This study examines cerebrospinal fluid from patients with three neuropsychiatric diseases of childhood for the presence and levels of several cytokines relevant to cell-mediated (type 1) and humoral (type 2) immunity. The patient groups include childhood-onset schizophrenia (n = 22), obsessive-compulsive disorder (OCD) (n = 24), and attention deficit hyperactivity disorder (n = 42). The cytokines examined include IL-2, IFN-gamma, TNF-beta/LT, IL-4, IL-5, IL-10, and TNF-alpha. Patients with OCD had a preponderance of type 1 cytokines. IL-4 was detectable only in samples from patients with schizophrenia. IL-10 was rarely detected and never in patients with OCD. Few patients with schizophrenia had detectable amounts of IFN-gamma in CSFL. We conclude that there is a relative skewing of CSFL profiles toward type 1 cytokines in patients with OCD, whereas in schizophrenia the relative preponderance is toward type 2 mediators. Patients with attention deficit hyperactivity disorder exhibited profiles intermediate between OCD and schizophrenia. We infer that cell-mediated immunity may be involved in the etiopathogenesis of OCD, whereas a relative lack of cell-mediated immunity and involvement of humoral immunity may be present in schizophrenia. These data provide a rationale for immune-based strategies of study and therapeutics in childhood neuropsychiatric disease.

CONCLUSIONS

The lymphotoxin (LT) system is part of the tumor necrosis factor family and is required for lymph node development. It has provided a wonderful tool for the dissection of processes critical not only for lymphoid organ development but also the maintenance of the adult immune architecture and the formation of ectopic organized lymphoid tissues in chronically inflamed sites. A soluble lymphotoxin-beta receptor-immunoglobulin (LTbetaR-Ig) fusion protein can block this pathway and is currently being tested in the treatment of autoimmune disease. This review focuses on the immunological consequences of combined LT and LIGHT inhibition with LTbetaR-Ig administration as distinct from the developmental biology.

Bangladesh experienced severe flooding and diarrheal epidemics in 2007. We compared flood data from 2007 with 2004 and 1998 for diarrheal patients attending the ICDDR,B hospital in Dhaka. In 2007, Vibrio cholerae O1 (33%), rotavirus (12%), and enterotoxigenic Escherichia coli (ETEC) (12%) were most prevalent. More severe dehydration was seen in 2007 compared with 2004 and 1998 (P < 0.001). In 2007, V. cholerae O1 Inaba (52%) and Ogawa (48%) were seen, whereas in 2004 and 1998 it was primarily Inaba and the Ogawa types, respectively (P < 0.001). In 2007, 51% of ETEC produced the heat labile toxin (LT) (P < 0.001 compared with 2004), 22% expressed the heat stable (ST) (P < 0.001), and 27% were ST/LT positive (P = 0.231). The CS7 colonization factor (CF) was the most prevalent in 2007 (20% compared with 6% in 2004; P = 0.05). Our findings demonstrate alterations in clinical features and phenotypic changes of major bacterial pathogens in the recent Bangladesh flood.

The 'classical' NF-kappaB activation pathway proceeds via IkappaB kinase (IKK)-beta/gamma-mediated phosphorylation, induced ubiquitination and the degradation of small IkappaBs. An alternative, NF-kappaB-inducing kinase and IKK-alpha-dependent pathway, which stimulates the processing of NF-kappaB2/p100, has recently been suggested. However, no physiological stimulus has been shown to trigger the activation of this pathway. Here we demonstrate that persistent stimulation with lymphotoxin beta (LT-beta) receptor agonists or lipopolysaccharide (LPS), but not with interleukin-1beta, tumour necrosis factor-alpha or 12-O-tetradecanoylphorbol-13-acetate, induces the generation of p52 DNA-binding complexes by activating the processing of the p100 precursor. Induction of p52 DNA-binding activity is delayed in comparison with p50/p65 complexes and depends on de novo protein synthesis. p100 is constitutively and inducibly polyubiquitinated, and both ubiquitination and p52 generation are coupled to continuing p100 translation. Thus, both LT-beta receptor agonists and LPS induce NF-kappaB/p100 processing to p52 at the level of the ribosome.

Recombinant preparations of TNF and lymphotoxin (LT) increase the expression of class I MHC antigens on cultured human endothelial cells (EC) without inducing expression of class II antigens. These actions are similar to those of rIFN-alpha or rIFN-beta. However, TNF and LT differ from IFN-alpha/beta in that the former synergize with IFN-gamma for class I regulation whereas the latter do not. Furthermore, LT or TNF do not affect IFN-gamma-mediated class II induction at optimal class I inducing concentrations (100 U/ml), whereas IFN-alpha and IFN-beta (at their optimal concentrations of 1,000 U/ml) are strikingly inhibitory. LT and TNF also can further increase expression of class I antigens on cells already maximally stimulated by IFN-alpha or IFN-beta. A recombinant preparation of IL-6 (formerly called 26-kD protein, IFN-beta 2, or B cell stimulating factor 2) was without effect on class I expression in EC. These data make it seem unlikely that the actions of LT or TNF on EC expression of MHC antigens are mediated through autocrine or paracrine production of IFN-alpha, IFN-beta or IL-6. More importantly, they suggest that LT or TNF are more likely to be immunostimulatory, whereas IFN-alpha or IFN-beta are more likely to be immunoinhibitory in vivo, a consideration of potential relevance for cytokine administration to various patient populations.

(<em>b</em>)Background:</<em>b</em>) The occurrence of anosmia/hyposmia during novel Coronavirus disease 2019 (COVID-19) may indicate a relationship <em>b</em>etween coincidence of olfactory dysfunction and coronavirus disease 2019 (COVID-19). This study aimed to assess the frequency of self-reported anosmia/hyposmia during COVID-19 epidemic in Iran. (<em>b</em>)Methods:</<em>b</em>) This population-<em>b</em>ased cross sectional study was performed through an online questionnaire from March 12 to 17, 2020. Cases from all provinces of Iran voluntarily participated in this study. Patients completed a 33-item patient-reported online questionnaire, including smell and taste dysfunction and their comor<em>b</em>idities, along with their <em>b</em>asic characteristics and past medical histories. The inclusion criteria were self-reported anosmia/hyposmia during the past 4 weeks, from the start of COVID-19 epidemic in Iran. (<em>b</em>)Resu<em>lt</em>s:</<em>b</em>) A total of 10 069 participants aged 32.5±8.6 (7-78) years took part in this study, of them 71.13% women and 81.68% nonsmokers completed the online questionnaire. The correlation <em>b</em>etween the num<em>b</em>er of olfactory disorders and reported COVID-19 patients in all provinces up to March 17, 2020 was highly significant (Spearman correlation coefficient = 0.87, P&<em>lt</em>; 0.001). A sudden onset of olfactory dysfunction was reported in 76.24% of the participations and persistent anosmia in 60.90% from the start of COVID19 epidemic. In addition, 80.38% of participants reported concomitant olfactory and gustatory dysfunctions. (<em>b</em>)Conclusion:</<em>b</em>) An out<em>b</em>reak of olfactory dysfunction occurred in Iran during the COVID-19 epidemic. The exact mechanisms <em>b</em>y which anosmia/hyposmia occurred in patients with COVID-19 call for further investigations.

Keywords: Anosmia; COVID; COVID-19; Coronavirus; Dysgeusia; ENT; Gustatory; Hyposmia; Infection; Olfaction; Olfactory; SARS-CoV-2; Smell; Taste loss.

Containment of intracellularly viable microorganisms requires an intricate cooperation between macrophages and T cells, the most potent mediators known to date being IFN-gamma and TNF. To identify novel mechanisms involved in combating intracellular infections, experiments were performed in mice with selective defects in the lymphotoxin (LT)/LT beta R pathway. When mice deficient in LT alpha or LT beta were challenged intranasally with Mycobacterium tuberculosis, they showed a significant increase in bacterial loads in lungs and livers compared with wild-type mice, suggesting a role for LT alpha beta heterotrimers in resistance to infection. Indeed, mice deficient in the receptor for LT alpha(1)beta(2) heterotrimers (LT beta R-knockout (KO) mice) also had significantly higher numbers of M. tuberculosis in infected lungs and exhibited widespread pulmonary necrosis already by day 35 after intranasal infection. Furthermore, LT beta R-KO mice were dramatically more susceptible than wild-type mice to i.p. infection with Listeria monocytogenes. Compared with wild-type mice, LT beta R-KO mice had similar transcript levels of TNF and IFN-gamma and recruited similar numbers of CD3(+) T cells inside granulomatous lesions in M. tuberculosis-infected lungs. Flow cytometry revealed that the LT beta R is expressed on pulmonary macrophages obtained after digestion of M. tuberculosis-infected lungs. LT beta R-KO mice showed delayed expression of inducible NO synthase protein in granuloma macrophages, implicating deficient macrophage activation as the most likely cause for enhanced susceptibility of these mice to intracellular infections. Since LIGHT-KO mice proved to be equally resistant to M. tuberculosis infection as wild-type mice, these data demonstrate that signaling of LT alpha(1)beta(2) heterotrimers via the LT beta R is an essential prerequisite for containment of intracellular pathogens.

Aluminum 1,4-benzenedicarboxylate Al(OH)[O(2)C-C(6)H(4)-CO(2)]. [HO(2)C-C(6)H(4)-CO(2)H](0.70) or MIL-53 as (Al) has been hydrothermally synthesized by heating a mixture of aluminum nitrate, 1,4-benzenedicarboxylic acid, and water, for three days at 220 degrees C. Its 3 D framework is built up of infinite trans chains of corner-sharing AlO(4)(OH)(2) octahedra. The chains are interconnected by the 1,4-benzenedicarboxylate groups, creating 1 D rhombic-shaped tunnels. Disordered 1,4-benzenedicarboxylic acid molecules are trapped inside these tunnels. Their evacuation upon heating, between 275 and 420 degrees C, leads to a nanoporous open-framework (MIL-53 ht (Al) or Al(OH)[O(2)C-C(6)H(4)-CO(2)]) with empty pores of diameter 8.5 A. This solid exhibits a Langmuir surface area of 1590(1) m(2)g(-1) together with a remarkable thermal stability, since it starts to decompose only at 500 degrees C. At room temperature, the solid reversibly absorbs water in its tunnels, causing a very large breathing effect and shrinkage of the pores. Analysis of the hydration process by solid-state NMR ((1)H, (13)C, (27)Al) has clearly indicated that the trapped water molecules interact with the carboxylate groups through hydrogen bonds, but do not affect the hydroxyl species bridging the aluminum atoms. The hydrogen bonds between water and the oxygen atoms of the framework are responsible for the contraction of the rhombic channels. The structures of the three forms have been determined by means of powder X-ray diffraction analysis. Crystal data for MIL-53 as (Al) are as follows: orthorhombic system, Pnma (no. 62), a = 17.129(2), b = 6.628(1), c = 12.182(1) A; for MIL-53 ht (Al), orthorhombic system, Imma (no. 74), a = 6.608(1), b = 16.675(3), c = 12.813(2) A; for MIL-53 lt (Al), monoclinic system, Cc (no. 9), a = 19.513(2), b = 7.612(1), c = 6.576(1) A, beta = 104.24(1) degrees.

Hepatic resection (HR) is the treatment of choice for small hepatocellular carcinoma (HCC) in a noncirrhotic liver, whereas liver transplantation (LT) offers better results in patients with impaired hepatic function (Child B and C). However, it is still debated whether HR or LT is the best strategy for patients with Child A cirrhosis. We conducted a retrospective study on 37 consecutive patients with Child A cirrhosis and small HCC, treated between 1991 and 1999. Seventeen of these patients, who underwent LT, were compared with 20 patients who underwent HR, and prognostic factors for survival and tumor recurrence were analyzed. The primary endpoints were the intention-to-treat, 3- and 5-year survival, and 3- and 5-year recurrence-free survival. Three- and 5-year patient survival rate both were significantly (P =.04) higher in the LT group (87% and 71%, respectively) than in the HR group (67 and 36% respectively). Similarly, the 3- and 5- year recurrence-free survival rates were 87% and 80% for the LT group, and 52% and 40% for the HR group (P =.03). Absence of microscopic vascular invasion was the only other prognostic factor correlated with significantly better recurrence-free survival (P =.02). Therefore, we concluded that in patients with Child A cirrhosis and small HCC, liver transplantation resulted in better overall and disease-free survival than HR.

<A<em>b</em>stractText>To compare the clinical characteristics and the dynamics of viral load <em>b</em>etween the imported and non-imported patients with COVID-19.</A<em>b</em>stractText><A<em>b</em>stractText>Data from 51 la<em>b</em>oratory-confirmed patients were retrospectively analyzed.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The incu<em>b</em>ation period in the tertiary group was longer than that in the imported and secondary groups (<em>b</em>oth P &<em>lt</em>; 0.05). Fever was the most common symptom at the onset of illness (73.33%, 58.82%, and 68.42%, respectively), and half of the patients had a low-grade temperature (&<em>lt</em>;38.0℃) with a short duration of fever (&<em>lt</em>;7 days). The CT scan showed that most patients had <em>b</em>ilateral pneumonia in the three groups (80.00%, 76.47%, and 73.68%, respectively). Ct values detected from the tertiary patients were similar to those from the imported and secondary groups at the time of admission (<em>b</em>oth P > 0.05). For the tertiary group, the viral load was undetecta<em>b</em>le for half of the patients (52.63%) on day 7, and all patients on day 14. For 1/3^rd of the patients in the imported and secondary groups, the viral load remained positive on day 14 after the admission.</p><A<em>b</em>stractText>COVID-19 can present as pneumonia with less onset of symptoms, and the infectivity of SARS-CoV2 may gradually decrease in the tertiary patients.</A<em>b</em>stractText>

Lymphotoxin (LT; also known as tumor necrosis factor-beta) is a pleiotropic cytokine whose expression is tightly regulated in most cells and is repressed prior to activation signals. In some early B cells and Abelson murine leukemia virus-transformed pre-B-cell lines, LT mRNA is constitutively expressed. To examine the molecular regulation of the LT gene in a constitutively expressing cell line, we studied the Abelson murine leukemia virus-transformed lines PD and PD31. As demonstrated by primer extension analysis, constitutively expressed pre-B-cell-derived and inducibly expressed T-cell-derived LT mRNA were initiated at the same cap sites and predominant cap site utilization was conserved. Furthermore, we delineated an upstream activating sequence that was an important functional component of lymphotoxin transcriptional activation in PD and PD31 cells. The upstream activating sequence was localized to an essentially homopolymeric A + T-rich region (LT-612/-580), which was bound specifically by recombinant human high-mobility group I protein (HMG-I) and a PD/PD31 nuclear extract HMG-I (HMG-I-like) protein. The nuclear extract-derived HMG-I-like protein was recognized by anti-HMG-I antibody and bound to LT DNA to effect an electrophoretic mobility shift identical to that of bound recombinant human HMG-I. These findings implicate HMG-I in the regulation of constitutive lymphotoxin gene expression in PD and PD31 cells. HMG-I and HMG-I-like proteins could facilitate the formation of active initiation complexes by altering chromatin structure and/or by creating recognition sites for other activator DNA-binding proteins, some of which may be unique to or uniquely modified in these constitutive LT mRNA producers.

Our previous study indicated that the core protein of hepatitis C virus (HCV) can associate with tumor necrosis factor receptor (TNFR)-related lymphotoxin-<em>beta</em> receptor (<em>LT</em>-<em>beta</em>R) and that this protein-protein interaction plays a modulatory effect on the cytolytic activity of recombinant form <em>LT</em>-<em>beta</em>R ligand (<em>LT</em>-alpha1<em>beta</em>2) but not tumor necrosis factor alpha (TNF-alpha) in certain cell types. Since both TNF-alpha/TNFR and <em>LT</em>-alpha1<em>beta</em>2/<em>LT</em>-<em>beta</em>R are also engaged in transcriptional activator NF-kappaB activation or c-Jun N-terminal kinase (JNK) activation, the biological effects of the HCV core protein on these regards were elucidated in this study. As demonstrated by the electrophoretic mobility shift assay, the expression of HCV core protein prolonged or enhanced the TNF-alpha or <em>LT</em>-alpha1<em>beta</em>2-induced NF-kappaB DNA-binding activity in HuH-7 and HeLa cells. The presence of HCV core protein in HeLa or HuH-7 cells with or without cytokine treatment also enhanced the NF-kappaB-dependent reporter plasmid activity, and this effect was more strongly seen with HuH-7 cells than with HeLa cells. Western blot analysis suggested that this modulation of the NF-kappaB activity by the HCV core protein was in part due to elevated or prolonged nuclear retention of p50 or p65 species of NF-kappaB in core protein-producing cells with or without cytokine treatment. Furthermore, the HCV core protein enhanced or prolonged the IkappaB-<em>beta</em> degradation triggering by TNF-alpha or <em>LT</em>-alpha1<em>beta</em>2 both in HeLa and HuH-7 cells. In contrast to that of IkappaB-<em>beta</em>, the increased degradation of IkappaB-alpha occurred only in <em>LT</em>-alpha1<em>beta</em>2-treated core-producing HeLa cells and not in TNF-alpha-treated cells. Therefore, the HCV core protein plays a modulatory effect on NF-kappaB activation triggering by both cytokines, though the mechanism of NF-kappaB activation, in particular the regulation of IkappaB degradation, is rather cell line and cytokine specific. Studies also suggested that the HCV core protein had no effect on TNF-alpha-stimulated JNK activity in both HeLa and HuH-7 cells. These findings, together with our previous study, strongly suggest that among three signaling pathways triggered by the TNF-alpha-related cytokines, the HCV core protein potentiates NF-kappaB activation in most cell types, which in turn may contribute to the chronically activated, persistent state of HCV-infected cells.

To investigate the roles of tumor necrosis factor (TNF) and lymphotoxin (LT)-alpha in the development and function of the immune system, the Tnf and Ltalpha genes were simultaneously inactivated in mice by homologous recombination. These mutant mice are highly susceptible to Listeria monocytogenes infection and resistant to endotoxic shock induced by the combined administration of D-galactosamine (D-GaIN) and lipopolysaccharide (LPS). Their splenic microarchitecture is disorganized, characterized by the loss of the clearly defined marginal zone, ill defined T and B cell areas, and absence of MAdCAM-1 and reduced ICAM-1, VCAM-1 and Mac-1 expression. They are devoid of peripheral lymph nodes and Peyer's patches, and show a strong reduction of IgA+ plasma cells in the intestinal lamina propria. The alymphoplasia is accompanied by a marked B lymphocytosis and reduced basal lg levels. Ig depositions in the renal glomerulus and a strong up-regulation of MHC class I antigen expression on endothelial cells of different tissues are observed. The primary humoral immune response towards sheep red blood cells reveals a defective IgG isotype switch, while that against vesicular stomatitis virus is normal. The cytotoxic T cell responses are attenuated, although still effective, against vaccinia, lymphocytic choriomeningitis virus (LCMV-ARM) and LCMV-WE. In conclusion, the combined inactivation of Tnf and Ltalpha confirms their essential role in the normal development and function of the immune system.

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B(4) and C(4) in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates on nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB(4) and 5-fold more LTC(4). IPF homogenate levels of LTB(4) were significantly correlated with histologic indices of both inflammation (r=0.861) and fibrosis (r=0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2+/-3.3% of cells) than in control lung (9.3+/-0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB(4) and LTC(4) than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy.

Isolated lymphoid follicles (ILFs) are organized lymphoid structures in the small intestine. ILFs were recently identified in the murine small intestine; however, the function of ILFs is unknown. To better understand ILFs and the role they play in the intestinal immune response, we have examined the composition of ILFs, the factors that are involved in the genesis of ILFs, and the ability of ILFs to support antigen-specific immunoglobulin production. We found that ILFs contain predominantly B-2 B lymphocytes, and CD4(+) TCRbeta(+) T lymphocytes. Similar to the formation of Peyer's patches (PPs), lymphotoxin beta receptor (LTbetaR)-dependent events are required for ILF formation; however, the timing of these events and the cellular source of LT differ. ILF formation can occur de novo in response to luminal stimuli and requires LT-sufficient B lymphocytes and TNF receptor I function for full maturation. The epithelium over ILFs resembles the PP follicle-associated epithelium, as M cells are present and pathogens such as Yersinia can be bound and taken up into the underlying follicle. Total fecal IgA production is not augmented in animals possessing ILFs; however, the production of antigen-specific IgA is increased in animals possessing ILFs orally challenged with Salmonella typhimurium. Similar to PPs, ILFs can support antigen-specific IgA production following oral immunization. These findings support the concept that ILFs are formed in response to mucosal challenges, and may play a physiological role in the production of antigen-specific intestinal IgA.

<A<em>b</em>stractText>Antipsychotic treatment is associated with meta<em>b</em>olic distur<em>b</em>ance. However, the degree to which meta<em>b</em>olic a<em>lt</em>erations occur in treatment with different antipsychotics is unclear. Predictors of meta<em>b</em>olic dysregulation are poorly understood and the association <em>b</em>etween meta<em>b</em>olic change and change in psychopathology is uncertain. We aimed to compare and rank antipsychotics on the <em>b</em>asis of their meta<em>b</em>olic side-effects, identify physiological and demographic predictors of antipsychotic-induced meta<em>b</em>olic dysregulation, and investigate the relationship <em>b</em>etween change in psychotic symptoms and change in meta<em>b</em>olic parameters with antipsychotic treatment.</A<em>b</em>stractText><A<em>b</em>stractText>We searched MEDLINE, EMBASE, and PsycINFO from inception until June 30, 2019. We included <em>b</em>linded, randomised controlled trials comparing 18 antipsychotics and place<em>b</em>o in acute treatment of schizophrenia. We did frequentist random-effects network meta-analyses to investigate treatment-induced changes in <em>b</em>ody weight, BMI, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, and glucose concentrations. We did meta-regressions to examine relationships <em>b</em>etween meta<em>b</em>olic change and age, sex, ethnicity, <em>b</em>aseline weight, and <em>b</em>aseline meta<em>b</em>olic parameter level. We examined the association <em>b</em>etween meta<em>b</em>olic change and psychopathology change <em>b</em>y estimating the correlation <em>b</em>etween symptom severity change and meta<em>b</em>olic parameter change.</A<em>b</em>stractText><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>Of 6532 citations, we included 100 randomised controlled trials, including 25 952 patients. Median treatment duration was 6 weeks (IQR 6-8). Mean differences for weight gain compared with place<em>b</em>o ranged from -0·23 kg (95% CI -0·83 to 0·36) for haloperidol to 3·01 kg (1·78 to 4·24) for clozapine; for BMI from -0·25 kg/m² (-0·68 to 0·17) for haloperidol to 1·07 kg/m² (0·90 to 1·25) for olanzapine; for total-cholesterol from -0·09 mmol/L (-0·24 to 0·07) for cariprazine to 0·56 mmol/L (0·26-0·86) for clozapine; for LDL cholesterol from -0·13 mmol/L (-0.21 to -0·05) for cariprazine to 0·20 mmol/L (0·14 to 0·26) for olanzapine; for HDL cholesterol from 0·05 mmol/L (0·00 to 0·10) for <em>b</em>rexpiprazole to -0·10 mmol/L (-0·33 to 0·14) for amisulpride; for triglycerides from -0·01 mmol/L (-0·10 to 0·08) for <em>b</em>rexpiprazole to 0·98 mmol/L (0·48 to 1·49) for clozapine; for glucose from -0·29 mmol/L (-0·55 to -0·03) for lurasidone to 1·05 mmol/L (0·41 to 1·70) for clozapine. Greater increases in glucose were predicted <em>b</em>y higher <em>b</em>aseline weight (p=0·0015) and male sex (p=0·0082). Non-white ethnicity was associated with greater increases in total cholesterol (p=0·040) compared with white ethnicity. Improvements in symptom severity were associated with increases in weight (r=0·36, p=0·0021), BMI (r=0·84, p&<em>lt</em>;0·0001), total-cholesterol (r=0·31, p=0·047), and LDL cholesterol (r=0·42, p=0·013), and decreases in HDL cholesterol (r=-0·35, p=0·035).</p><A<em>b</em>stractText>Marked differences exist <em>b</em>etween antipsychotics in terms of meta<em>b</em>olic side-effects, with olanzapine and clozapine exhi<em>b</em>iting the worst profiles and aripiprazole, <em>b</em>rexpiprazole, cariprazine, lurasidone, and ziprasidone the most <em>b</em>enign profiles. Increased <em>b</em>aseline weight, male sex, and non-white ethnicity are predictors of suscepti<em>b</em>ility to antipsychotic-induced meta<em>b</em>olic change, and improvements in psychopathology are associated with meta<em>b</em>olic distur<em>b</em>ance. Treatment guidelines should <em>b</em>e updated to reflect our findings. However, the choice of antipsychotic should <em>b</em>e made on an individual <em>b</em>asis, considering the clinical circumstances and preferences of patients, carers, and clinicians.</A<em>b</em>stractText><A<em>b</em>stractText>UK Medical Research Council, Wellcome Trust, National Institute for Hea<em>lt</em>h Research Oxford Hea<em>lt</em>h Biomedical Research Centre.</A<em>b</em>stractText>

Background: National immunisation programmes globally are at risk of suspension due to the severe health system constraints and physical distancing measures in place to mitigate the ongoing COVID-19 pandemic. We aimed to compare the health benefits of sustaining routine childhood immunisation in Africa with the risk of acquiring severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through visiting routine vaccination service delivery points.

Methods: We considered a high-impact scenario and a low-impact scenario to approximate the child deaths that could be caused by immunisation coverage reductions during COVID-19 outbreaks. In the high-impact scenario, we used previously reported country-specific child mortality impact estimates of childhood immunisation for diphtheria, tetanus, pertussis, hepatitis B, Haemophilus influenzae type b, Streptococcus pneumoniae, rotavirus, measles, meningitis A, rubella, and yellow fever to approximate the future deaths averted before 5 years of age by routine childhood vaccination during a 6-month COVID-19 risk period without catch-up campaigns. In the low-impact scenario, we approximated the health benefits of sustaining routine childhood immunisation on only the child deaths averted from measles outbreaks during the COVID-19 risk period. We assumed that contact-reducing interventions flattened the outbreak curve during the COVID-19 risk period, that 60% of the population will have been infected by the end of that period, that children can be infected by either vaccinators or during transport, and that upon child infection the whole household will be infected. Country-specific household age structure estimates and age-dependent infection-fatality rates were applied to calculate the number of deaths attributable to the vaccination clinic visits. We present benefit-risk ratios for routine childhood immunisation, with 95% uncertainty intervals (UIs) from a probabilistic sensitivity analysis.

Findings: In the high-impact scenario, for every one excess COVID-19 death attributable to SARS-CoV-2 infections acquired during routine vaccination clinic visits, 84 (95% UI 14-267) deaths in children could be prevented by sustaining routine childhood immunisation in Africa. The benefit-risk ratio for the vaccinated children is 85 000 (4900-546 000), for their siblings (<20 years) is 75 000 (4400-483 000), for their parents or adult carers (aged 20-60 years) is 769 (148-2700), and for older adults (>60 years) is 96 (14-307). In the low-impact scenario that approximates the health benefits to only the child deaths averted from measles outbreaks, the benefit-risk ratio to the households of vaccinated children is 3 (0-10); if the risk to only the vaccinated children is considered, the benefit-risk ratio is 3000 (182-21 000).

Interpretation: The deaths prevented by sustaining routine childhood immunisation in Africa outweigh the excess risk of COVID-19 deaths associated with vaccination clinic visits, especially for the vaccinated children. Routine childhood immunisation should be sustained in Africa as much as possible, while considering other factors such as logistical constraints, staff shortages, and reallocation of resources during the COVID-19 pandemic.

Funding: Gavi, the Vaccine Alliance; Bill & Melinda Gates Foundation.

The expression of membrane-associated forms of lymphotoxin (LT) and TNF were examined on cell lines of T, B, and myeloid origin, IL-2 dependent T cell clones, and peripheral blood lymphocytes. Inducible and constitutive patterns of surface LT expression were found on T cells as exemplified by the II-23.D7, a CD4+T cell hybridoma, and HUT-78, a T cell lymphoma. Phorbol ester induced surface LT expression on Ramos, an EBV transformed B cell line, but at a slower rate of appearance when compared to the II-23.D7. Secretion of LT was rapidly inducible by phorbol ester in II-23.D7 and also in HUT-78 but with slower kinetics; surface LT expression continued in both lines after secretion had ceased. Low levels of membrane TNF were transiently induced on II-23.D7 and HUT-78, but none was observed on Ramos. Peripheral blood monocytes and some myeloid tumor lines did not express surface LT. Several T cell clones expressed surface LT after Ag-specific stimulation, and expression persisted several days. Stimulation through the TCR or by IL-2 rapidly induced surface LT on resting peripheral T cells and CD56+ NK cells; pokeweed mitogen activation induced expression on CD20+ B cells. Consistent with previous results, immunoprecipitation with anti-LT mAb showed that LT was complexed with a distinct 33 kDa glycoprotein (p33) on cells that expressed surface LT, whereas secreted LT was not associated with p33. Surface and secreted modes of LT expression by activated T, B, and NK cells suggests that LT can be utilized as either a localized or diffusible mediator in immune responses.

<A<em>b</em>stractText>Sodium-glucose co-transporter-2 (SGLT2) inhi<em>b</em>itors have shown <em>b</em>eneficial effects on renal outcomes mainly in patients with esta<em>b</em>lished atherosclerotic cardiovascular disease. Here we report analyses of renal outcomes with the SGLT2 inhi<em>b</em>itor dapagliflozin in the DECLARE-TIMI 58 cardiovascular outcomes trial, which included patients with type 2 dia<em>b</em>etes <em>b</em>oth with and without esta<em>b</em>lished atherosclerotic cardiovascular disease and mostly with preserved renal function.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>In DECLARE-TIMI 58, patients with type 2 dia<em>b</em>etes, H<em>b</em>A<su<em>b</em>)1c</su<em>b</em>) 6·5-12·0% (47·5-113·1 mmol/mol), with either esta<em>b</em>lished atherosclerotic cardiovascular disease or mu<em>lt</em>iple risk factors, and creatinine clearance of at least 60 mL/min were randomly assigned (1:1) to 10 mg dapagliflozin or place<em>b</em>o once daily. A prespecified secondary cardiorenal composite outcome was defined as a sustained decline of at least 40% in estimated glomerular fi<em>lt</em>ration rate [eGFR] to less than 60 mL/min per 1·73m², end-stage renal disease (defined as dialysis for at least 90 days, kidney transplantation, or confirmed sustained eGFR &<em>lt</em>;15mL/min per 1·73 m²), or death from renal or cardiovascular causes; a prespecified renal-specific composite outcome was the same <em>b</em>ut excluding death from cardiovascular causes. In this renal analysis, we report findings for the components of these composite outcomes, su<em>b</em>group analysis of these composite outcomes, and changes in eGFR at different timepoints. DECLARE-TIMI 58 is registered with ClinicalTrials.gov, num<em>b</em>er NCT01730534.</p><p><div>(<em>b</em>)FINDINGS</<em>b</em>)</div>The trial took place <em>b</em>etween April 25, 2013, and Sept 18, 2018; median follow-up was 4·2 years (IQR 3·9-4·4). Of the 17 160 participants who were randomly assigned, 8162 (47·6%) had an eGFR of at least 90 mL/min per 1·73 m², 7732 (45·1%) had an eGFR of 60 to less than 90 mL/min per 1·73 m², and 1265 (7·4%) had an eGFR of less than 60 mL/min per 1·73 m² at <em>b</em>aseline (one participant had missing data for eGFR); 6974 (40·6%) had esta<em>b</em>lished atherosclerotic cardiovascular disease and 10 186 (59·4%) had mu<em>lt</em>iple risk factors. As previously reported, the cardiorenal secondary composite outcome was significantly reduced with dapagliflozin versus place<em>b</em>o (hazard ratio [HR] 0·76, 95% CI 0·67-0.87; p&<em>lt</em>;0·0001); excluding death from cardiovascular causes, the HR for the renal-specific outcome was 0·53 (0·43-0·66; p&<em>lt</em>;0·0001). We identified a 46% reduction in sustained decline in eGFR <em>b</em>y at least 40% to less than 60 mL/min per 1·73 m² (120 [1·4% vs 221 [2·6%]; HR 0·54 [95% CI 0·43-0·67]; p&<em>lt</em>;0·0001). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the place<em>b</em>o group (11 [0·1%] vs 27 [0·3%]; HR 0·41 [95% CI 0·20-0·82]; p=0·012). Both the cardiorenal and renal-specific composite outcomes were improved with dapagliflozin versus place<em>b</em>o across various prespecified su<em>b</em>groups, including those defined <em>b</em>y <em>b</em>aseline eGFR (cardiorenal outcome p<su<em>b</em>)interaction</su<em>b</em>)=0·97; renal-specific outcome p<su<em>b</em>)interaction</su<em>b</em>)=0·87) and the presence or a<em>b</em>sence of esta<em>b</em>lished atherosclerotic cardiovascular disease (cardiorenal outcome p<su<em>b</em>)interaction</su<em>b</em>)=0·67; renal-specific outcome p<su<em>b</em>)interaction</su<em>b</em>)=0·72). 6 months after randomisation, the mean decrease in eGFR was larger in the dapagliflozin group than in the place<em>b</em>o group. The mean change equalised <em>b</em>y 2 years, and at 3 and 4 years the mean decrease in eGFR was less with dapagliflozin than with place<em>b</em>o.</p><A<em>b</em>stractText>Dapagliflozin seemed to prevent and reduce progression of kidney disease compared with place<em>b</em>o in this large and diverse population of patients with type 2 dia<em>b</em>etes with and without esta<em>b</em>lished atherosclerotic cardiovascular disease, most of whom had preserved renal function.</A<em>b</em>stractText><A<em>b</em>stractText>AstraZeneca.</A<em>b</em>stractText>

Natural killer cells mediate spontaneously secretory/necrotic killing against rare leukemia cell lines and a nonsecretory/apoptotic killing against a large variety of tumor cell lines. The molecules involved in nonsecretory/apoptotic killing are largely undefined. In the present study, freshly isolated, nonactivated, human NK cells were shown to express TNF, lymphotoxin (<em>LT</em>)-alpha, <em>LT</em>-<em>beta</em>, Fas ligand (L), CD27L, CD30L, OX40L, 4-1BBL, and TNF-related apoptosis-inducing ligand (TRAIL), but not CD40L or nerve growth factor. Complementary receptors were demonstrated to be expressed on the cell surface of solid tumor cell lines susceptible to apoptotic killing mediated by NK cells. Individually applied, antagonists of TNF, <em>LT</em>-alpha1<em>beta</em>2, or FasL fully inhibited NK cell-mediated apoptotic killing of tumor cells. On the other hand, recombinant TNF, <em>LT</em>-alpha1<em>beta</em>2, or FasL applied individually or as pairs were not cytotoxic. In contrast, a mixture of the three ligands mediated significant apoptosis in tumor cells. These findings demonstrate that human NK cells constitutively express several of the TNF family ligands and induce apoptosis in tumor cells by simultaneous engagement of at least three of these cytotoxic molecules.

Early in ontogeny, the secondary lymphoid organs become populated with numerous cells of mesodermal origin which forms both the lymphoid and stromal elements. The critical receptor/ligand interactions necessary for lymphoid organogenesis to occur are for the most part unknown. Although lymphotoxin-alpha (LT alpha) has been shown to be required for normal lymph node, Peyer's patch, and splenic development, it is unclear if soluble LT alpha 3, and/or cell-bound lymphotoxin-alpha beta (LT alpha beta) mediate these developmental events. Here we report that blocking LT alpha beta/lymphotoxin-beta receptor (LT beta R) interaction in vivo by generating mice which express a soluble LT beta R-Fc fusion protein driven by the human cytomegalovirus promoter results in an array of anatomic abnormalities affecting both the spleen and Peyer's patches, but not the lymph nodes. These results demonstrate that surface LT alpha beta ligand plays a critical role in normal lymphoid organ development.

Lethal toxin (LT) was purified from Clostridium sordellii IP82 by DEAE-Trisacryl, Ultrogel AcA3-4 gel filtration, and hydroxyapatite column chromatography. The molecular weight of purified LT was estimated to be 240,000 to 250,000, and the pI was at pH 4.55. LT was lethal for mice by intraperitoneal injection (3.4 X 10(5) mouse lethal doses per mg of protein), cytotoxic for Vero cells (6.1 X 10(4) cytotoxic units per mg of protein), erythematous and edematous by intradermal injection in guinea pigs, and induced a moderate fluid accumulation in the guinea pig intestinal loop test. The lethal activity was inactivated by N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, and sodium dodecyl sulfate. The data suggest that tryptophan and methionine residues present in the toxin are important for lethal activity. Furthermore, LT was inactivated by oxidized glutathione and activated by dithiothreitol. Inactivation by sulfhydryl-group reagents 5,5'-dithiobis(2-nitrobenzoic acid) and iodoacetamide was only obtained with dithiothreitol-treated LT. Thiol groups which are protected as a disulfide bond(s) seem to be essential for the LT activity. A specific antiserum against LT neutralized the biological activities of LT and also cytotoxic activity and lethal activity of Clostridium difficile toxin B but not of C. difficile toxin A. However, this serum did not recognize antigen from C. difficile culture supernatant by immunoblotting. It was concluded that antibodies prepared from C. sordellii LT that neutralized C. difficile cytotoxic activity recognized a low number of epitopes or tertiary structures of C. difficile cytotoxin.

OBJECTIVE

Recurrence of hepatitis C after liver transplantation (LT) is universal and may cause premature graft loss. We evaluated the efficacy and safety of antiviral therapy in HCV-infected patients with decompensated cirrhosis awaiting LT.

METHODS

Fifty-one patients underwent treatment with peginterferon-alfa-2a and ribavirin. A control group of 51 untreated individuals awaiting LT were matched by age, Child-Pugh and MELD scores and time on the waiting list.

RESULTS

Case and control patients were comparable for all relevant variables. Fifteen treated patients (29%) had undetectable HCV-RNA at the time of transplantation and 10 (20%) achieved SVR. Early virological response and non-1 genotype were the strongest predictors of viral clearance. There was a higher incidence of bacterial infections in treated patients vs controls, particularly in Child-Pugh B-C individuals (17 vs 3 episodes) (log-rank=0.0016). Importantly, the incidence of spontaneous bacterial peritonitis (SBP) in patients who were not receiving norfloxacin prophylaxis (n=83) was significantly higher in the treated group than in controls (log-rank=0.01).

CONCLUSIONS

Our data demonstrate that antiviral treatment prevents hepatitis C recurrence in 20% of HCV-infected patients. However, treatment should be recommended with caution in individuals with poor liver function who do not receive norfloxacin prophylaxis for SBP, since it increases the risk of bacterial infections.

OBJECTIVE

The effects of leukotriene (LT) D(4) on intestinal epithelial cells govern events that are involved in cell survival and colon cancer, notably increased expression of cyclooxygenase (COX)-2 and enhanced production of prostaglandin E(2). We investigated possible correlations between distribution of the recently described LTD(4) receptor CysLT(1)R and factors previously shown to be up-regulated by LTD(4) as well as clinicopathologic traits.

METHODS

Immunohistochemistry and in situ hybridization were performed on tissue arrays, which were made using colorectal cancer samples from 84 patients.

RESULTS

CysLT(1)R was significantly correlated to COX-2, 5-lipoxygenase, and Bcl-x(L). Male subjects more often exhibited high levels of this receptor relative to female subjects, and Dukes' B patients with elevated CysLT(1)R expression showed markedly poorer survival than those with low-level expression. Furthermore, this was paralleled by an increased viability of CysLT(1)R-overexpressing cells in a colon cancer cell line.

CONCLUSIONS

Our results further implicate the involvement of LTs in colorectal carcinoma. Based on our present and earlier findings, we propose that LT/CysLT(1)R signaling facilitates survival of colon cancer cells, which may affect disease outcome. Like COX-2, LTs are accessible targets for pharmacologic treatment.