Functional asplenia in hemoglobin SC disease

The incidence of functional asplenia in sickle-hemoglobin C (SC) disease has not been defined, and the use of prophylactic penicillin to prevent life-threatening septicemia in this disorder is controversial. The percentage of red blood cells with pits (pit count) is a reliable assay of splenic function in other disorders but has not been validated in hemoglobin SC disease. To address these issues, we conducted a prospective, multicenter study of splenic function in persons with hemoglobin SC disease. Baseline clinical data were recorded, and red blood cell pit counts were performed on 201 subjects, aged 6 months to 90 years, with hemoglobin SC; 43 subjects underwent radionuclide liver- spleen scanning. Pit counts greater than 20% were associated with functional asplenia as assessed by liver-spleen scan, whereas pit counts less than 20% were found in subjects with preserved splenic function. Pit counts greater than 20% were present in 0 of 59 subjects (0%) less than 4 years of age, in 19 of 86 subjects (22%) 4 to 12 years of age, and in 25 of 56 subjects (45%) greater than 12 years of age. Other subjects with hemoglobin SC, who had previously undergone surgical splenectomy, had higher pit counts (59.7% +/- 9.5%) than splenectomized subjects without hemoglobinopathy (38.5% +/- 8.8%) or with sickle cell anemia (20.5% +/- 1.9%; P < .001). Two subjects with hemoglobin SC disease (not splenectomized), ages 14 and 15 years, with pit counts of 40.3% and 41.7% died from pneumococcal septicemia. These data indicate that functional asplenia occurs in many patients with hemoglobin SC disease, but its development is usually delayed until after 4 years of age. The pit count is a reliable measure of splenic function in hemoglobin SC disease, but values indicative of functional asplenia (> 20% in our laboratory) are higher than in other disorders. The routine administration of prophylactic penicillin to infants and young children with hemoglobin SC disease may not be necessary.     

Tailoring nanoparticle designs to target cancer based on tumor pathophysiology

Nanoparticles can provide significant improvements in the diagnosis and treatment of cancer. How nanoparticle size, shape, and surface chemistry can affect their accumulation, retention, and penetration in tumors remains heavily investigated, because such findings provide guiding principles for engineering optimal nanosystems for tumor targeting. Currently, the experimental focus has been on particle design and not the biological system. Here, we varied tumor volume to determine whether cancer pathophysiology can influence tumor accumulation and penetration of different sized nanoparticles. Monte Carlo simulations were also used to model the process of nanoparticle accumulation. We discovered that changes in pathophysiology associated with tumor volume can selectively change tumor uptake of nanoparticles of varying size. We further determine that nanoparticle retention within tumors depends on the frequency of interaction of particles with the perivascular extracellular matrix for smaller nanoparticles, whereas transport of larger nanomaterials is dominated by Brownian motion. These results reveal that nanoparticles can potentially be personalized according to a patient’s disease state to achieve optimal diagnostic and therapeutic outcomes.Nanotechnology remains an emerging and important research discipline for detecting and treating cancer. Nanomaterials can be engineered with different sizes, shapes, and surface chemistries, as well as assembled into hierarchical nanosystems (1). Nanomaterials can also be engineered with unique properties such as emission of light for fluorescence detection (2), magnetism for magnetic resonance imaging (3, 4), and thermal emission for ablation of tumor cells (5). Despite the potential of nanomaterials, typically less than 5% of an administered dose reaches the tumor compartment (6) because of poor retention within the tumor space and uptake by the skin (7), spleen, and liver (8–10). Refinements to the size, shape, and surface chemistry of nanomaterials have improved their blood half-lives (11, 12) and interactions with cancer cells (13–15). Unfortunately, clinical translation of cancer nanomedicine remains stagnated by adherence to the ideology that nanoparticles and other agents can be designed to “universally” detect and treat tumors independent of type or stage of cancer progression. Tumor growth leads to physiological changes in their tissue composition (cell density, vascularity, necrosis, and stroma). If nanoparticles could be tailored according to the physiological state of each tumor, cancer detection and treatment may be drastically improved. However, investigations into the effect of tumor pathophysiology on nanoparticle accumulation and kinetics have been limited.Fundamental analysis of tumor pathophysiology has identified unique cellular and structural properties associated with various stages of cancer progression. We currently understand that the increasing vascular tortuosity, inhomogeneity, and restricted blood flow (and subsequent low blood pressure) associated with tumor growth prevents chemotherapeutic agents from reaching their target. This impairment of drug delivery may lead to poor therapeutic efficacy and cancer recurrence (16, 17). As we learn more about the cellular, vascular, and compositional characteristics of tumors, it is increasingly evident that tailoring drug delivery vehicles to the physiological state of a tumor may be instrumental to improving treatment of this disease (18, 19). However, enabling clinicians to personalize patient care will require a deeper understanding of the implications of tumor anatomy and pathophysiology on the delivery and function of medicinal agents.Here, we determine whether the delivery of spherical gold nanoparticles (AuNPs) can be affected by changes in tumor volume—a surrogate of cancer progression. Specifically, we (i) characterize the changes in the physiological structures and microenvironment of tumors as they grow in a tumor xenograft mouse model, and (ii) explore how such changes impact uptake, permeation, and retention of polyethylene glycol (PEG)-coated AuNPs. Understanding these variations will enable clinicians to personalize cancer therapy by catering nanotherapeutic regimens according to tumor characteristics. As a proof of concept, we successfully demonstrate that observable changes in tumor pathophysiology can be used in a decision matrix to rationally select AuNP designs according to desired function.     

Macrochimerism in Intestinal Transplantation: Association With Lower Rejection Rates and Multivisceral Transplants,Without GVHD

Blood chimerism has been reported sporadically among visceral transplant recipients, mostly in association with graft‐vs‐host disease (GVHD). We hypothesized that a higher degree of mixed chimerism would be observed in multivisceral (MVTx) than in isolated intestinal (iITx) and isolated liver transplant (iLTx) recipients, regardless of GVHD. We performed a longitudinal prospective study investigating multilineage blood chimerism with flow cytometry in 5 iITx and 4 MVTx recipients up to one year posttransplant. Although only one iITx patient experienced GVHD, T cell mixed chimerism was detected in 8 out of 9 iITx/MVTx recipients. Chimerism was significantly lower in the four subjects who displayed early moderate to severe rejection. Pre‐formed high‐titer donor‐specific antibodies, bound in vivo to the circulating donor cells, were associated with an accelerated decline in chimerism. Blood chimerism was also studied in 10 iLTx controls. Among nonsensitized patients, MVTx recipients exhibited greater T and B cell chimerism than either iITx or iLTx recipients. Myeloid lineage chimerism was present exclusively among iLTx and MVTx (6/13) recipients, suggesting that its presence required the hepatic allograft. Our study demonstrates, for the first time, frequent T cell chimerism without GVHD following visceral transplantation and a possible relationship with reduced rejection rate in MVTx recipients.     

Intrathoracic migration of a silicone breast implant 5 months after video-assisted thoracoscopic surgery

A 72-year-old woman, who had previous bilateral reconstruction mammoplasty, underwent video-assisted thoracoscopic surgery for a right middle lobe pulmonary carcinoid. Five months after her surgery, the patient noticed an acute pronounced reduction in her right breast volume, with shortness of breath and cough. A computed tomography study of the chest revealed intrathoracic migration and rupture of her right breast implant, with associated silicone thorax. Subsequent video-assisted thoracoscopic surgery confirmed this diagnosis.     

An audit of the complications of intercostal chest drain insertion in a high volume trauma service in South Africa

IntroductionIntercostal chest drain (ICD) insertion is a commonly performed procedure in trauma and may be associated with significant morbidity.MethodsThis was a retrospective review of ICD complications in a major trauma service in South Africa over a four-year period from January 2010 to December 2013.ResultsA total of 1,050 ICDs were inserted in 1,006 patients, of which 91% were male. The median patient age was 24 years (interquartile range [IQR]: 20–29 years). There were 962 patients with unilateral ICDs and 44 with bilateral ICDs. Seventy-five per cent (758/1,006) sustained penetrating trauma and the remaining 25% (248/1006) sustained blunt trauma. Indications for ICD insertion were: haemopneumothorax (n=338), haemothorax (n=314), simple pneumothorax (n=265), tension pneumothorax (n=79) and open pneumothorax (n=54).Overall, 203 ICDs (19%) were associated with complications: 18% (36/203) were kinked, 18% (36/203) were inserted subcutaneously, 13% (27/203) were too shallow and in 7% (14/203) there was inadequate fixation resulting in dislodgement. Four patients (2%) sustained visceral injuries and two sustained vascular injuries. Forty-one per cent (83/203) were inserted outside the ‘triangle of safety’ but without visceral or vascular injuries. One patient had the ICD inserted on the wrong side. Junior doctors inserted 798 ICDs (76%) while senior doctors inserted 252 (24%). Junior doctors had a significantly higher complication rate (24%) compared with senior doctors (5%) (p<0.001). There was no mortality as a direct result of ICD insertion.ConclusionsICD insertion is associated with a high rate of complications. These complications are significantly higher when junior doctors perform the procedure. A multifaceted quality improvement programme is needed to improve the situation.     

Impaired cerebrovascular hemodynamics are associated with cerebral white matter damage

White matter hyperintensities (WMH) in elderly individuals with vascular diseases are presumed to be due to ischemic small vessel diseases; however, their etiology is unknown. We examined the cross-sectional relationship between cerebrovascular hemodynamics and white matter structural integrity in elderly individuals with vascular risk factors. White matter hyperintensity volumes, fractional anisotropy (FA), and mean diffusivity (MD) were obtained from MRI in 48 subjects (75±7years). Pulsatility index (PI) and dynamic cerebral autoregulation (dCA) was assessed using transcranial Doppler ultrasound of the middle cerebral artery. Dynamic cerebral autoregulation was calculated from transfer function analysis (phase and gain) of spontaneous blood pressure and flow velocity oscillations in the low (LF, 0.03 to 0.15 Hz) and high (HF, 0.16 to 0.5 Hz) frequency ranges. Higher PI was associated with greater WMH (P<0.005). Higher phase across all frequency ranges was associated with greater FA and lower MD (P<0.005). Lower gain was associated with higher FA in the LF range (P=0.001). These relationships between phase and FA were significant in the territories limited to the middle cerebral artery as well as across the entire brain. Our results show a strong relationship between impaired cerebrovascular hemodynamics (PI and dCA) and loss of cerebral white matter structural integrity (WMH and DTI metrics) in elderly individuals.     

Xenotransplantation: immunological hurdles and progress toward tolerance

The discrepancy between organ need and organ availability represents one of the major limitations in the field of transplantation. One possible solution to this problem is xenotransplantation. Research in this field has identified several obstacles that have so far prevented the successful development of clinical xenotransplantation protocols. The main immunologic barriers include strong T-cell and B-cell responses to solid organ and cellular xenografts. In addition, components of the innate immune system can mediate xenograft rejection. Here, we review these immunologic and physiologic barriers and describe some of the strategies that we and others have developed to overcome them. We also describe the development of two strategies to induce tolerance across the xenogeneic barrier, namely thymus transplantation and mixed chimerism, from their inception in rodent models through their current progress in preclinical large animal models. We believe that the addition of further beneficial transgenes to Gal knockout swine, combined with new therapies such as Treg administration, will allow for successful clinical application of xenotransplantation.