoma, especially in cases with clefts affecting more than 50% of circumference in at least 50% of suspicious glands.


Preparation and characterization of cross-linked carboxymethyl chitin porous membrane scaffold for biomedical applications.
Porous dermal scaffold membrane (PDSM) was successfully prepared by using a so-called sol-gel freeze-drying method. In this method, the carboxymethyl chitin (CMC) hydrosol was first cross-linked by 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), and then lyophilized to form the PDSM. For the first time, this research focused on the cross-linked CMC as the only component for three-dimensional PDSM. The effects of cross-linking conditions on the performance of the PDSM were investigated. And PDSM with optimal performance was obtained through 4-h cross-linking at 4 wt% of CMC concentration in the hydrosol, where the mass ratio of EDC to NHS to CMC was 5:3:10. The porosity of the optimized PDSM was more than 90% and the water swelling rate was above 4000%. The pore size was well distributed and was between 100 μm and 200 μm. And the tensile strength was above 0.09 MPa. The as-made PDSM could be degraded above 80% in 12 days in the presence of a 0.2mg/mL lysozyme solution. Very importantly, the PDSM had no cytotoxicity and good biocompatibility from MTT assays. Our results showed the application possibility of the as-prepared PDSM as dermal scaffold for skin tissue engineering.


Beneficial effect of rotational atherectomy with low platform speed on late outcomes.
Modification of rotational atherectomy (RA) procedures might be expected to alter restenosis rates. From June 1998 (period 2), platform speed was decreased to 150,000-160,000 rpm from the 170,000-190,000 rpm performed from August 1997 to May 1998 (period 1). Patients for the two periods (period 1: 62 patients, 70 lesions; period 2: 85 patients, 91 lesions) demonstrated comparable clinical and angiographic baseline data, allowing immediate and late outcomes to be evaluated for comparison. Restenosis rates in periods 1 and 2 were 57.9% and 33.8%, respectively (P=0.01). Platform speed and lesion length were independent predictors of restenosis by multivariate logistic regression analysis. RA with a low platform speed (150,000-160,000 rpm) can be performed with a high success rate and with a lower incidence of restenosis than with a high platform speed (170,000-190,000 rpm).


Highly sensitive benzothiazole-based chemosensors for detection and bioimaging of peroxynitrite in living cells.
It is well accepted that peroxynitrite (ONOO-) plays a crucial role in various physiological and pathological processes. Thus, the detection and imaging of ONOO- in vitro and in vivo with high selectivity and sensitivity is of great significance. Here we report two simple benzothiazole-based fluorescent chemosensors, BS1 and BS2. Under physiological pH, both probes could quickly sense ONOO- with a remarkable "turn-on" fluorescence signal at 430 nm. The limit of detection (LOD) of BS1 and BS2 toward ONOO- was 12.8 nM and 25.2 nM, respectively, much lower than the reported values. Experimental results indicated that BS1 with a diphenyl phosphonate unit presented higher selectivity for ONOO- than BS2. Furthermore, based on the advantages of lower cytotoxicity and pH-stabilities of BS1, probe BS1 was successfully employed to detect and image ONOO- in HepG2 cells. More importantly, we used BS1 to successfully showcase drug-induced hepatotoxicity via imaging ONOO- upregulated by acetaminophen (APAP), and also evaluated the remediation effect of GSH. All the results illustrated that the fluorescent probe BS1 has great potential for the detection of ONOO- and to further uncover the roles of ONOO- during the drug-induced liver injury (DILI) process.


Bowel obstruction in patients with ovarian cancer: a search for prognostic factors.
Patients with concomitant ovarian cancer and bowel obstruction were studied in an effort to find objective prognostic factors predictive of patient outcome. A total of 62 patients were followed from 31 to 354 weeks, and a total of 20 variables were considered in the analyses. At the end of the study 49 patients were dead of their disease, and 13 were alive (six disease free and seven with persistent disease). Survival probabilities of the sample were 79% at 6 weeks, 48% at 20 weeks, and 24% at 104 weeks. Univariate analyses revealed no significant difference in the survival times of medically versus surgically treated patients; age greater than 60 years at diagnosis of cancer, presence of ascites, low serum albumin levels, elevated blood urea nitrogen levels, elevated alkaline phosphatase levels, lack of previous radiotherapy (p less than 0.002 for all), advanced tumor stage, normal/ileus x-ray results, and a short diagnosis to obstruction interval (p less than 0.04 for all) resulted in lower survival probabilities.