Ingredients and pH are key to clear beverages that contain whey protein.
A challenge of shelf stable beverages that contain whey protein is that a small portion of protein can be denatured and aggregated during thermal processing, resulting in a turbid solution or white precipitate that consumers perceive as a defect. In this study, 3 approaches were taken to reduce turbidity in heat-treated beverages that contain whey protein: (1) centrifugation to remove insoluble protein aggregates, (2) addition of ingredients, and (3) alteration of pH in the range from 3.0 to 4.0. At pH 3.6 and below, all samples were essentially clear both before and after heating for all ingredients. At a pH of 3.8 and above, ingredient selection was crucial to solution clarity after heat treatment. At a pH of 4.0, addition of salts at both 10 and 50 mM increased the turbidity significantly compared to the control, which contained only whey protein in water. Neither addition of sugars at 25, 50, and 100 g/L, nor addition of sugar alcohols at 25 g/L significantly affected turbidity after heat treatment compared to the control. However, sugar alcohols added at 50 or 100 g/L significantly reduced turbidity after heat treatment compared to the control. Removal of insoluble protein aggregates by centrifugation prior to heat treatment resulted in a statistically significant decrease in turbidity after heat treatment. Understanding these results at the molecular level will assist food scientists in selecting processing treatments, ingredients, and pH in the development of shelf stable clear beverages that contain whey protein.


Low prevalence of diabetes distress following total pancreatectomy with islet autotransplantation.
Diabetes distress (DD), or psychological fatigue associated with diabetes management, is common in type 1 and 2 diabetes mellitus and is associated with poor glycemic control. Diabetes distress has never been evaluated in patients undergoing total pancreatectomy with islet autotransplant (TPIAT) for chronic pancreatitis. We analyzed DD after TPIAT in 260 patients (average age 34.3 [standard deviation 15], 75.5% F) undergoing TPIAT between 2006 and 2014. Each patient completed 1 or more diabetes distress scale (DDS) questionnaires from 1 to 7 years post-TPIAT (631 total). We examined changes in DD over 7 years and also patient characteristics associated with DD 1 year post-TPIAT (n = 189). One year after TPIAT, 151 of 189 (80%) reported no or low distress (DD<2). Diabetes distress increased over time by an average of 0.084 (SE 0.017) points per year, an average 0.59 point increase from years 1 to 7 (P < .0001). Insulin-dependent patients had significantly greater DD 1 year post-TPIAT compared to insulin-independent patients (P < .0001). Higher DD was associated with poorer glycemic control as indicated by HbA1c (P < .0001). Prevalence of DD is low but increases over time after TPIAT. Insulin dependence and poorer glycemic control are associated with higher levels of DD.


Herpes simplex virus 2 infection: a risk factor for HIV infection in heterosexuals.
Genital ulcerative disease is one of the risk factors for acquisition of HIV. As HSV-2 infection is currently the most common cause of genital ulcerative disease, it acts as a potential risk factor for HIV infection. The present study was undertaken to know the seroprevalence of antibodies to HSV-2 in HIV seropositive individuals and in the general population, and to ascertain if HSV-2 is a risk factor for developing HIV infection. The study group included one hundred new HIV seropositive persons irrespective of active genital herpes or history of genital herpes. Fifty age- and sex- matched healthy volunteers were included as controls. In all patients and controls, diagnostic serology was done for HSV-2 using HSV-2-specific glycoprotein IgG2 by indirect immunoassay using the ELISA test. Statistical value 'P' was calculated using the Chi-squared test. Out of the 100 HIV seropositives, 66 were males and 34 were females with an age range of 20-54 years. In only 22 (19 males and 3 females) of these, positive history of genital herpes was obtained. In 49 out of the 100 HIV seropositives, IgG2 antibodies against HSV-2 were detected. In the control group, 11 out of 50 controls were seropositive for HSV-2 IgG2 antibody. There was a statistically significant association between HSV-2 and HIV seropositivity with 'P' value The high prevalence of HSV-2 seropositivity in the HIV-infected group (49%) as compared to normal controls (22%) was statistically significant. Prior HSV-2 infection could be an important risk factor for acquisition of HIV in our patients.


Temperate Conditions Limit Zika Virus Genome Replication.
Zika virus is a mosquito-borne flavivirus known to cause severe birth defects and neuroimmunological disorders. We have previously demonstrated that mosquito transmission of Zika virus decreases with temperature. While transmission was optimized at 29°C, it was limited at cool temperatures (<22°C) due to poor virus establishment in the mosquitoes. Temperature is one of the strongest drivers of vector-borne disease transmission due to its profound effect on ectothermic mosquito vectors, viruses, and their interaction. Although there is substantial evidence of temperature effects on arbovirus replication and dissemination inside mosquitoes, little is known about whether temperature affects virus replication directly or indirectly through mosquito physiology. In order to determine the mechanisms behind temperature-induced changes in Zika virus transmission potential, we investigated different steps of the virus replication cycle in mosquito cells (C6/36) at optimal (28°C) and cool (20°C) temperatures. We found that the cool temperature did not alter Zika virus entry or translation, but it affected genome replication and reduced the amount of double-stranded RNA replication intermediates. If replication complexes were first formed at 28°C and the cells were subsequently shifted to 20°C, the late steps in the virus replication cycle were efficiently completed. These data suggest that cool temperature decreases the efficiency of Zika virus genome replication in mosquito cells. This phenotype was observed in the Asian lineage of Zika virus, while the African lineage Zika virus was less restricted at 20°C. IMPORTANCE With half of the human population at risk, arboviral diseases represent a substantial global health burden. Zika virus, previously known to cause sporadic infections in humans, emerged in the Americas in 2015 and quickly spread worldwide. There was an urgent need to better understand the disease pathogenesis and develop therapeutics and vaccines, as well as to understand, predict, and control virus transmission. In order to efficiently predict the seasonality and geography for Zika virus transmission, we need a deeper understanding of the host-pathogen interactions and how they can be altered by environmental factors such as temperature. Identifying the step in the virus replication cycle that is inhibited under cool conditions can have implications in modeling the temperature suitability for arbovirus transmission as global environmental patterns change. Understanding the link between pathogen replication and environmental conditions can potentially be exploited to develop new vector control strategies in the future.


Potassium channel blockers inhibit the triggers of attacks in the calcium channel mouse mutant tottering.
Humans with the disorder episodic ataxia type 2 (EA2) and the tottering mouse mutant exhibit episodic attacks induced by emotional and chemical stress. Both the human and mouse disorders result from mutations in CACNA1A, the gene encoding the alpha(1)2.1 subunit of Ca(v)2.1 voltage-gated calcium channels. These mutations predict reduced calcium currents, particularly in cerebellar Purkinje cells, where these channels are most abundant. 4-Aminopyridine (4-AP), a nonselective blocker of K(v) voltage-gated potassium channels, alleviates attacks of ataxia in EA2 patients. To test the specificity of the effect for K(v) channels, aminopyridine analogs were assessed for their ability to ameliorate attacks of dyskinesia in tottering mice. 4-AP and 3,4-diaminopyridine (3,4-DiAP), which have relatively high affinities for K(v) channels, reduced the frequency of restraint- and caffeine-induced attacks. Furthermore, microinjection of 3,4-DiAP into the cerebellum completely blocked attacks in tottering mice. Other aminopyridine analogs reduced attack frequency but, consistent with their lower affinities for K(v) channels, required comparatively higher doses. These results suggest that aminopyridines block tottering mouse attacks via cerebellar K(v) channels. That both stress- and caffeine-induced attacks were blocked by aminopyridines suggests that these triggers act via similar mechanisms. Although 4-AP and 3,4-DiAP were effective in preventing attacks in tottering mice, these compounds did not affect the severity of "breakthrough" attacks that occurred in the presence of a drug. These results suggest that the aminopyridines increase the threshold for attack initiation without mitigating the character of the attack, indicating that attack initiation is mediated by mechanisms that are independent of the neurological phenotype.


[Event-related brain potentials when Russian verbs being conjugated: to the problem of language processing modularity].
In the light of alternative conceptions of "two-system" and "single-system" models of language processing the efforts have been undertaken to study brain mechanisnis for generation of regular and irregular forms of Russian verbs. The 19 EEG channels of evoked activity were registered along with casual alternations of speech morphology operations to be compared. Verbs of imperfective aspect in the form of an infinitive, belonging either to a group of productive verbs (default, conventionally regular class), or toan unproductive group of verbs (conventionally irregular class) were presented to healthy subjects. The subjects were requested to produce first person present time forms of these verbs. Results of analysis of event related potentials (ERP) for a group of 22 persons are presented. Statistically reliable ERP amplitude distinctions between the verb groups are found onlyin the latencies 600-850 ms in central and parietal zones of the cortex. In these latencies ERP values associated with a presentation of irregular verbs are negative in relation to ERP values associated with the presentation of regular verbs. The received results are interpreted as a consequence of various complexity of mental work with verbs of these different groups and presumably don't support a hypothesis of universality of the "two-system" brain mechanism for processing of the regular and irregular language forms.


Kidney-Related Research in the United States: A Position Statement From the National Kidney Foundation and the American Society of Nephrology.
Kidney disease is an important US public health problem because it affects over 37 million Americans, and Medicare expenditures for patients with chronic kidney disease now alone exceed $130 billion annually. Kidney disease is characterized by strong racial, ethnic, and socioeconomic disparities, and reducing kidney disease incidence will positively impact US health disparities. Due to the aging of the US population and an unabated obesity epidemic, the number of patients receiving treatment for kidney failure is anticipated to increase, which will escalate kidney disease health expenditures. The historical and current investment in kidney-related research via the National Institute of Diabetes and Digestive and Kidney Diseases has severely lagged behind ongoing expenditures for kidney disease care. Increasing research investment will identify, develop, and increase implementation of interventions to slow kidney disease progression, reduce incidence of kidney failure, enhance survival, and improve quality of life. This perspective states the urgent reasons why increasing investment in kidney-related research is important for US public health. The National Kidney Foundation and the American Society of Nephrology are working together to advocate for increased funding for the National Institute of Diabetes and Digestive and Kidney Diseases. The long-term goal is to reduce the burden of kidney disease in the US population and improve the quality of life of patients living with kidney disease.


Multiple sclerosis in research workers studying swayback in lambs: an updated report.
Four out of seven research workers into swayback disease, a neurological disease of lambs, developed symptoms and signs of multiple sclerosis, and were reported in 1947. A further worker later joined the group. All of the original seven have died and two at necropsy had multiple areas of demyelination in the brain and spinal cord. The chance of four or more out of a random group of eight men developing multiple sclerosis is about one in a thousand million. Multiple sclerosis has not occurred in other workers on swayback disease elsewhere.


Diabetic neuropathies: components of etiology.
This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies - principally oxidative stress (via both the polyol pathway and glucoxidation) and non-enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen-activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain.


Effect of the tyrosine kinase inhibitors (sunitinib, sorafenib, dasatinib, and imatinib) on blood glucose levels in diabetic and nondiabetic patients in general clinical practice.
Tyrosine kinase is a key enzyme activity utilized in many intracellular messaging pathways. Understanding the role of particular tyrosine kinases in malignancies has allowed for the design of tyrosine kinase inhibitors (TKIs), which can target these enzymes and interfere with downstream signaling. TKIs have proven to be successful in the treatment of chronic myeloid leukemia, renal cell carcinoma and gastrointestinal stromal tumor, and other malignancies. Scattered reports have suggested that these agents appear to affect blood glucose (BG). We retrospectively studied the BG concentrations in diabetic (17) and nondiabetic (61) patients treated with dasatinib (8), imatinib (39), sorafenib (23), and sunitinib (30) in our clinical practice. Mean declines of BG were dasatinib (53 mg/dL), imatinib (9 mg/dL), sorafenib (12 mg/dL), and sunitinib (14 mg/dL). All these declines in BG were statistically significant. Of note, 47% (8/17) of the patients with diabetes were able to discontinue their medications, including insulin in some patients. Only one diabetic patient developed symptomatic hypoglycemia while on sunitinib. The mechanism for the hypoglycemic effect of these drugs is unclear, but of the four agents tested, c-kit and PDGFRβ are the common target kinases. Clinicians should keep the potential hypoglycemic effects of these agents in mind; modification of hypoglycemic agents may be required in diabetic patients. These results also suggest that inhibition of a tyrosine kinase, be it c-kit, PDGFRβ or some other undefined target, may improve diabetes mellitus BG control and it deserves further study as a potential novel therapeutic option.


The secretion of ibuprofen metabolites interferes with the capillary chromatography of urinary homovanillic acid and 4-hydroxy-3-methoxymandelic acid in neuroblastoma diagnosis.
Neuroblastoma is the most common extracranial solid tumor in children. Abnormal secretion of catecholamines in tissues and body fluids allows for the differential diagnosis of neuroblastoma from other neoplasms and its distinction from non-neoplastic inflammatory diseases. This is achieved by assaying homovanillic acid and 4-hydroxy-3-methoxymandelic acid, the catabolites of catecholamine metabolism. In the course of an evaluation of children with suspected neuroblastoma, homovanillic acid and 4-hydroxy-3-methoxymandelic acid were analyzed in urine samples by capillary gas chromatography with flame ionization detection after extraction and derivatization of these compounds as trimethylsilyl derivatives. In three urine samples a significant increase in biogenic amines was observed, but these results were not confirmed by thin-layer chromatography. Patient history revealed that these children had been treated with ibuprofen, an analgesic and anti-inflammatory drug. To verify how ibuprofen or its metabolites may have interfered with capillary gas chromatography with flame ionization detection, we analyzed the same samples by capillary gas chromatography-mass spectrometry. In urine samples from patients on the drug, the presence of a peak identified as the trimethylsilyl ester of hydroxyibuprofen, which had the same retention time as 4-hydroxy-3-methoxymandelic acid, was found to interfere with the capillary gas chromatography with flame ionization detection analysis of the metabolite. This interference must be taken into account during the laboratory diagnosis of neuroblastoma.


Online tremor suppression using electromyography and low-level electrical stimulation.
Tremor is one of the most prevalent movement disorders. There is a large proportion of patients (around 25%) in whom current treatments do not attain a significant tremor reduction. This paper proposes a tremor suppression strategy that detects tremor from the electromyographic signals of the muscles from which tremor originates and counteracts it by delivering electrical stimulation to the antagonist muscles in an out of phase manner. The detection was based on the iterative Hilbert transform and stimulation was delivered above the motor threshold (motor stimulation) and below the motor threshold (sensory stimulation). The system was tested on six patients with predominant wrist flexion/extension tremor (four with Parkinson disease and two with Essential tremor) and led to an average tremor reduction in the range of 46%-81% and 35%-48% across five patients when using the motor and sensory stimulation, respectively. In one patient, the system did not attenuate tremor. These results demonstrate that tremor attenuation might be achieved by delivering electrical stimulation below the motor threshold, preventing muscle fatigue and discomfort for the patients, which sets the basis for the development of an alternative treatment for tremor.


Rash and Mucositis Associated With Mycoplasma pneumoniae and Chlamydophila pneumoniae: A Recurrence of MIRM?
A new concept has come to light recently, that is, Mycoplasma-induced rash and mucositis (MIRM). Here, we report the first case of recurrent rash, mucositis, and conjunctivitis involving Mycoplasma pneumoniae and C. pneumoniae that fits under the criteria of what is currently defined as MIRM. A patient aged 12 years with a history of recurrent aphthous ulcers presented in 2013 with worsening oral lesions, conjunctivitis, and vesicular rash. Her respiratory polymerase chain reaction (PCR) panel was positive for M. pneumoniae. She was diagnosed with Stevens-Johnson syndrome (SJS) secondary to M. pneumoniae and treated with a macrolide, acyclovir, and intravenous immunoglobulin (IVIG). The same patient returned 3 years later with an identical constellation of symptoms, at which time her PCR was positive for C. pneumoniae. In addition to IVIG and a macrolide, a corticosteroid treatment was administered. Here, we present the case of a pediatric patient with a recurrence of mucocutaneous disease that is more consistent with MIRM than the proposed SJS or erythema multiforme (EM) documented via histology. Our patient's symptoms were controlled with azithromycin and IVIG and, in the second episode, with corticosteroids as well. This case adds to that of Mayor-Ibarguren et al, providing further evidence that C. pneumonia may also be a trigger for MIRM. Patients will benefit from expanding the definition of MIRM, as the pathogenesis differs from SJS and EM and could result in more specific treatment options.


Mosaic deletion of EXOC6B: further evidence for an important role of the exocyst complex in the pathogenesis of intellectual disability.
We describe a boy with developmental delay, speech delay, and minor dysmorphic features with a heterozygous de novo ∼460 kb deletion at 2p13.2 involving only parts of EXOC6B present in about 50% of lymphocytes. This widely expressed gene encodes the exocyst component 6B, which is part of a multiprotein complex required for targeted exocytosis. Little is known about the effect of EXOC6B haploinsufficiency. In 2008, a patient with a complex syndromic phenotype, including left renal agenesis, neutropenia, recurrent pulmonary infections, long bone diaphysis broadening, growth retardation, and developmental delay (DD) was found to carry a de novo translocation t(2;7) involving TSN3 and EXOC6B. Further characterization of the translocation indicated that disruption of TSN3 may be responsible for the skeletal phenotype. Recently, a heterozygous deletion of EXOC6B along with a deletion of the CYP26B1 gene has been reported in a boy with intellectual disability, speech delay, hyperactivity, facial asymmetry, a dysplastic ear, brachycephaly, and mild joint contractures. Additionally, disruption of EXOC6B by a de novo balanced translocation t(2;8) has been described in a patient with developmental delay, epilepsy, autistic and aggressive behavior. This is the first report of a de novo deletion affecting only EXOC6B in an individual with developmental delay. In conclusion, based on our findings and recent data from the literature, there is evidence that EXOC6B and the exocyst complex might play an important role in the molecular pathogenesis of intellectual disability.


Asymtomatic Bacteriuria as a Model to Study the Coevolution of Hosts and Bacteria.
During asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract for extended periods of time without causing symptoms of urinary tract infection. Previous studies indicate that many Escherichia coli (E. coli) strains that cause ABU have evolved from uropathogenic E. coli (UPEC) by reductive evolution and loss of the ability to express functional virulence factors. For instance, the prototype ABU strain 83972 has a smaller genome than UPEC strains with deletions or point mutations in several virulence genes. To understand the mechanisms of bacterial adaptation and to find out whether the bacteria adapt in a host-specific manner, we compared the complete genome sequences of consecutive reisolates of ABU strain 83972 from different inoculated individuals and compared them with the genome of the parent strain. Reisolates from different hosts exhibited individual patterns of genomic alterations. Non-synonymous SNPs predominantly occurred in coding regions and often affected the amino acid sequence of proteins with global or pleiotropic regulatory function. These gene products are involved in different bacterial stress protection strategies, and metabolic and signaling pathways. Our data indicate that adaptation of E. coli 83972 to prolonged growth in the urinary tract involves responses to specific growth conditions and stresses present in the individual hosts. Accordingly, modulation of gene expression required for survival and growth under stress conditions seems to be most critical for long-term growth of E. coli 83972 in the urinary tract.


Efficient optimization of crystallization conditions by manipulation of drop volume ratio and temperature.
An efficient optimization method for the crystallization of biological macromolecules has been developed and tested. This builds on a successful high-throughput technique for the determination of initial crystallization conditions. The optimization method takes an initial condition identified through screening and then varies the concentration of the macromolecule, precipitant, and the growth temperature in a systematic manner. The amount of sample and number of steps is minimized and no biochemical reformulation is required. In the current application a robotic liquid handling system enables high-throughput use, but the technique can easily be adapted in a nonautomated setting. This method has been applied successfully for the rapid optimization of crystallization conditions in nine representative cases.


Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm.
Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria. An 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31). CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.


Germline and somatic mutations in homologous recombination genes among Chinese ovarian cancer patients detected using next-generation sequencing.
To define genetic profiling of homologous recombination (HR) deficiency in Chinese ovarian cancer patients. we have applied next-generation sequencing to detect deleterious mutations through all exons in 31 core HR genes. Paired whole blood and frozen tumor samples from 50 Chinese women diagnosed with epithelial ovarian carcinomas were tested to identify both germline and somatic variants. Deleterious germline HR-mutations were identified in 36% of the ovarian cancer patients. Another 5 patients had only somatic mutations. BRCA2 was most frequently mutated. Three out of the 5 somatic mutations were in RAD genes and a wider distribution of other HR genes was involved in non-serous carcinomas. BRCA1/2-mutation carriers had favorable platinum sensitivity (relative risk, 1.57, p<0.05), resulting in a 100% remission probability and survival rate. In contrast, mutations in other HR genes predicted poor prognosis. However, multivariate analysis demonstrated that platinum sensitivity and optimal cytoreduction were the independent impact factors influencing survival (hazards ratio, 0.053) and relapse (hazards ratio, 0.247), respectively. our results suggest that a more comprehensive profiling of HR defect than merely BRCA1/2 could help elucidate tumor heterogeneity and lead to better stratification of ovarian cancer patients for individualized clinical management.


Altered cytokine production by specific human peripheral blood cell subsets immediately following space flight.
In this study, flow cytometry was used to positively identify the specific lymphocyte subsets exhibiting space flight-induced alterations in cytokine production. Whole blood samples were collected from 27 astronauts at three points (one preflight, two postflight) surrounding four space shuttle missions. Assays performed included serum/urine stress hormones, white blood cell (WBC) phenotyping, and intracellular cytokine production following mitogenic stimulation. Absolute levels of peripheral granulocytes were significantly elevated following space flight, but the levels of circulating lymphocytes and monocytes were unchanged. Lymphocyte subset analysis demonstrated a decreased percentage of T cells, whereas percentages of B cells and natural killer (NK) cells remained unchanged after flight. Nearly all the astronauts exhibited an increased CD4/CD8 T cell ratio. Assessment of naive (CD45RA+) vs. memory (CD45RO+) CD4+ T cell subsets was ambiguous, and subjects tended to group within specific missions. Although no significant trend was seen in absolute monocyte levels, a significant decrease in the percentage of the CD14+ CD16+ monocytes was seen following space flight in all subjects tested. T cell (CD3+) production of interleukin-2 (IL-2) was significantly decreased after space flight, as was IL-2 production by both CD4+ and CD8+ T cell subsets. Production of interferon-gamma (IFN-gamma) was not altered by space flight for the CD8+ cell subset, but there was a significant decrease in IFN-gamma production for the CD4+ T cell subset. Serum and urine stress hormone analysis indicated significant physiologic stresses in astronauts following space flight. Altered peripheral leukocyte subsets, altered serum and urine stress hormone levels, and altered T cell cytokine secretion profiles were all observed postflight. In addition, there appeared to be differential susceptibility to space flight regarding cytokine secretion by T cell subsets. These alterations may be the result of either microgravity exposure or the physiologic stresses of landing and readaptation to unit gravity. Future studies, including in-flight analysis or sampling, will be necessary to determine the cause of these alterations.


Qualitative ultrasonography scale of the intensity of local twitch response during dry needling and its association with modified joint range of motion: a cross-sectional study.
The relevance of local twitch response (LTR) during dry needling technique (DNT) is controversial, and it is questioned whether LTR is necessary for successful outcomes. Furthermore, because the LTR during the deep DNT may be evoked with different intensities, it is unknown whether the magnitude of LTR intensity is associated with optimal clinical results, especially concerning to the effects of joint maximal range of motion (ROM). This study aimed to (i) determine whether visual inspections can quantify the LTR intensity during the DNT through a qualitative ultrasonography scale of LTR intensity (US-LTR scale), and (ii) assess the differences of US-LTR scale associated with changes in the maximal joint ROM. Using a cross-sectional design, seven asymptomatic individuals were treated with DNT in the latent myofascial trigger point in both medial gastrocnemius muscles. During DNT, three consecutive LTRs were collected. The US-LTR scale was used to classify the LTRs into strong, medium, and weak intensities. The categories of US-LTR were differentiated by the velocity of LTRs using the optical flow algorithm. ROM changes in ankle dorsiflexion and knee extension were assessed before and immediately after DNT. The US-LTR scale showed the third LTR was significantly smaller than the first one (p < 0.05). A significant difference in velocity was observed between US-LTR categories (p < 0.001). A significant difference in the ROM was observed between the strong and weak-medium intensity (p < 0.05). The present findings suggest that the LTR intensity can be assessed using a qualitative US-LTR scale, and the effects of DNT on joint maximal ROM is maximized with higher LTR intensity. This study reports a novel qualitative method for LTR analysis with potential applications in research and clinical settings. However, further research is needed to achieve a broader application.


Anterior cervical plate stabilization in one- and two-level degenerative disease: overtreatment or benefit?
This consecutive case retrospective chart review of 356 patients compares the reoperation rate of one- and two-level anterior cervical discectomies for degenerative disease with and without anterior cervical plate stabilization (ACPS). A total of 210 patients underwent surgery without ACPS (bone alone) and 146 patients underwent surgery with the addition of ACPS. Follow-up ranged from 1 to 9 years. A total of 22 patients with one- or two-level cervical arthrodesis required a second surgical intervention (19 bone alone, 3 with ACPS). Reoperations were performed in the bone-alone group for pseudarthrosis in 12 cases and for progression of degenerative disease in 7 cases. The reoperations in the ACPS group were performed for pseudarthrosis in one case and settling of the graft with screw fracture before fusion in two cases. The log-rank test, which uses all patients and their total follow-up periods, was statistically significant in favoring ACPS (p = 0.05). Furthermore, the reoperation rate after 1 year was also significantly lower when ACPS was utilized compared with bone alone (p = 0.0308, Fisher's exact test, two tailed). These data provide evidence that the addition of ACPS in one- and two-level cervical degenerative disease does not constitute overtreatment but rather supplements the internal stabilization initially provided by the bone graft and yields a lower reoperation rate.


Harnessing the Reactivity of Duclauxin toward Obtaining hPTP1B1-400 Inhibitors.
Duclauxin (1) from Talaromyces sp. IQ-313 was reported as a putative allosteric modulator of human recombinant protein tyrosine phosphatase 1B (400 amino acids) (hPTP1B1-400), a validated target for the treatment of type II diabetes. Based on these findings, a one-strain-many-compound (OSMAC) experiment on the IQ-313 strain generated derivatives 5a, 6, and 7. Moreover, a one-/two-step semisynthetic approach guided by docking toward hPTP1B1-400 produced 38 analogs, a series (A) incorporating a lactam functionalization at C-1 (8a-15a, 36a, and 37a) and a series (B) containing a lactam at C-1 and an extra unsaturation between C-7 and C-8 (5b, 11b-37b). In vitro evaluation and structure-activity relationship (SAR) analysis revealed that analogs from the B series are up to 10-fold more active than 1 and derivatives from the A series. Furthermore, duclauxin (1) and 36b were assessed for their potential acute toxicity, estimating their LD50 to be higher than 300 mg/kg. Moreover, 36b significantly reduced glycemia in an insulin tolerance test in mice, suggesting that its mechanism of action is through the PTP1B inhibition.


Shape matching of two-dimensional objects.
In this paper we present results in the areas of shape matching of nonoccluded and occluded two-dimensional objects. Shape matching is viewed as a ``segment matching'' problem. Unlike the previous work, the technique is based on a stochastic labeling procedure which explicitly maximizes a criterion function based on the ambiguity and inconsistency of classification. To reduce the computation time, the technique is hierarchical and uses results obtained at low levels to speed up and improve the accuracy of results at higher levels. This basic technique has been extended to the situation where various objects partially occlude each other to form an apparent object and our interest is to find all the objects participating in the occlusion. In such a case several hierarchical processes are executed in parallel for every object participating in the occlusion and are coordinated in such a way that the same segment of the apparent object is not matched to the segments of different actual objects. These techniques have been applied to two-dimensional simple closed curves represented by polygons and the power of the techniques is demonstrated by the examples taken from synthetic, aerial, industrial and biological images where the matching is done after using the actual segmentation methods.


[Diagnostic approach in mechanical jaundice, complicated by purulent cholangitis].
Up-to-date high-informative non-invasive diagnostic methods were used in 54 patients with obstructive jaundice (OJ) complicated by purulent cholangitis (PC). Treatment-diagnostic algorithm can to improve results of diagnosis. This algorithm is the following: ultrasonic examination as a screening method; if a case of jaundice is unclear and obturation is prolonged magnetic-resonance tomography and magnetic-resonance cholangiopancreaticography are carried out; in block of a distal part of the common bile duct--spiral computed tomography with bolus amplification and duodenoscopy. Invasive diagnostic methods--endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography (PTCG) are performed in buit indications in possibility to perform lithextraction and effective endoscopic decompression or in the tumor of Vater's papilla in case of low block. PTCG is used in high block and finished by percutaneous transhepatic bile outflow. General diagnostic efficacy of the complex in OJ was 97.8%. Diagnostic algorithm permitted us to make diagnosis and to start treatment in 85% during 1-2 days after hospitalization. Bile ducts decompression as a main stage of PC treatment was performed in the first 2 days after hospitalization. Diagnostic quest was performed at the same time with therapy after detoxication and correction of hemostasis disturbances.


Effect of crosslinking on the mechanical properties of mineralized and non-mineralized collagen fibers.
Problems associated with current bone substitutes led to an increased interest in tissue engineered surrogates with properties similar to natural bones. Commonly used materials lack the ultimate mechanical properties. In this study, we examined the influence of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) as a crosslinking agent on the strength of collagen fibers. Collagen fibers are crosslinked with EDC, or EDC/N-hydroxysulfosuccinimide (Sulfo-NHS) in water or EDC in acetone. After which fibers are mineralized using calcium chloride and potassium phosphate. The mechanical properties of the treated fibers are measured using tensile testing. In addition, the effect of crosslinking on cellular behavior was tested by culturing bone marrow mesenchymal stem cells (BMMSCs) on modified fibers. We found that the mechanical properties of non-mineralized and mineralized collagen fibers are significantly affected by the crosslinking method. The tensile strength of single fibers is greatly improved by crosslinking with EDC in acetone. BMMSCs were found to attach and spread well on modified fibers confirming biocompatibility.


Congenital Infantile Fibrosarcoma in the Premature Infant.
Congenital infantile fibrosarcoma (CIF) is rare and represents less than 1% of all childhood cancers. It is a tumor that originates in the connective fibrous tissue found at the ends of long bones and then spreads to other surrounding soft tissues. These lesions are typically large, grow rapidly, and can often be mistaken for teratomas. Diagnosis is confirmed by pathology, where cellular proliferation of fibroblasts occurs. Imaging is an important part of the diagnosis, which includes the use of magnetic resonance imaging and/or computed tomography scan. Although surgical resection is the primary treatment, chemotherapeutic agents may be used as adjuvant therapy. To describe modalities for accurate diagnosis and treatment of CIF. PubMed was searched using terms "congenital infantile fibrosarcoma" and "infantile fibrosarcoma." Eleven relevant, English language articles were identified and utilized in the preparation of this case presentation. Complications addressed in this case presentation are prenatal diagnostic challenges, pharmacologic interventions in the setting of prematurity, immunosuppression, and acute liver and renal failure. Pharmacologic treatments will include chemotherapy agents, antimicrobial agents, as well as granulocyte colony-stimulating factor for immunosuppression. Nursing challenges included positioning and integumentary disturbances. Utilization of diagnostic imaging and pathology to accurately identify and diagnose CIF is essential. Safety and efficacy of chemotherapeutic agents in premature infants with CIF need to be established.


Bio-inspired formation of functional calcite/metal oxide nanoparticle composites.
Biominerals are invariably composite materials, where occlusion of organic macromolecules within single crystals can significantly modify their properties. In this article, we take inspiration from this biogenic strategy to generate composite crystals in which magnetite (Fe3O4) and zincite (ZnO) nanoparticles are embedded within a calcite single crystal host, thereby endowing it with new magnetic or optical properties. While growth of crystals in the presence of small molecules, macromolecules and particles can lead to their occlusion within the crystal host, this approach requires particles with specific surface chemistries. Overcoming this limitation, we here precipitate crystals within a nanoparticle-functionalised xyloglucan gel, where gels can also be incorporated within single crystals, according to their rigidity. This method is independent of the nanoparticle surface chemistry and as the gel maintains its overall structure when occluded within the crystal, the nanoparticles are maintained throughout the crystal, preventing, for example, their movement and accumulation at the crystal surface during crystal growth. This methodology is expected to be quite general, and could be used to endow a wide range of crystals with new functionalities.


Cancer in 2023.
Excerpts from the 13th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to U.S. Congress and the public highlight current challenges in achieving the goal of the Cancer Moonshot to reduce the cancer death rate in the United States by 50% by 2047 and a call to action for robust, sustained support of medical research funding is issued.


Computer application in a general practice.
Computer application in General Practice has improved the standard of healthcare. Computers have been used in the clinic for general administration and accounting. A Clinic Management System in addition can be used in most of the functions required in the running of a clinic. It will be able to generate useful data to help the doctors make sound decisions based on valid, up-to-date information. Communications and accessing of medical databases can be made available with a central network such as MediNet. There are currently no well developed medical record management systems suitable enough for implementation in general practice. Computerisation of the general practice will require careful planning and gradual implementation using a reliable application software backed by good support from the original developer. Commitment to continued research and development of the software will ensure that the implemented system will not be outdated.


Increased shark bite survivability revealed by two centuries of Australian records.
The perceived and real threat of shark bites have significant direct health and indirect economic impacts. Here we assess the changing odds of surviving an unprovoked shark bite using 200 years of Australian records. Bite survivability rates for bull (Carcharhinus leucas), tiger (Galeocerdo cuvier) and white (Carcharodon carcharias) sharks were assessed relative to environmental and anthropogenic factors. Survivability of unprovoked bull, tiger and white shark bites were 62, 75 and 53% respectively. Bull shark survivability increased over time between 1807 and 2018. Survivability decreased for both tiger and white sharks when the person was doing an in water activity, such as swimming or diving. Not unsurprisingly, a watercraft for protection/floatation increased survivability to 92% from 30%, and 88% from 45%, for tiger and white sharks respectively. We speculate that survival may be related to time between injury and treatment, indicating the importance of rapid and appropriate medical care. Understanding the predictors of unprovoked bites, as well as survivability (year and water activity), may be useful for developing strategies that reduce the number of serious or fatal human-shark interactions without impacting sharks and other marine wildlife.


Evaluation of a decellularized bronchial patch transplant in a porcine model.
Biological scaffolds for airway reconstruction are an important clinical need and have been extensively investigated experimentally and clinically, but without uniform success. In this study, we evaluated the use of a decellularized bronchus graft for airway reconstruction. Decellularized left bronchi were procured from decellularized porcine lungs and utilized as grafts for airway patch transplantation. A tracheal window was created and the decellularized bronchus was transplanted into the defect in a porcine model. Animals were euthanized at 7 days, 1 month, and 2 months post-operatively. Histological analysis, immunohistochemistry, scanning electron microscopy, and strength tests were conducted in order to evaluate epithelialization, inflammation, and physical strength of the graft. All pigs recovered from general anesthesia and survived without airway obstruction until the planned euthanasia timepoint. Histological and electron microscopy analyses revealed that the decellularized bronchus graft was well integrated with native tissue and covered by an epithelial layer at 1 month. Immunostaining of the decellularized bronchus graft was positive for CD31 and no difference was observed with immune markers (CD3, CD11b, myeloperoxidase) at two months. Although not significant, tensile strength was decreased after one month, but recovered by two months. Decellularized bronchial grafts show promising results for airway patch reconstruction in a porcine model. Revascularization and re-epithelialization were observed and the immunological reaction was comparable with the autografts. This approach is clinically relevant and could potentially be utilized for future applications for tracheal replacement.


Family-Based Interventions Targeting Childhood Obesity: A Meta-Analysis.
With the rising prevalence of childhood obesity over the last several decades, and the call for more family-based intervention research to combat childhood obesity, it is important to examine the extant research on family-based interventions in order to make recommendations and improve future research. To conduct a meta-analysis of family-based interventions targeting childhood obesity in the last decade in order to inform the research in the next decade. A literature review was conducted between December 2009-April 2010. Studies published between the years 2000-2009 that used family-based interventions to treat childhood obesity were included. A total of 20 studies met inclusionary criteria. Although results varied by study design, the majority of studies had a moderate to large effect size for change in the target child's BMI (BMI percentile, zBMI, percent overweight) after participating in a family-based intervention. Long-term change varied by study, but the majority of studies produced sustainable change in child BMI, although smaller effect sizes. Change in secondary variables (dietary intake, sugar-sweetened beverage intake, physical activity) were substantially different between studies and are reported as trends. To date, there is preliminary evidence suggesting that family-based interventions targeting childhood obesity are successful in producing weight loss in the short and long-term. Including families in weight loss treatment of obese children warrants further implementation and study. Limitations with the research, recommendations for future research, and implications for practitioners working with overweight/obese children are discussed.


[Massage and health].
In this first article, the author, Dr. Sagrera Ferrandiz, introduces us to the most generic aspects of massage and its relationship with health. In order to do so, he carries out a historical review in the use of massage beginning with the Vedas, Hinduism's sacred texts, and ending in our days. In future articles, the author will deal with different types and uses of massage and their relationships with health.


Developmental trends in interpolation and its spatial constraints: A comparison of subjective and occluded contours.
We examined interpolation in 6- and 9-year-old children and in adults, in the two most common forms of fragmentation: subjective and partially occluded contours. Experiment 1 examined the effects on adults' interpolation of contour geometry, specifically, the effect of a scale-dependent factor (i.e., retinal size) and a scale-independent factor (i.e., support ratio). For both subjective and partially occluded contours, interpolation was affected more by support ratio than absolute size. However, subjective contours were less precisely interpolated and their interpolation was affected more by support ratio than was the case for partial occlusion. Experiment 2 used a subset of retinal size and support ratio levels in children and adults. Interpolation of both subjective and occluded contours improved significantly with age, with the two types of contours equally affected by spatial constraints during early childhood. However, while interpolation of occluded contours became more precise with age and less dependent on support ratio by adulthood, interpolation of subjective contours was less improved and became even more tied to support ratio in adulthood. The implications of these differential age-related changes in the spatial constraints on interpolation of the two types of contours for the mechanisms of perceptual completion are discussed.


Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies.
Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.


Mozart versus new age music: relaxation states, stress, and ABC relaxation theory.
Smith's (2001) Attentional Behavioral Cognitive (ABC) relaxation theory proposes that all approaches to relaxation (including music) have the potential for evoking one or more of 15 factor-analytically derived relaxation states, or "R-States" (Sleepiness, Disengagement, Rested / Refreshed, Energized, Physical Relaxation, At Ease/Peace, Joy, Mental Quiet, Childlike Innocence, Thankfulness and Love, Mystery, Awe and Wonder, Prayerfulness, Timeless/Boundless/Infinite, and Aware). The present study investigated R-States and stress symptom-patterns associated with listening to Mozart versus New Age music. Students (N = 63) were divided into three relaxation groups based on previously determined preferences. Fourteen listened to a 28-minute tape recording of Mozart's Eine Kleine Nachtmusik and 14 listened to a 28-minute tape of Steven Halpern's New Age Serenity Suite. Others (n = 35) did not want music and instead chose a set of popular recreational magazines. Participants engaged in their relaxation activity at home for three consecutive days for 28 minutes a session. Before and after each session, each person completed the Smith Relaxation States Inventory (Smith, 2001), a comprehensive questionnaire tapping 15 R-States as well as the stress states of somatic stress, worry, and negative emotion. Results revealed no differences at Session 1. At Session 2, those who listened to Mozart reported higher levels of At Ease/Peace and lower levels of Negative Emotion. Pronounced differences emerged at Session 3. Mozart listeners uniquely reported substantially higher levels of Mental Quiet, Awe and Wonder, and Mystery. Mozart listeners reported higher levels, and New Age listeners slightly elevated levels, of At Ease/Peace and Rested/Refreshed. Both Mozart and New Age listeners reported higher levels of Thankfulness and Love. In summary, those who listened to Mozart's Eine Kleine Nachtmusik reported more psychological relaxation and less stress than either those who listened to New Age music or read popular recreational magazines. Results suggest the usefulness of ABC relaxation theory in comparing the different effects of music and relaxation techniques.


On the evolution of task-based analysis of manual materials handling, and its applicability in contemporary ergonomics.
The industrial revolution significantly changed the way work was organized and analyzed by the introduction and widespread implementation of the division of labor philosophy. This philosophy has continued to dominate work design, and has evolved beyond the factory to include many facets of service industries, and even professional occupations. The analysis of manual work, particularly materials handling tasks, remains an active domain of ergonomics research and practice. Many of the task-analytic tools used for workplace analysis are rooted in the philosophy of dividing work into elements, analyzing the individual elements, and synthesizing the results into conclusions about the entire job, including the risk of contracting musculoskeletal disorders (MSDs). The authors discuss the notion that the nature of modern work, which is characterized by multiple tasks in a complex time pattern, and the complex nature of MSDs, which are influenced by biomechanical as well as psychological, political, and economic factors, may limit the effectiveness of classical task analytic techniques in preventing MSDs.


Sociocultural factors perpetuating the practices of early marriage and childbirth in Sylhet District, Bangladesh.
The practice of adolescent marriage continues in communities throughout Bangladesh, with adolescent childbearing a common result. This early childbearing is associated with increased medical risks for both mothers and their newborns. Because of the need to understand the persistence of these behaviors in spite of the risks, various qualitative research methods were used to identify and better understand the various socio cultural factors perpetuating the practices of early marriage and childbirth. Delaying the first birth after marriage can cause rumors of infertility, bring shame on the family, and in some cases lead the husband's family to seek another wife for their son. In addition, social stigma for childless women, emigration of husbands, and the belief that using modern contraceptives prior to the birth of the first child results in infertility also inhibits couples from delaying their first pregnancy. Future efforts to promote delay in marriage and subsequent early childbearing should focus on allaying the fears of infertility related to delay in childbearing or secondary to contraceptive use, both for newly married couples and household decision-makers such as mothers-in-law.


Spontaneous and pronase-induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines.
A subgroup of HER2-overexpressing breast tumours co-expresses p95(HER2), a truncated HER2 receptor that retains a functional HER2 kinase domain but lacks the extracellular domain, thus impairing trastuzumab binding. We evaluated p95(HER2) expression in 99 frozen breast carcinoma samples by western blot analysis. The HER2-positive cell line BT474 treated with pervanadate or pronase was used as a positive control for p95(HER2) expression. Immunohistochemistry was performed on parallel formalin-fixed, paraffin-embedded sections of the same case series using antibodies directed against either the intra- or extra-cellular binding domain of HER2. In particular, biotinylated trastuzumab (BiotHER) was used to evaluate the binding capacity of the humanized antibody. To avoid a subjective evaluation of the score values and the percentage of immunostained cells, the slides were scanned and automatically analysed. The number of cases with HER2 overexpression (score 3+) and HER2 gene amplification was higher in the p185(HER2)-positive/p95(HER2)-positive samples than in the p185(HER2)-positive/p95(HER2)-negative group. Automated analysis confirmed a significantly higher percentage of 3+ scored cells in p95(HER2)-positive cases. Conversely, the percentage of 2+ scored cells was higher inp95(HER2)-negative cases. The status of the HER2 extracellular domain was then studied using flow cytometry on BT474 cells after pronase enzymatic digestion using trastuzumab and pertuzumab, while the presence of HER2-HER3 dimers was studied using a proximity-ligation assay. In vitro experiments showed that short-term pronase digestion of BT474 cells produced two HER2 fragments (of 95 and 150 kDa, detectable in tissue specimens as well), increased the binding affinity of trastuzumab, reduced the rate of HER2-HER3 dimers, and did not interfere with pertuzumab-binding capacity. In conclusion, the presence of p95(HER2 as detected by western blot analysis does not compromise the immunohistochemical detection of HER2. Our data suggest that a reduction of the receptor steric hindrance as induced by enzymatic shedding may facilitate the binding capacity of trastuzumab.


Hydrogen-rich medium protects human skin fibroblasts from high glucose or mannitol induced oxidative damage.
Reactive oxygen species (ROS) are an important factor in the development of skin lesions in diabetes. A new antioxidant, hydrogen, can selectively neutralize hydroxyl radicals (()OH) and peroxynitrite (ONOO(-)) in cell-free systems, whereas it seldom reacts with other ROS. Fibroblasts are a key component of skin. In the present study, we investigated the protective effects of hydrogen-rich medium on human skin fibroblasts (HSFs) under oxidative stress. Confocal microscopy was used to assay both the intracellular superoxide anion (O(2)(-)) concentration and the mitochondrial membrane potential (ΔΨ). Cell viability was determined using the Cell Counting Kit-8 (CCK-8). The concentrations of cellular malonaldehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 3-nitrotyrosine (3-NT) were also measured. The results revealed that both mannitol and high glucose could cause oxidative stress in HSFs. Interestingly, the use of a hydrogen-rich medium significantly reduced the level of intracellular O(2)(-), stabilized the ΔΨ and attenuated production of MDA, 8-OHdG and 3-NT which efficiently enhanced the antioxidative defense system and protected the HSFs from subsequent oxidative stress damage. In other words, hydrogen decreased the excessive generation of intracellular O(2)(-) and elevated the cellular antioxidative defense. Based on our results, hydrogen may have applications in the treatment of skin diseases caused by diabetes.


Synthesis of two glucagon antagonists: receptor binding, adenylate cyclase, and effects on blood plasma glucose levels.
In diabetes mellitus, hyperglycemia is often associated with elevated levels of glucagon in the blood. This suggests that glucagon is a contributing factor in the metabolic abnormalities of diabetes mellitus. A glucagon-receptor antagonist would provide direct evidence for glucagon's role in diabetes mellitus. On the basis of careful consideration of conformational, amphiphilic, and structural factors, we have synthesized two new glucagon analogues with antagonist biological activities by using solid-phase methodology. These two new analogues, [Asp3,D-Phe4,Ser5,Lys17,18,Glu21]glucagon (2) and [D-Phe4,Tyr5,3,5-I2-Tyr10,Arg12,Lys17,18,G lu21]glucagon (3) had IC50 values 5.4% and 50% those of glucagon, respectively, and showed no measurable adenylate cyclase activity. When tested in normal rats, 2 lowered plasma glucose levels and suppressed glucagon-mediated hyperglycemia 105 +/- 8%, back to basal levels. Analogue 3, which lowered the basal adenylate cyclase activity in rat liver plasma membranes, increased plasma glucose levels at very high concentration in vivo and inhibited glucagon-mediated hyperglycemia in normal rats by 50%. However, neither of the new glucagon antagonists lowered the plasma glucose levels of diabetic animals. The data would suggest these new glucagon-receptor antagonists may have two actions: (a) in normal rats they can act as standard glucagon-receptor inhibitors of glucagon-mediated glycogenolysis; (b) in diabetic rats, however, because of the low levels of glycogen in the liver, the antagonists apparently have little or no antagonist effect or enhancement on glucagon-mediated glucose production.


Effects of vitamin E and alpha-lipoic acid on skeletal muscle contractile properties.
Initial experiments were conducted using an in situ rat tibialis anterior (TA) muscle preparation to assess the influence of dietary antioxidants on muscle contractile properties. Adult Sprague-Dawley rats were divided into two dietary groups: 1) control diet (Con) and 2) supplemented with vitamin E (VE) and alpha-lipoic acid (alpha-LA) (Antiox). Antiox rats were fed the Con rats' diet (AIN-93M) with an additional 10,000 IU VE/kg diet and 1.65 g/kg alpha-LA. After an 8-wk feeding period, no differences existed (P > 0.05) between the two dietary groups in maximum specific tension before or after a fatigue protocol or in force production during the fatigue protocol. However, in unfatigued muscle, maximal twitch tension and tetanic force production at stimulation frequencies < or = 40 Hz were less (P < 0.05) in Antiox animals compared with Con. To investigate which antioxidant was responsible for the depressed force production, a second experiment was conducted using an in vitro rat diaphragm preparation. Varying concentrations of VE and dihydrolipoic acid, the reduced form of alpha-LA, were added either individually or in combination to baths containing diaphragm muscle strips. The results from these experiments indicate that high levels of VE depress skeletal muscle force production at low stimulation frequencies.


Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype.
Expansions of the noncoding GGGGCC hexanucleotide repeat in the Chromosome 9 open reading frame 72 (C9ORF72) gene cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study we aimed to determine whether the length of the normal-unexpanded-allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS, and 160 FTD-ALS patients, and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or nonmutation carriers.


[Adipokines and liver function in patients with nonalcoholic fatty liver disease, type 2 diabetes mellitus and its combination].
The aim of the study was to assess the links between leptin, resistin and tumor necrosis factor-alpha (TNF-α) and indexes of the functional liver condition in patients with non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (DM 2) and with its combination. It were examined 110 patients: 20 of them were with NAFLD, 20 patients with DM 2 and 70 patients with combined disorders (NAFLD+ DM 2), which were divided into 2 subgroups -20 patients with normal body weight and 50 patients with obesity (body mass index ≥ 30 kg/m2). The control group included 20 healthy individuals. It was a complex clinical, laboratory (with definition of indexes of protein, pigment, enzyme and carbohydrate metabolism, levels of adipokines) and instrumental (ultrasound of the liver and liver biopsy (for 8 patients)) investigation. It was shown a significant increase of plasma levels of leptin, resistin, TNF-α in patients with this combined pathology. It was established the significant correlations between leptin, resistin, TNF-α and indexes of functional liver condition in these patients. In patients with NAFLD, DM 2 and with its combination, particularly with concomitant obesity, there is an imbalance of the products of adipose tissue, which sign is increasing of leptin, resistin and TNF-α. Relationships between leptin, resistin, TNF-α and indexes of the functional liver condition mainly in subgroup 3-b would give a reason to believe that obesity is activated and compounded te hormone-metabolic disorders that affect liver function.


Characterization and expression of the odorant-binding protein 7 gene in Anopheles stephensi and comparative analysis among five mosquito species.
Odorant-binding proteins (OBPs) are important molecular players in insect olfaction, which has a great influence on the host-seeking behaviour of mosquitoes and other disease vectors. The mRNA level of the Anopheles gambiae Obp7 gene (Agam-Obp7) is higher in the adult female antennae and is slightly reduced in the female heads after blood-feeding. Here we report the cloning, sequencing, chromosomal mapping and transcript analysis of Aste-Obp7, the Obp7 gene from the Asian malaria mosquito Anopheles stephensi. Quantitative reverse transcription PCR showed that in adult female mosquitoes, Aste-Obp7 was expressed abundantly in the antennae, much less in pooled maxillary palp and proboscis and at the lowest level in the legs. The Aste-Obp7 level in female antennae was significantly higher than in male antennae and it slightly increased 24 h after a bloodmeal. The same pattern held for leg samples as well. The Aste-Obp7 mRNA level dropped more than 10-fold in the female maxillary palp and proboscis after a bloodmeal, although it was still significantly higher than in the males. Together, the above expression profiles suggest that Aste-Obp7 probably functions in female olfaction and may possibly be involved in behaviour related to blood-feeding. We also characterized the Obp7 gene from Anopheles quadriannulatus. Comparison among Anopheles Obp7 genes revealed conserved noncoding sequences that contain potential regulatory elements. The coding sequence and gene structure of Obp7 as well as local synteny of surrounding genes are conserved among the three Anopheles species and two divergent mosquitoes, Aedes aegypti and Culex pipiens quinquefasciatus. OBP7 protein phylogeny is congruent with the mosquito phylogeny and there is evidence of purifying selection acting on the mosquito Obp7 gene. Comparative genomics analysis will improve our understanding of the evolution and regulation of genes involved in mosquito olfaction.


[Osteotomy techniques close to the knee. Effect on wedge volume and bony contact surface].
Bone geometry following osteotomy around the knee suggests that biplanar rather than uniplanar open wedge techniques simultaneously create smaller wedge volumes and larger bone surface areas. However, precise data on the bone surface area and wedge volume resulting from both open and closed wedge high tibial osteotomy (HTO) and distal femoral osteotomy (DFO) techniques remain unknown. It was hypothesized that biplanar rather than uniplanar osteotomy techniques better reflect the ideal geometrical requirements for bone healing, representing a large cancellous bone surface combined with a small wedge volume. Tibial and femoral artificial bones were assigned to four different groups of valgisation and varisation osteotomy consisting of open wedge and closed wedge techniques in a uniplanar and biplanar fashion. Bone surface areas of all osteotomy planes were quantified. Wedge volumes were determined using a prism-based algorithm and applying standardized wedge heights of 5 mm, 10 mm and 15 mm. Both femoral and tibial biplanar osteotomy techniques created larger contact areas and smaller wedge volumes compared to the uniplanar open wedge techniques. Although this idealized geometrical view of bony geometry excludes all biological factors that might influence bone healing, the current data suggest a general rule for the standard osteotomy techniques applied and all surgical modifications: reducing the amount of slow gap healing and simultaneously increasing the area of faster contact healing may be beneficial for osteotomy healing. Thus, biplanar rather than uniplanar osteotomy should be performed for osteotomy around the knee.


Intracellular Toll-Like Receptors Modulate Adaptive Immune Responses in Head and Neck Cancer.
The percentage of head and neck cancer (HNC) positive for human papillomavirus (HPV) is unknown in most parts of India. How toll-like receptors (TLRs) affect the adaptive immune response in HNC is also mainly unknown. We here assessed the expressions of HPV DNA, p16, inflammation, and TLRs in oral squamous cell carcinoma (OC) and oropharyngeal squamous cell carcinoma (OPC). Patients with OC (n = 31) and OPC (n = 41), diagnosed during 2017-2018 at the Malabar Cancer Centre (tertiary cancer center), Kerala, India, were included in the study. Immunohistochemistry was performed on tumor specimens against p16, TLR3, TLR7, TLR8, TLR9, CD4, and CD8. Quantitate polymerase chain reaction for 14 high-risk HPVs (HPV16/18/31/33/35/39/45/51/52/56/58/59/66/68) was performed. Seven out of 31 OC (22.6%) were p16+ but only 3.2% (1/31) of OC were positive for HPV DNA. While 24.4% (10/41) of OPC were p16+, HPV DNA was found in only one P16+ OPC and in no P16- OPC. TLR3, TLR7, TLR8, and TLR9 were expressed both in OC and in OPC. The expression of TLR7 was significantly higher in OPC compared with OC. TLR8 expression was correlated with and TLR7 tended to be correlated with the inflammatory score in OPC (r = 0.56, p < 0.05 and r = 0.52, p = 0.08, respectively). In conclusion, the role of HPV in OC and OPC is minor, and p16 constitutes a poor biomarker for HPV positivity in Kerala, India. Intracellular TLRs are correlated with the degree of inflammation in OPC but not in OC and may potentially constitute a medical target in the therapy of HNC in the future.


Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.
Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up.


Renal disease in patients with HIV infection: epidemiology, pathogenesis and management.
With the introduction of highly active antiretroviral therapy, we have witnessed prolonged survival with the potential for normal life expectancy in HIV-infected individuals. With improved survival and increasing age, HIV-infected patients are increasingly likely to experience co-morbidities that affect the general population, including kidney disease. Although HIV-associated nephropathy, the most ominous kidney disease related to the direct effects of HIV, may be prevented and treated with antiretrovirals, kidney disease remains an important issue in this population. In addition to the common risk factors for kidney disease of diabetes mellitus and hypertension, HIV-infected individuals have a high prevalence of other risk factors, including hepatitis C, cigarette smoking and injection drug use. Furthermore, they have exposures unique to this population, including antiretrovirals and other medications. Therefore, the differential diagnosis is vast. Early identification (through efficient screening) and definitive diagnosis (by kidney biopsy when indicated) of kidney disease in HIV-infected individuals are critical to optimal management. Earlier interventions with disease-specific therapy, often with the help of a nephrologist, are likely to lead to better outcomes. In those with chronic kidney disease, interventions, such as aggressive blood pressure control with the use of ACE inhibitors or angiotensin receptor antagonists where tolerated, tight blood glucose control in those with diabetes, and avoidance of potentially nephrotoxic medications, can slow progression and prevent end-stage renal disease. Only with greater awareness of kidney-disease manifestations and their implications in this particularly vulnerable population will we be able to achieve success in confronting this growing problem.


A Rare Presentation of Immunoglobulin A Nephropathy: Acute Kidney Injury.
Acute kidney injury (AKI) is known as an uncommon presentation in immunoglobulin A nephropathy (IgAN). The aim of our study was to analyze the clinical data and biopsy findings in IgAN patients presenting with AKI. We performed a retrospective analysis of all subjects who had biopsy-proven IgAN and presented with AKI during June 2002 September 2015. The following data were obtained from medical records. A total of 15 patients of 123 patients (12.2%) with primary IgAN admitted with AKI. Patients were generally male (73.3%), with a median age of 38 (interquartile range; IQR, 2,944) years. The serum creatinine at admission was above the normal range (median 2.3 [IQR, 2.14.7] mg/dL]). On histology, cellular/fibrocellular crescents were present in 6 patients. In most cases (53.3%), pathologic abnormalities associated with acute tubular injury/necrosis were defined. Red blood cell casts in tubules were present in 6 cases (40%). In all cases, interstitial mixed inflammatory cell infiltration was observed. In 4 cases, admixed eosinophils were also found. In 3 patients, biopsy specimens showed acute thrombotic microangiopathy lesions (20%). Median follow-up time was 13 (IQR, 346) months. Six patients (40%) progressed to end-stage renal disease (ESRD). Among patients diagnosed with primary IgAN and presenting without AKI, only 4 patients progressed to ESRD. The proportion of patients who progressed to ESRD presenting with AKI was significantly higher than the patients presenting without AKI (p = 0.000). In conclusion, AKI complicates IgAN more often.


Tolvaptan Reduces Long-Term Total Medical Expenses and Length of Stay in Aquaporin-Defined Responders.
The vasopressin type-2 antagonist tolvaptan (TLV) has clinical advantages including amelioration of congestion and normalization of hyponatremia in patients with decompensated heart failure (HF). However, there have been no studies on the cost-effectiveness of TLV therapy. We enrolled 60 consecutive hospitalized patients with stage D HF who received TLV [TLV (+) group], and 60 propensity score-matched HF patients without TLV treatment [TLV (-) group]. We excluded 54 patients who died or received cardiac replacement therapy within 1 year, and finally enrolled 32 patients who received TLV and 34 who did not, who were followed for > 1 year. Among 45 aquaporin-defined responders, whose urine aquaporin-2 relative to plasma arginine vasopressin level was > 1.4 × 10(3) L/g Cre, the TLV (+) group required significantly lower total medical expenses and shorter lengths of stay (LOS) compared with the TLV (-) group [11.2 (1.233.3) versus 31.2 (2.2-71.4) × 10(5) JPY/year, P < 0.001; 30 (0-304) versus 70 (20-221) days, P = 0.030]. In contrast, among the remaining 21 aquaporin-defined non-responders, medical expenses and LOS were comparable irrespective of TLV administration (P = 0.087 and P = 0.407). In conclusion, TLV therapy may reduce total medical expenses in aquaporin-defined responders with stage D HF.


From adversary to partner: have quality improvement organizations made the transition?
To describe the perceived impact of the Centers for Medicare and Medicaid Services Quality Improvement Organizations (QIOs) on quality of care for patients hospitalized with acute myocardial infarction, in the context of new efforts to work more collaboratively with hospitals in the pursuit of quality improvement. Primary data collected from a national random sample of 105 hospital quality management directors interviewed between January and July 2002. We interviewed quality management directors concerning their interactions with the QIO interventions, the helpfulness of QIO interventions and the degree to which they helped or hindered their hospital quality efforts, and their recommendations for improving QIO effectiveness. More than 90% of hospitals reported that their QIO had initiated specific interventions, the most common being the provision of educational materials, benchmark data, and hospital performance data. Many respondents (60%) rated most QIO interventions as helpful or very helpful, although only one-quarter of respondents believed quality of care would have been worse without the QIO interventions. To increase QIO efficacy, respondents recommended that QIOs appeal more directly to senior administration, target physicians (not just hospital employees), and enhance the perceived validity and timeliness of data used in quality indicators. Our study demonstrates that the QIOs have overcome, to some degree, the previously adversarial and punitive roles of Peer Review Organizations with hospitals. The generally positive view among most hospital quality improvement directors concerning the QIO interventions suggests that QIOs are potentially poised to take a leading role in promoting quality of care. However, the full potential of QIOs will likely not be realized until QIOs are able to engender greater engagement from senior hospital administration and physicians.


Potential Applications of NRF2 Modulators in Cancer Therapy.
The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) regulatory pathway plays an essential role in protecting cells and tissues from oxidative, electrophilic, and xenobiotic stress. By controlling the transactivation of over 500 cytoprotective genes, the NRF2 transcription factor has been implicated in the physiopathology of several human diseases, including cancer. In this respect, accumulating evidence indicates that NRF2 can act as a double-edged sword, being able to mediate tumor suppressive or pro-oncogenic functions, depending on the specific biological context of its activation. Thus, a better understanding of the mechanisms that control NRF2 functions and the most appropriate context of its activation is a prerequisite for the development of effective therapeutic strategies based on NRF2 modulation. In line of principle, the controlled activation of NRF2 might reduce the risk of cancer initiation and development in normal cells by scavenging reactive-oxygen species (ROS) and by preventing genomic instability through decreased DNA damage. In contrast however, already transformed cells with constitutive or prolonged activation of NRF2 signaling might represent a major clinical hurdle and exhibit an aggressive phenotype characterized by therapy resistance and unfavorable prognosis, requiring the use of NRF2 inhibitors. In this review, we will focus on the dual roles of the NRF2-KEAP1 pathway in cancer promotion and inhibition, describing the mechanisms of its activation and potential therapeutic strategies based on the use of context-specific modulation of NRF2.


Expression of immunoregulatory genes and its relationship to lead exposure and lead-mediated oxidative stress in wild ungulates from an abandoned mining area.
Lead (Pb) is a highly toxic metal that can induce oxidative stress and affect the immune system by modifying the expression of immunomodulator-related genes. The aim of the present study was to investigate the association between Pb exposure and the transcriptional profiles of some cytokines, as well as the relationship between Pb exposure and changes in oxidative stress biomarkers observed in the spleen of wild ungulates exposed to mining pollution. Red deer and wild boar from the mining area studied had higher spleen, liver, and bone Pb levels than controls, indicating a chronic exposure to Pb pollution. Such exposure caused a depletion of spleen glutathione levels in both species and disrupted the activity of antioxidant enzymes, suggesting the generation of oxidative stress conditions. Deer from the mining area also showed an induced T-helper (Th )-dependent immune response toward the Th 2 pathway, whereas boar from the mining area showed a cytokine profile suggesting an inclination of the immune response toward the Th 1 pathway. These results indicate that environmental exposure to Pb may alter immune responses in wild ungulates exposed to mining pollution. However, evidence of direct relationships between Pb-mediated oxidative stress and the changes detected in immune responses were not found. Further research is needed to evaluate the immunotoxic potential of Pb pollution, also considering the prevalence of chronic infectious diseases in wildlife in environments affected by mining activities.


The intramitochondrial volume measured using sucrose as an extramitochondrial marker overestimates the true matrix volume determined with mannitol.
The matrix volume of isolated liver and heart mitochondria has been estimated at various osmolarities and in various osmotic supports using 36Cl- and [14C]sucrose, D-mannitol, D-3-methoxyglucose and choline as extramitochondrial markers. The use of 3-methoxyglucose was only possible at 0 degree C since it entered mitochondria at physiological temperatures. All extramitochondrial markers used gave linear plots of apparent matrix volume against the reciprocal of the osmolarity, but the slope of this plot was greater when sucrose was used than with the other extramitochondrial markers. When extrapolated to infinite osmolarity the mean matrix volume was zero when mannitol was used, but about 0.6 microliter/mg of protein for sucrose and Cl- and -0.4 microliter/mg of protein when choline was used. At physiological osmolarity (about 330 m-osmol) the mean matrix volume of de-energized liver mitochondria in KCl medium estimated using mannitol was 0.46 microliter/mg of protein, whereas that obtained using sucrose was 1.68 microliters/mg of protein. Values in mannitol, choline and sucrose media were similar when mannitol but not sucrose was used as extramitochondrial marker. It is argued that the 3H2O/[14C]mannitol space more accurately reflects the true mitochondrial matrix volume than does the 3H2O/[14C]sucrose space. The consequences of this for measurements of the protonmotive force and the intramitochondrial concentration of metabolites are discussed.


Multiple sclerosis update.
Multiple sclerosis (MS) is the most common cause of neurological disability in young European and North American adults. It is defined as dysfunction in different parts of the central nervous system at different points in time. The etiology is likely autoimmune, resulting from environmental and genetic factors. This article summarizes the symptoms, progression, diagnosis, and treatment of MS. MRI and CSF studies have been extremely helpful in identifying individual cases, but the diagnosis remains a clinical diagnosis, and one of exclusion. Methylprednisolone remains the preferred treatment for acute relapses, although plasma exchange has been shown to be helpful in cases when methylprednisolone has failed. Preventive immunomodulatory treatments are the focus of many current research efforts. Although these treatments have been shown to reduce the frequency of MS attacks, the reduction is modest, at 30%. The data that these drugs alter the progression of disability is less compelling.


Effects of isolectin B4-conjugated saporin, a targeting cytotoxin, on bladder overactivity induced by bladder irritation.
In order to clarify the functional role of the isolectin B4 (IB4)-binding afferent pathway in the micturition reflex, we investigated the effects on bladder activity of intrathecal application of the IB4-saporin conjugate, a targeting cytotoxin that destroys neurons binding IB4. In rats, IB4-saporin (2.5 micro m) or vehicle was administered through an intrathecal catheter implanted at the level of the L6-S1 spinal cord. Three weeks after IB4-saporin administration, cystometry in conscious animals revealed a reduction in bladder overactive responses induced by intravesical capsaicin or ATP infusion without affecting normal voiding function. In histochemical studies, double staining for IB4 and saporin was detected in L6 dorsal root ganglia (DRG) neurons 2 days after the treatment. Three weeks after the treatment, the area in lamina II of the L6 spinal cord stained with IB4 was significantly reduced compared with the area stained in control rats. The staining in the L1 spinal cord was not affected. The percentage of neurons in the L6 DRG intensely labeled with IB4 was also reduced in IB4-saporin-treated rats. These results indicate that intrathecal treatment with the IB4-saporin conjugate at the level of L6-S1 spinal cord, which reduces IB4 afferent nerve terminal staining in lamina II of the L6 spinal cord as well as the number of IB4-binding neurons in L6 DRG, suppressed bladder overactivity induced by bladder irritation without affecting normal micturition. Thus targeting IB4-binding, non-peptidergic afferent pathways sensitive to capsaicin and adenosine 5'-triphosphate may be an effective treatment for overactivity and/or pain responses in the bladder.


Regulation of facilitative glucose transporters and AKT/MAPK/PRKAA signaling via estradiol and progesterone in the mouse uterine epithelium.
Adequate uterine glucose metabolism is an essential part of embryo implantation and the development of an adequate utero-fetal environment. However, expression of facilitative glucose transporters (GLUTs [solute transporter family SLC2A]) and AKT/MAPK/PRKAA (PRKAA) signaling has not been described in the mouse uterine cells, to our knowledge. The objective of this study was to determine the hormonal regulation of SLC2A protein expression and AKT/MAPK/PRKAA signaling in the mouse uterine epithelial cells during estrous cycles and peri-implantation periods. SLC2As 1, 4, 8, and 9B were highly expressed in the luminal and glandular epithelia of estrous stage. In metestrous and diestrous stages, expression of SLC2As 1, 4, 8, and 9B was lower than that in proestrous stage. Levels of activated phospho-AKT (p-AKT), p-MAPK3, and p-MAPK1 also varied during the estrous cycle. Estrogen and progesterone injection in an ovariectomized mouse (delayed implantation model) resulted in a decrease and an increase, respectively, in expression of GLUTs in the luminal epithelial cells of the uterus. The expression of SLC2A1, SLC2A8, SLC2A9B, p-AKT, p-MAPK3/1, and p-PRKAA was increased in the decidual region of the implantation sites and was significantly increased in the uterus of activated implantation. Using an artificial decidualization mouse model, it was also demonstrated that expression of the same GLUTs, p-MAPK3/1, and p-PRKAA was dramatically higher in the decidualized uteri than that in the control uteri. These results suggest that steroid hormones regulate expression of uterine epithelial GLUTs possibly through AKT/MAPK/PRKAA signaling pathways and that glucose utilization may have an important role in decidualization and possibly in the maintenance of pregnancy.


Interactions between color and luminance in the perception of orientation.
At the early stages of visual processing in humans and other primates, chromatic signals are carried to primary visual cortex (V1) via two chromatic channels and a third achromatic (luminance) channel. The sensitivities of the channels define the three cardinal axes of color space. A long-standing though controversial hypothesis is that the cortical pathways for color and form perception maintain this early segregation with the luminance channel dominating form perception and the chromatic channels driving color perception. Here we show that a simple interaction between orientation channels (the tilt illusion) is influenced by both chromatic and luminance mechanisms. We measured the effect of oriented surround gratings upon the perceived orientation of a test grating as a function of the axes of color space along which the gratings were modulated. We found that the effect of a surround stimulus on the perceived orientation of the test is largest when both are modulated along the same axis of color space, regardless of whether that is a cardinal axis. These results show that color and orientation are intimately coupled in visual processing. Further, they suggest that the cardinal chromatic axes have no special status at the level(s) of visual cortex at which the tilt illusion is mediated.


Endosomal entry regulates Notch receptor activation in Drosophila melanogaster.
Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that gamma-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation.


Prospective evaluation of safety of immune-cell therapy for patients with various types of advanced cancer.
Several types of immune-cell therapies, such as αβ T-cell, γδ T-cell, and dendritic cell (DC) vaccine therapies, are clinically employed for cancer treatment. The safety of immune-cell therapy for the treatment of patients with malignancies should be maintained by continuous assessment of adverse events. In the present study, we surveyed the adverse events associated with immune-cell therapy using large-scale prospective data and analyzed the side-effect profiles. For the assessment of adverse events associated with immune-cell therapy, we evaluated 771 treatment profiles (484 for αβ T-cell therapy, 58 for γδ T-cell therapy, 206 for DC vaccine therapy, and 23 for concurrent therapy with αβ T-cells and DC vaccines) from 144 patients with various malignancies. For the assessment of fever, fatigue, and itching, each of these adverse events was found to be grade 1 or 2 in most of the treated patients, except for one patient who had grade 3 itching. It was suggested that αβ T-cell therapy could elicit a more rapid and direct immune reaction in patients than DC vaccine therapy, as shown by the earlier development of fever and higher incidence rate of fatigue. It was found that grade 1 or 2 reaction at the injection site developed in 10.2% of the patients injected with DC vaccines. Most of the grade 3 non-hematological and hematological adverse events were associated with disease progression or side-effects of chemotherapy, and were not considered to be related to immune-cell therapy. In conclusion, immune-cell therapy, such as αβ T-cell, γδ T-cell, or DC vaccine therapy, was well-tolerated for cancer treatment.


coronaSPAdes: from biosynthetic gene clusters to RNA viral assemblies.
The COVID-19 pandemic has ignited a broad scientific interest in viral research in general and coronavirus research in particular. The identification and characterization of viral species in natural reservoirs typically involves de novo assembly. However, existing genome, metagenome and transcriptome assemblers often are not able to assemble many viruses (including coronaviruses) into a single contig. Coverage variation between datasets and within dataset, presence of close strains, splice variants and contamination set a high bar for assemblers to process viral datasets with diverse properties. We developed coronaSPAdes, a novel assembler for RNA viral species recovery in general and coronaviruses in particular. coronaSPAdes leverages the knowledge about viral genome structures to improve assembly extending ideas initially implemented in biosyntheticSPAdes. We have shown that coronaSPAdes outperforms existing SPAdes modes and other popular short-read metagenome and viral assemblers in the recovery of full-length RNA viral genomes. coronaSPAdes version used in this article is a part of SPAdes 3.15 release and is freely available at http://cab.spbu.ru/software/spades. Supplementary data are available at Bioinformatics online.


[Research advances on size selection and vault prediction of posterior chamber phakic intraocular lens].
Posterior chamber phakic intraocular lens (pIOL) implantation has been widely adopted for the correction of refractive errors. Among pIOLs, the Implantable Collamer Lens is the most common choice. The selection of the appropriate pIOL size and achieving the desired postoperative vault to minimize complications has consistently been a focal point in academic research. With the advancement of ophthalmic biometric measurement technology and the application of artificial intelligence in the field of medicine, numerous new technologies and methods for pIOL size selection and vault prediction have emerged in recent years. This paper provides a comprehensive review on the topic of how to choose the pIOL size and predict the vault.


Interchangeable Use of Proton Pump Inhibitors Based on Relative Potency.
Although proton pump inhibitors (PPIs) are widely used, their relative potency and ideal dosing regimens remain unclear. We analyzed data from randomized clinical trials that performed pH testing in patients receiving solid-dose PPI formulations (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) for a minimum of 5 days. We used omeprazole equivalency and the surrogate biomarker, percentage time pH > 4 over a 24-hour period (pH4time), to compare PPI effectiveness for different PPIs given once, twice, or 3 times daily. We found that increasing strength of once-daily PPIs (9-64 mg omeprazole equivalents) increased pH4time linearly from approximately 10.0 to 15.6 hours; higher doses produced no further increase in pH4time. Increasing the frequency to twice-daily PPI increased pH4time linearly, from approximately 15.8 to 21.0 hours. Three-times daily PPIs performed similarly to twice-daily PPIs. The costs of PPIs varied greatly, but the cost variation was not directly related to potency. We conclude that PPIs can be used interchangeably based on potency. Using twice-daily PPIs is more effective in increasing efficacy increasing once-daily PPI dosage. Omeprazole and lansoprazole (30 mg) and 20 mg of esomeprazole rabeprazole are functionally equivalent.


Comparison of pediatric Clarion recipients with and without the electrode positioner.
To compare surgical experience and measures of electrode and patient performance of children who were implanted with the Clarion (Advanced Bionics, Sylmar, CA, U.S.A.) device with and without the new electrode positioner (EP). Prospectively and retrospectively collected data were compared between two independent groups. Tertiary care children's hospital. Twenty-four children (mean age, 3.0 years) implanted during the original Food and Drug Administration (FDA) clinical trial required for commercial approval of the Clarion and 15 children (mean age, 3.4 years) implanted with the EP as part of an ongoing FDA trial. Cochlear implant with and without EP. Electrical psychophysical threshold, most comfortable loudness level (MCL), electrode impedance, and speech perception measures were compared at 3 and 6 months after initial stimulation. All children had complete insertion of electrodes. No difficulty inserting the EP occurred nor did subsequent related complications. Subjects with the EP had significantly lower threshold and MCL levels. Electrode impedance declined on stimulated electrodes in both groups. Meaningful Auditory Integration Scale scores significantly improved in both groups; the EP group appeared to receive as much benefit as the non-EP group.