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We performed a multicenter prospective study on the incidence and prognosis of Guillain-Barre syndrome (GBS) in the Emilia-Romagna region (3,909,512 inhabitants), Italy, over a 2-year period (1992-1993). The case finding method was based on a surveillance system including neurologic departments, all private and public general hospitals, and all practicing neurologists. We also reviewed all the ICD codes of hospital discharges. Ninety-four patients with GBS were identified, giving a mean incidence rate of 1.20 per 100,000 per year. Men/women ratio was 1.94. Incidence rate increased with age for both sexes. There were no significant incidence variations among seasons or months. Antecedent infections were reported in 59% of the patients. There was an overall good prognosis. After 6 months, 64% of patients had recovered and only 4% was still severely disabled. Acute mortality was 3%. Older age was the strongest predictor of poor outcome. NEUROLOGY 1997;48: 214-221

C/EBP beta is considered a key element of interleukin-6 (IL-6) signalling as well as an important transcriptional regulator of the IL-6 gene itself. We describe here how mice lacking C/EBP beta develop a pathology similar to mice overexpressing IL-6 and nearly identical to multicentric Castleman's disease in human patients, with marked splenomegaly, peripheral lymphadenopathy and enhanced haemopoiesis. Humoral, innate and cellular immunity are also profoundly distorted, as shown by the defective activation of splenic macrophages, the strong impairement of IL-12 production, the increased susceptibility to Candida albicans infection and the altered T-helper function. Our data show that C/EBP beta is crucial for the correct functional regulation and homeostatic control of haemopoietic and lymphoid compartments.

During the past 10 years, minimally invasive surgical techniques have been applied more and more widely in both adult and pediatric populations, especially in female patients. Right anterolateral minithoracotomy is an alternative to median sternotomy that yields a better cosmetic outcome. From May 1997 through September 2008, 132 patients (107 females, 25 males) underwent open-heart surgery through right anterolateral minithoracotomy. Ages ranged from 1 to 49 years (mean, 10.12 yr). Mean body weight was 21.3 kg (range, 9.4-78 kg). Corrected defects included atrial septal defect, partial anomalous pulmonary venous connection, partial atrioventricular canal defect, ventricular septal defect alone or with pulmonary valve stenosis, tetralogy of Fallot, cor triatriatum, mitral valve defect, and pericardial cyst. The anterolateral skin incision was 5 to 7 cm. Our control group-which in the same period underwent the same interventional procedures through median sternotomy-consisted of 415 patients, 245 of whom were female (59%). There was no early or late death or major illness as a sequela. No patient required conversion to full sternotomy. All patients had gratifying cosmetic results at longer follow-up. Indeed the mortality and morbidity rates obtained through our approach were almost the same as those obtained through median sternotomy, and there were no significant differences in cardiopulmonary bypass time, aortic cross-clamp time, ventilation time, or postoperative hospital stay. We conclude that the right anterolateral minithoracotomy for correction of congenital heart defects offers superior cosmetic results without increasing morbidity or mortality rates and confers upon patients psychological and social satisfaction.

Nine patients with uni-or bilateral stenosis of vertebral arteries, not associated with other lesions of supraaortic trunks are reported. They showed a vertebrobasilar insufficiency syndrome not due to other assessable causes. Seven of them underwent surgical treatment always as reimplantation of the vertebral into the subclavian artery. The procedure was unilateral also in cases with bilateral lesions. In all 7 patients a favourable result was obtained: 5 patients recovered completely and 2 showed a marked improvement. The study demonstrates that the surgical repair of symptomatic unilateral lesions of vertebral arteries is able to cure the vertebrobasilar insufficiency syndrome.

Three different substrates for the analysis of liquid samples by Total Reflection X-Ray Fluorescence with Synchrotron Radiation (SR-TXRF) were investigated and compared: Lucite (Perspex), Kimfoil and Mylar. Dry targets were prepared by pipetting 5 mul aliquotes of the liquid samples (synthetic standards and fresh water samples) on the different substrates. A five fold reduction of the continuous background and a corresponding reduction of the elementary detection limits were observed when thin polymer film substrates were used instead of the common thick Perspex substrate.

In the tumor microenvironment, Cancer Associated Fibroblasts (CAFs) become activated by cancer cells and increase their secretory activity to produce soluble factors that contribute to tumor cells proliferation, invasion and dissemination to distant organs. The pro-tumorigenic transcription factor STAT3 and its canonical inducer, the pro-inflammatory cytokine IL-6, act conjunctly in a positive feedback loop that maintains high levels of IL-6 secretion and STAT3 activation in both tumor and stromal cells. Here, we demonstrate that STAT3 is essential for the pro-tumorigenic functions of murine breast cancer CAFs both in vitro and in vivo, and identify a STAT3 signature significantly enriched for genes encoding for secreted proteins. Among these, ANGPTL4, MMP13 and STC-1 were functionally validated as STAT3-dependent mediators of CAF pro-tumorigenic functions by different approaches. Both in vitro and in vivo CAFs activities were moreover impaired by MMP13 inhibition, supporting the feasibility of a therapeutic approach based on inhibiting STAT3-induced CAF-secreted proteins. The clinical potential of such an approach is supported by the observation that an equivalent CAF-STAT3 signature in humans is expressed at high levels in breast cancer stromal cells and characterizes patients with a shorter disease specific survival, including those with basal-like disease.

During gram-negative septicemia, interactions between platelets and neutrophils initiate a detrimental feedback loop that sustains neutrophil extracellular trap (NET) induction, disseminated intravascular coagulation, and inflammation. Understanding intracellular pathways that control platelet-neutrophil interactions is essential for identifying new therapeutic targets. Here, we found that thrombin signaling induced activation of the transcription factor NFAT in platelets. Using genetic and pharmacologic approaches, as well as iNFATuation, a newly developed mouse model in which NFAT activation can be abrogated in a cell-specific manner, we demonstrated that NFAT inhibition in activated murine and human platelets enhanced their activation and aggregation, as well as their interactions with neutrophils and NET induction. During gram-negative septicemia, NFAT inhibition in platelets promoted disease severity by increasing disseminated coagulation and NETosis. NFAT inhibition also partially restored coagulation ex vivo in patients with hypoactive platelets. Our results define non-transcriptional roles for NFAT that could be harnessed to address pressing clinical needs.

The genetic elements required to tune gene expression are partitioned in active and repressive nuclear condensates. Chromatin compartments include transcriptional clusters whose dynamic establishment and functioning depend on multivalent interactions occurring among transcription factors, cofactors and basal transcriptional machinery. However, how chromatin players contribute to the assembly of transcriptional condensates is poorly understood. By interrogating the effect of KMT2D (also known as MLL4) haploinsufficiency in Kabuki syndrome, we found that mixed lineage leukemia 4 (MLL4) contributes to the assembly of transcriptional condensates through liquid-liquid phase separation. MLL4 loss of function impaired Polycomb-dependent chromatin compartmentalization, altering the nuclear architecture. By releasing the nuclear mechanical stress through inhibition of the mechanosensor ATR, we re-established the mechanosignaling of mesenchymal stem cells and their commitment towards chondrocytes both in vitro and in vivo. This study supports the notion that, in Kabuki syndrome, the haploinsufficiency of MLL4 causes an altered functional partitioning of chromatin, which determines the architecture and mechanical properties of the nucleus.

Activation of the innate immune system via pattern recognition receptors (PRRs) is key to generate lasting adaptive immunity. PRRs detect unique chemical patterns associated with invading microorganisms, but whether and how the physical properties of PRR ligands influence the development of the immune response remains unknown. Through the study of fungal mannans, we show that the physical form of PRR ligands dictates the immune response. Soluble mannans are immunosilent in the periphery but elicit a potent pro-inflammatory response in the draining lymph node (dLN). By modulating the physical form of mannans, we developed a formulation that targets both the periphery and the dLN. When combined with viral glycoprotein antigens, this mannan formulation broadens epitope recognition, elicits potent antigen-specific neutralizing antibodies, and confers protection against viral infections of the lung. Thus, the physical properties of microbial ligands determine the outcome of the immune response and can be harnessed for vaccine development.

STAT3 can mediate epigenetic silencing of tumor suppressor genes (TSG). However, little is known about the molecular mechanisms involved, except that this action is mediated by DNA methylation and requires STAT3 acetylation. In this issue of Cancer Research, Gambi and colleagues confirm that oncogene-driven constitutive STAT3 acetylation is responsible for TSG silencing. Furthermore, they show that the Sin3a transcriptional repressor complex is an obligatory partner of STAT3 on the promoters of the repressed genes, shedding light on the mechanisms involved in STAT3-mediated transcriptional repression, and more importantly, identifying that the STAT3–Sin3a axis is a potential selective therapeutic target in STAT3-dependent tumors. See related article by Gambi et al., p. 3076