Difficulties during delivery, brain ventricle enlargement and cognitive impairment in first episode psychosis.

BACKGROUND: Patients with a first episode of psychosis (FEP) display clinical, cognitive, and structural brain abnormalities at illness onset. Ventricular enlargement has been identified in schizophrenia since the initial development of neuroimaging techniques. Obstetric abnormalities have been associated with an increased risk of developing psychosis but also with cognitive impairment and brain structure abnormalities. Difficulties during delivery are associated with a higher risk of birth asphyxia leading to brain structural abnormalities, such as ventriculomegaly, which has been related to cognitive disturbances. METHODS: We examined differences in ventricular size between 142 FEP patients and 123 healthy control participants using magnetic resonance imaging. Obstetric complications were evaluated using the Lewis-Murray scale. We examined the impact of obstetric difficulties during delivery on ventricle size as well as the possible relationship between ventricle size and cognitive impairment in both groups. RESULTS: FEP patients displayed significantly larger third ventricle size compared with healthy controls. Third ventricle enlargement was associated with diagnosis (higher volume in patients), with difficulties during delivery (higher volume in subjects with difficulties), and was highest in patients with difficulties during delivery. Verbal memory was significantly associated with third ventricle to brain ratio. CONCLUSIONS: Our results suggest that difficulties during delivery might be significant contributors to the ventricular enlargement historically described in schizophrenia. Thus, obstetric complications may contribute to the development of psychosis through changes in brain architecture.

Infectious meningitis. Why are the leptomeninges preferentially involved? Electron microscopic insights.

In infectious meningitis, pathogens preferentially attack the leptomeninges (pia mater and arachnoid) rather than the pachymeninges (dura mater). This study aims to provide ultra-anatomical insights from our extensive collection of electron microscopy images and propose mechanisms, highlighting structures that favor the introduction, adherence, colonization, and proliferation of microorganisms leading to spinal meningitis. Over several years, we analyzed an extensive collection of transmission and scanning electron microscopy images of human spinal meninges captured in our laboratories. Upon examining 378 of those images, we identified potential sites for the iatrogenic or hematogenic introduction and adherence of microorganisms, as well as sites for their colonization and proliferation. These included the outer surface of the spinal dural sac, structures within the epidural space, and the spinal dural sac itself, which comprises compact dura mater with interwoven collagen fibers and tightly bound arachnoid cells. Also, the subdural (extra-arachnoid) compartment, consisting of fragile neurothelial cells prone to rupture under force, formed an acquired spinal subdural space, a new subarachnoid compartment, limited by arachnoid trabeculae, that surrounded the nerve roots and spinal cord and the pia mater. Macrophages, fibroblasts, mast cells, and plasma cells were also observed within the dura mater, arachnoid layer, arachnoid trabeculae, and pia mater. These images illustrate how the characteristics of the meningeal layers could contribute to bacterial adhesion and proliferation at various locations, inducing selective inflammation during (iatrogenic) spinal meningitis. In addition, the images help to explain why magnetic resonance imaging enhancement appears preferentially at specific sites.

A histology guide for performing human cadaveric studies: SQIP 2024 what to look for with light microscopy.

Histological observation under light microscopy has long been used in human cadaveric studies. However, it can distort the interpretations of findings if not used appropriately; there is no guide for its proper use. The aim of this article is to revisit and discuss the correct use of histology in human cadaveric studies, following discussions with experts in multiple fields of medicine, and to create the first guide for such usage. We reached a consensus with the experts, agreeing that when this principle (structure, quantification, interaction, position: SQIP) is applied to histological observations, the findings will be interpreted correctly. Appropriate use of this recommendation can make human cadaveric studies more accurate and informative. This is the first histology guide for human cadaveric studies.

Neuropsychological functioning and its correlates at 1 year follow-up of severe COVID-19.

BACKGROUND: Short-term cognitive impairment is associated with SARS-CoV-2 infection but the long-term impact is yet to be examined in detail. We aim to study the evolution of these symptoms in severe COVID-19 patients admitted to the intensive care unit (ICU) between April and December 2020 1 year after hospital discharge and to analyze its clinical correlates. METHOD: A total of 58 patients agreed to participate in the 6 months follow-up and 30 at 1 year after hospital discharge. Demographic, clinical and laboratory data were collected and a comprehensive neuropsychological battery including validated tests for the main cognitive domains was administered. To test the magnitude of neurocognitive sequelae, two standard deviations below normative group were considered. To compare the neuropsychological performance at 6 and 12 months follow-up we used repeated measures tests. Finally, regression analyses were performed to test the main effects of medical and psychological factors on multiple cognition. RESULTS: Almost half of the sample continued to have impaired performance on neuropsychological tests at 12 months follow-up. In comparison with the results obtained at 6 months, significant improvements were found in immediate recall (d = 0.49), delayed recall (d = 0.45), and inhibitory control (d = 0.53). Medical variables predicted cognitive performance at 6 months but not at 12 months follow-up, while anxiety and depression predicted cognitive deficits in the long-term. CONCLUSIONS: A generalised improvement was observed in severe COVID-19 patients at follow-up. This improvement was particularly notable in verbal memory and executive functioning. However, a considerable proportion of the sample continued to present deficits at 1 year follow-up.

Nerve to subclavius for neurotization procedures: an anatomical feasibility study.

Injuries to the inferior trunk of the brachial plexus and its components can be debilitating. As such injuries are prioritized by surgeons during repair, an additional nerve transfer is considered herein. In the supine position, 13 adult cadavers (26 sides) underwent dissection of the nerve to subclavius and the proximal brachial plexus in the supraclavicular region. Once the nerve was located and isolated from origin to termination, measurements of its length and diameter were made. Next, the C8 and T1 roots and inferior trunk were identified. The distal end of the nerve to subclavius was transected and swung to these roots and the inferior trunk. Once the nerves to subclavius were transposed and in a tension-free manner, the length of excess nerve following being brought to each of these nerves was measured. A nerve to subclavius was identified on all sides. The nerve originated from the superior trunk and traveled anterior to the middle and inferior trunks on all sides. The mean diameter of the nerve to subclavius was 0.8 mm, and the mean length was 57 mm. After cutting the nerve to subclavius at its entrance into the subclavius muscle, the distal nerve could be transferred tension free to the inferior trunk of the brachial plexus and T1 ventral ramus on all sides. The distal nerve to subclavius reached the T1 ventral ramus with an average of 18 mm of additional length and to the C8 ventral ramus with an average of 19 mm. The nerve also could be transferred to the inferior trunk of the brachial plexus with an average of 20 mm of additional length. The nerve to subclavius was found to have approximately 3000 axons. To our knowledge, use of the nerve to subclavius has previously not been used for nerve transfer procedures. Based on our cadaveric study, this often-overlooked nerve can be easily transposed to other regional nerves such as the inferior trunk of the brachial plexus.

What is the C2 pedicle, pars interarticularis, and isthmus? Anatomical study and review of the literature regarding these confusing terms with proposal of new nomenclature.

INTRODUCTION: The atypical anatomy of the C2 vertebra has led to terminological discrepancies within reports and studies in the literature regarding the location of its pedicle, pars interarticularis, and isthmus. These discrepancies not only limit the power of morphometric analyses, but they also confuse technical reports regarding operations involving C2, and thus confuse our ability to properly communicate this anatomy. Herein, we examine the variations in nomenclature regarding the pedicle, pars interarticularis, and isthmus of C2, and via an anatomical study, propose new terminology. METHODS: The articular surface and underlying superior and inferior articular processes and adjacent transverse processes were removed from 15 C2 vertebrae (30 sides). Specifically, the areas regarded as the pedicle, pars interarticularis, and isthmus were evaluated. Morphometrics were performed. RESULTS: Our results indicate that, anatomically, C2 has no "isthmus" and that a pars interarticularis for C2, when present, is very short. Deconstruction of the attached parts allowed for visualization of a bony arch extending from the anterior most aspect of the lamina to the body of C2. The arch is composed almost entirely of trabecular bone and without its attached parts, e.g., transverse process, really has no cortical bone laterally. CONCLUSIONS: We propose a more accurate terminology, the pedicle, for pars/pedicle screw placement of C2. Such a term more accurately describes this unique structure of the C2 vertebra and would alleviate terminological confusion in the future literature on this topic.

The superior vesical artery: A review of conflicting definitions and how these could affect invasive procedures.

Since the superior umbilical artery is the only functioning branch of the patent umbilical artery, some anatomical and surgical books/atlases fail to clarify that it is a branch of the umbilical artery and not a direct branch of the anterior division of the internal iliac artery and so specifically state that it is a direct branch of the internal iliac artery. This discrepancy in nomenclature can obviously affect invasive procedures and communication between physicians. Therefore, the present review is intended to highlight this issue. The term "superior vesical artery" was searched using standard search engines, for example, PubMed and Google Scholar. Several standard and specialized anatomy textbooks were also examined to ascertain how the superior vesical artery was described. Thirty-two articles were identified that used the terms "superior vesical artery" or "superior vesical arteries." After applying exclusion criteria, in 28 papers, the definition of the superior vesical artery was undetermined in eight, described as a direct branch of the internal iliac artery in 13, described as a branch of the umbilical artery in six, and defined as being equivalent to the umbilical artery in one. Of the sampled textbooks, some defined the superior vesicle artery as a branch of the umbilical artery, some as a direct branch of the internal iliac artery and some as both. Taken all together, most define the superior vesical artery as a branch of the umbilical artery. As the superior vesical artery is described as a branch of the umbilical artery in the internationally accepted terminology (Terminologia Anatomica), we recommend that this definition be used by anatomists and physicians alike so that communication is clear.

The sublingual branch of the lingual nerve: Anatomical study and suggestion for a new terminology.

The lingual nerve carries somatosensory fibers from the anterior two-thirds of tongue. The parasympathetic preganglionic fibers arising from the chorda tympani also travel with the lingual nerve in the infratemporal fossa to synapse in the submandibular ganglion to innervate the sublingual gland. However, only a few studies have investigated the specific nerve that innervates the sublingual gland and surrounding tissue i.e., the so-called sublingual nerve. Therefore, this study aimed to clarify the anatomy and definition of the sublingual nerves. Thirty sides from formalin fixed cadaveric hemiheads underwent microsurgical dissection of the sublingual nerves. The sublingual nerves were found on all sides and categorized into three branches, i.e., branches to the sublingual gland, branches to the mucosa of the floor of the mouth, and gingival branches. Additionally, branches to the sublingual gland were subcategorized into types I and II based on the origin of the sublingual nerve. We suggest that the lingual nerve branches should be categorized into five branches, i.e., branches to the isthmus of the fauces, sublingual nerves, lingual branches, posterior branch to the submandibular ganglion, and branches to the sublingual ganglion.

Human lumbar sympathetic blockade: An anatomical study to address potential block failure.

The lumbar sympathetic block is often used to treat complex regional pain syndrome, but it seems to have a high failure rate. This study seeks anatomical explanations for this apparent failure in order to refine our block procedure. Two simulated sympathetic trunk blocks were carried out on four fresh, cryopreserved unembalmed human cadavers under fluoroscopic control at the L2 vertebral body level, followed by two further simulated blocks at the L4 vertebral body level on the other side. Dye was injected, and the areas were dissected following a specific protocol. We then describe the anatomy and the spread of the dye compared to the spread of the contrast medium on fluoroscopy. The ganglia were differently located at different vertebral levels, and differed among the cadavers. Following this anatomical clarification, we now prefer to perform lumbar sympathetic blocks at the fourth lumbar vertebra level, using an extraforaminal approach at the caudal end of ​​the vertebra, avoiding the anterolateral margin of the vertebral body at the midpoint.

Pulmonary barotrauma in SCUBA diving-related fatalities: a histological and histomorphometric analysis.

Arterial gas embolism following pulmonary barotrauma occurs in 13-24% of cases of diving deaths. The study aimed to evaluate the usefulness of a histomorphometric digital analysis in the detection of air space over-distension due to pulmonary barotrauma. The study was performed on lung parenchyma specimens of 12 divers: six had died due to arterial gas embolism following pulmonary barotrauma (mean age at death of 54 years, range of 41-61 years), and six had drowned in saltwater without a diagnosis of pulmonary barotrauma (mean age at death of 54 years, range of 41-66 years) (positive controls). For negative controls, six cases of non-SCUBA divers (mean age of death of 42 years, range of 23-55 years) who died of intracerebral haemorrhage were evaluated. No significant differences were observed in the characteristics of the air spaces between control groups (positive and negative). However, differences were observed in the area occupied by air spaces and the percentage of air space area when we compared the case group to the controls (p < 0.01); and there was a slight difference in the maximum and minimum diameters of air space (p < 0.05). The mean area occupied by air spaces and the mean percentage of air space were the most useful for discriminating pulmonary barotrauma from other causes of death (100% sensitivity and 91.7% specificity). Based on our study, inclusion of an increased pattern of air spaces as a possible diagnostic criterion for pulmonary barotrauma would be useful in discerning the cause of diving death.

Towards the Search for Potential Biomarkers in Osteosarcoma: State-of-the-Art and Translational Expectations.

Osteosarcoma represents a rare cause of cancer in the general population, accounting for <1% of malignant neoplasms globally. Nonetheless, it represents the main cause of malignant bone neoplasm in children, adolescents and young adults under 20 years of age. It also presents another peak of incidence in people over 50 years of age and is associated with rheumatic diseases. Numerous environmental risk factors, such as bone diseases, genetics and a history of previous neoplasms, have been widely described in the literature, which allows monitoring a certain group of patients. Diagnosis requires numerous imaging tests that make it possible to stratify both the local involvement of the disease and its distant spread, which ominously determines the prognosis. Thanks to various clinical trials, the usefulness of different chemotherapy regimens, radiotherapy and surgical techniques with radical intent has now been demonstrated; these represent improvements in both prognosis and therapeutic approaches. Osteosarcoma patients should be evaluated in reference centres by multidisciplinary committees with extensive experience in proper management. Although numerous genetic and rheumatological diseases and risk factors have been described, the use of serological, genetic or other biomarkers has been limited in clinical practice compared to other neoplasms. This limits both the initial follow-up of these patients and screening in populations at risk. In addition, we cannot forget that the diagnosis is mainly based on the direct biopsy of the lesion and imaging tests, which illustrates the need to study new diagnostic alternatives. Therefore, the purpose of this study is to review the natural history of the disease and describe the main biomarkers, explaining their clinical uses, prognosis and limitations.

The cell biology behind the oncogenic PIP3 lipids.

The different mechanisms of phosphoinositide 3-kinase (PI3K) activation in cancer as well as the events that result in PI3K pathway reactivation after patient treatment with PI3K inhibitors was discussed on October 15-17th, 2018, in the medieval town of Baeza (Universidad Internacional de Andalucía, Spain) at the workshop entitled 'The cell biology behind the oncogenic PIP3 lipids'. These topics and the data presented regarding cellular functions altered by PI3K deregulation, the cooperation of PI3K/PTEN mutations with other tumor drivers, and the lessons learned for PI3K-targeted therapy, are discussed below.

Chromatin regulation by Histone H4 acetylation at Lysine 16 during cell death and differentiation in the myeloid compartment.

Histone H4 acetylation at Lysine 16 (H4K16ac) is a key epigenetic mark involved in gene regulation, DNA repair and chromatin remodeling, and though it is known to be essential for embryonic development, its role during adult life is still poorly understood. Here we show that this lysine is massively hyperacetylated in peripheral neutrophils. Genome-wide mapping of H4K16ac in terminally differentiated blood cells, along with functional experiments, supported a role for this histone post-translational modification in the regulation of cell differentiation and apoptosis in the hematopoietic system. Furthermore, in neutrophils, H4K16ac was enriched at specific DNA repeats. These DNA regions presented an accessible chromatin conformation and were associated with the cleavage sites that generate the 50 kb DNA fragments during the first stages of programmed cell death. Our results thus suggest that H4K16ac plays a dual role in myeloid cells as it not only regulates differentiation and apoptosis, but it also exhibits a non-canonical structural role in poising chromatin for cleavage at an early stage of neutrophil cell death.

A comparison of two designs of postoperative shoe for hallux valgus surgery: A biomechanical study in a cadaveric model.

BACKGROUND: Hallux Valgus Surgery success depends not only on the operative technique, but also on the care of the foot during the postoperative period. Orthopedic shoes have been developed to decrease the weight load on the first ray, an excess of which might lead to a loss of fixation or pseudoarthrosis. The goal of this study was to determine how the load distribution changed as the forced applied to the foot increased, with and without an orthopedic shoe. Also, we compared to different shoe models. METHODS: Pressure sensors were placed under the first metatarsal head and the heel of twenty specimens of fresh cadaveric adult feet. Two orthopedic shoes were chosen, a double padded (MS) and a reverse camber shoe (RCS). 10 kg loads were progressively applied, up to 60 kg. We first compared three instances: no shoe, MS and RCS. A secondary analysis comparing barefoot versus shoes was performed. A mean comparison was performed (ANOVA/T-student). RESULTS: The mean pressure of the heed and the first metatarsal showed that there were significant differences between groups (P < .005). The secondary analysis (no shoe vs orthopedic shoes) showed that the pressure without shoe was significantly higher than with any orthopedic shoe (P < .005). There were no statistically significant differences between models of shoes (P = .402). CONCLUSION: After a surgical procedure for hallux valgus fixation, postoperative shoes should be indicated to decrease the pressure on the first metatarsal head and heel in order to avoid an overload of the postoperative area. LEVEL OF EVIDENCE: Cadaveric study. Level V.

Functions of Nuclear Polyphosphoinositides.

Despite interest in phosphoinositide (PtdIns) kinases, such as PtdIns 3 kinases (PI3K), as targets for controlling plasma membrane PtdIns levels in disease, the PtdIns have another less well-known site of action in the cell nucleus.Recent studies show that PtdIns use a variety of strategies to alter DNA responses. Here, we provide an overview of these newly identified forms of gene expression control, which should be considered when studying the therapeutic use of PtdIns-directed compounds. As PI3K is one of the most important clinical targets in recent years, we will focus on two polyphosphoinositides, the PI3K substrate PtdIns(4,5)di-phosphate (PI4,5P2) and its product PtdIns(3,4,5)tri-phosphate (PI3,4,5P3).

Persistent regulatory T-cell response 2 years after 3 years of grass tablet SLIT: Links to reduced eosinophil counts, sIgE levels, and clinical benefit.

BACKGROUND: In the first 2 years of grass tablet sublingual immunotherapy treatment, we have previously demonstrated a progressive development of a regulatory T-cell response, which was preceded by an early decrease in the frequency of both IL-4+ cells and sIgE levels. A progressive increase in sIgG4 levels and FAB blockage were also found. METHODS: By monitoring immunological kinetics during 3 years of active treatment + 2 years of follow-up, we aimed to identify key immunological parameters that could explain sustained clinical benefit of grass tablet sublingual immunotherapy. RESULTS: Thirty patients completed the 5-year clinical trial protocol. Although individual responses were heterogeneous, reduction in both sIgE and circulating IL-4+ cells compared to the initial 1- to 4-month peak was maintained throughout the 3-year treatment period and for 2 years after discontinuation. Meanwhile, after a 2-year increase in sIgG4, the levels were stabilized during the third year and decreased post-therapy. FAB inhibition remained significantly inhibited throughout the study compared to preimmunotherapy in 83% of patients. A sustained regulatory T-cell response, after IT cessation, occurs in two-thirds of the patients. There was a statistical association between this regulatory response, the maintenance of lower eosinophil counts during grass pollen seasons, and sIgE titers lower than before immunotherapy treatment, and the latter were significantly associated with clinical response. CONCLUSION: Our results suggest that the immunological mechanisms underlying the sustained response after 2 years of cessation of immunotherapy (3-year treatment period) are linked to the acquisition and maintenance of a regulatory T-cell response.

Diving-related fatalities: multidisciplinary, experience-based investigation.

To describe the technical characteristics of fatal diving mishaps and to elucidate the causes of death using a sequence analysis and a multidisciplinary investigation of diving-related fatalities. All cases of diving deaths recorded on the coast of Girona (Spain) between January 2009 and May 2018 were analyzed. Most data were obtained from the police technical reports and the forensic pathology service. Each accident was analyzed in order to identify the trigger, disabling agent, disabling injury, and cause of death. During the study period 25 diving-related fatalities were recorded. Most of the victims were males aged 50-69 years, and 11 were experienced divers. Almost all victims were using open-circuit SCUBA to breathe with compressed air as their sole gas supply. None of the victims were diving alone. The most common identified triggers included exertion, panic, buoyancy problems, disorientation and confusion. The main factors identified as disabling agents were rapid ascent, a cardiac incident, panic and entrapment. Asphyxia, lung over expansion, and myocardial ischemia were the most frequent disabling injuries. Finally, drowning represented the main cause of death, followed by arterial gas embolism and natural causes or internal diseases. A differential diagnosis, performed in the setting of a multidisciplinary investigation, is essential for elucidating the cause of death in diving-related fatalities. The proposed sequence analysis allows to clarify underlying problems in these cases and to identify risk factors and unsafe behaviors in diving.

Chronic Obstructive Pulmonary Disease in Lung Cancer Patients: Prevalence, Underdiagnosis, and Clinical Characterization.

BACKGROUND: Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality. The differential clinical and functional features among LC patients with or without COPD have not been defined. OBJECTIVES: The aims of this study were to examine the prevalence and underdiagnosis rate of COPD in LC patients and to compare the clinical and functional features of LC patients with and without COPD. METHODS: We designed a multicenter hospital-based study including all LC cases diagnosed from January 2014 to August 2016. We assessed epidemiological, clinical, radiological, functional, and histological variables in all cases. RESULTS: We recruited 602 patients with LC, most of them men (77.9%), with a median age of 67 ± 15 years. The COPD prevalence among LC patients was 51.5%, with a underdiagnosis rate of 71.6%. The LC+COPD patients were older and the proportion of men was higher compared with the LC-only patients. The LC+COPD patients had more pack-years, more squamous LC, a lower monoxide transfer coefficient (KCO), and higher Charlson index scores than patients with LC only. The median survival of LC-only patients was 37% longer than that of LC+COPD patients (22 vs. 16 months), but this difference was not statistically significant. CONCLUSIONS: Among LC patients, COPD is prevalent and underdiagnosed. Patients with LC+COPD more often have squamous LC, have greater comorbidities, and have a lower KCO. More effort should be made for an early diagnosis of COPD to select patients at higher risk of developing LC.

Diagnosis of arterial gas embolism in SCUBA diving: modification suggestion of autopsy techniques and experience in eight cases.

The purpose of this study was to suggest modifications of autopsy techniques in order to improve post-mortem diagnosis of arterial gas embolism (AGE) based on multidisciplinary investigation of SCUBA diving fatalities. Five adult human cadavers from the voluntary donation program of the Human Anatomy Laboratory, and eight judicial autopsied bodies of SCUBA divers from the Forensic Pathology Service were assessed. Before performing any autopsies, we accessed the diving plan and the divers' profiles for each case. We then introduced a new dissection procedure that included identification, isolation, and manipulation of carotid, vertebral and thoracic arterial systems. The dissected vascular structures that allowed optimall isolation of the systemic arterial circulation were identified and ligated. In three of the eight judicial cases, we had a strongly suggestive history of arterial gas embolism following pulmonary barotrauma (PBt/AGE). In these cases, the additional arterial dissection allowed us to clearly diagnose AGE in one of them. The autopsy of the rest of the cases showed other causes of death such as asphyxia by drowning and heart attack. In all cases we were able to reject decompression sickness, and in some of them we showed the presence of artefacts secondary to decomposition and resuscitation maneuvers. These results allow us to suggest a specific autopsy technique divided into four steps, aimed at confirming or excluding some evidence of dysbaric disorders according to a re-enactment of the incident. We have demonstrated the presence of large volumes of intravascular air, which is typical of PBt/AGE.

Inhibition of PI3Kδ reduces kidney infiltration by macrophages and ameliorates systemic lupus in the mouse.

Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4(+) effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.