Splenic cysts in the pediatric population: a report of 21 cases with review of the literature.

Splenic cysts are rare lesions that can occur in parasitic and non-parasitic forms. Because they are uncommon, the classification, pathogenesis, and management techniques are still debated. The continual review of splenic cyst cases in the pediatric population is essential for establishing a clear diagnosis and course of treatment. This report presents 21 cases of pediatric splenic cysts observed at Children's Healthcare of Atlanta over an 18 year period (1993-2011). The cases include both parasitic and and nonparasitic cysts. The current splenic cyst classification and treatment methods are analyzed through a review of the current theories and based on our experiences.

Neurosarcoidosis presenting as acute infarction on diffusion-weighted MR imaging: summary of radiologic findings.

A 36-year-old woman presented with acute-onset right lower extremity paresthesias, dysarthria, right facial droop, and right hemiparesis. CT and MR imaging of the brain revealed extensive white matter disease and left basal ganglia infarction with dural and leptomeningeal enhancement. Differential considerations included vasculitis, granulomatous disease, and neoplasm. Chest, abdomen, and pelvis CTs were normal. Right temporal lobe biopsy revealed noncaseating granulomatous inflammation consistent with neurosarcoidosis.

RGS18 is a myeloerythroid lineage-specific regulator of G-protein-signalling molecule highly expressed in megakaryocytes.

Myelopoiesis and lymphopoiesis are controlled by haematopoietic growth factors, including cytokines, and chemokines that bind to G-protein-coupled receptors (GPCRs). Regulators of G-protein signalling (RGSs) are a protein family that can act as GTPase-activating proteins for G(alphai)- and G(alphaq)-class proteins. We have identified a new member of the R4 subfamily of RGS proteins, RGS18. RGS18 contains clusters of hydrophobic and basic residues, which are characteristic of an amphipathic helix within its first 33 amino acids. RGS18 mRNA was most highly abundant in megakaryocytes, and was also detected specifically in haematopoietic progenitor and myeloerythroid lineage cells. RGS18 mRNA was not detected in cells of the lymphoid lineage. RGS18 was also highly expressed in mouse embryonic 15-day livers, livers being the principal organ for haematopoiesis at this stage of fetal development. RGS1, RGS2 and RGS16, other members of the R4 subfamily, were expressed in distinct progenitor and mature myeloerythroid and lymphoid lineage blood cells. RGS18 was shown to interact specifically with the G(alphai-3) subunit in membranes from K562 cells. Furthermore, overexpression of RGS18 inhibited mitogen-activated-protein kinase activation in HEK-293/chemokine receptor 2 cells treated with monocyte chemotactic protein-1. In yeast cells, RGS18 overexpression complemented a pheromone-sensitive phenotype caused by mutations in the endogeneous yeast RGS gene, SST2. These data demonstrated that RGS18 was expressed most highly in megakaryocytes, and can modulate GPCR pathways in both mammalian and yeast cells in vitro. Hence RGS18 might have an important role in the regulation of megakaryocyte differentiation and chemotaxis.

CCR9-positive lymphocytes and thymus-expressed chemokine distinguish small bowel from colonic Crohn's disease.

BACKGROUND & AIMS: Thymus-expressed chemokine (TECK) or CCL25) is selectively expressed in the small bowel (SB), where lamina propria lymphocytes (LPL) and intraepithelial leukocyte expressing the cognate chemokine receptor CCR9 predominate. We characterize the role of TECK and CCR9-expresing lymphocytes in small intestinal Crohn's disease. METHODS: CCR9 expression on lymphocytes from lamina propria, mesenteric lymph node, and peripheral blood was analyzed by flow cytometry and by Northern blotting for LPL. TECK expression was analyzed in inflamed SB and colon by reverse-transcription polymerase chain reaction and immunohistochemistry. RESULTS: The fraction of CCR9(+) T cells in inflamed SB was significantly lower than in uninvolved SB mucosa. In contrast, in peripheral blood lymphocytes, CCR9(+) lymphocytes were markedly elevated in patients with small bowel Crohn's or celiac disease, but not in patients with purely colonic Crohn's. Also, TECK expression is altered in inflamed small bowel, being intensely expressed in a patchy distribution in crypt epithelial cells in proximity to lymphocytic infiltrates. TECK is not expressed in either normal or inflamed colon. CONCLUSIONS: In SB immune-mediated diseases, there is repartitioning of CCR9(+) lymphocytes between SB and blood and an altered pattern of TECK expression in SB Crohn's. The TECK/CCR9 ligand/receptor pair may play an important role in the pathogenesis of SB Crohn's disease.

Unique subpopulations of CD56+ NK and NK-T peripheral blood lymphocytes identified by chemokine receptor expression repertoire.

CD56, an adhesion molecule closely related to neural cell adhesion molecule, is an immunophenotypic marker for several unique populations of PBLS: Although CD56(+) cells derive from multiple lymphocyte lineages, they share a role in immunosurveillance and antitumor responses. We have studied the chemokine receptor expression patterns and functional migratory responses of three distinct CD56(+) populations from human peripheral blood. NK-T cells were found to differ greatly from NK cells, and CD16(+) NK cells from CD16(-) NK cells. CD16(+) NK cells were the predominant population responding to IL-8 and fractalkine, whereas NK-T cells were the predominant population responding to the CCR5 ligand macrophage-inflammatory protein-1beta. CD16(-) NK cells were the only CD56(+) population that uniformly expressed trafficking molecules necessary for homing into secondary lymphoid organs through high endothelial venule. These findings describe a diverse population of cells that may have trafficking patterns entirely different from each other, and from other lymphocyte types.

Expression of chemokine receptors by lung T cells from normal and asthmatic subjects.

The lung is an important tertiary lymphoid organ with constant trafficking of T cells through the lung in both health and disease. T cell migration is controlled by a combination of adhesion receptors and chemokines expressed on vascular endothelium and in the tissue, often in an organ-specific manner. This leads to selective accumulation of different T cell subsets, a process called lymphocyte homing. There is evidence for a distinct lung-homing pathway, but no specific lung-homing receptors have been described. We analyzed the chemokine receptor profile of lung T cells to determine the extent to which lung T cells shared homing pathways with other organs such as the gut and skin. In addition, we compared expression of receptors in normal and asthmatic individuals to determine whether different pathways were used in health and disease. We observed that lung T cells expressed a profile of chemokine and adhesion receptors distinct from that of gut- and skin-homing T cells although no chemokine receptor specific for the lung was found. In particular, lung T cells expressed CCR5 and CXCR3, but not CCR9 or cutaneous lymphocyte Ag, and only low levels of CCR4 and alpha(4)beta(7). No differences were observed between lung T cells from normal vs asthmatic subjects. This study provides added support for the concept of a lung-homing pathway separate from other mucosal organs such as the gut and suggests that the chemokine pathways that control T cell migration in normal homeostasis and Th2-type inflammatory responses are similar.

Exercise program effects on women with fibromyalgia syndrome.

The purpose of this study (evaluation) was to examine the effects of an exercise program on 13 women with physician-diagnosed fibromyalgia syndrome (FMS). Participants engaged in exercise for 60 minutes each session. Group 1 (N=7) was in a 3-day-per-week program for 12 months, and group 2 (N= 6) was in a 3-day-per-week program for six months. Group 3 (N= 3) consisted of three participants from Group 1 who participated for six additional months past the 12-month period (total--18 months). Group 3 attended five sessions per week during the six additional months. All participants engaged in aerobic and resistance training. Information was collected on physical fitness, psychosocial, and FMS symptom variables. A majority of the participants appeared to experience a positive outcome on numerous measures of physical fitness, psychosocial factors, and FMS symptoms. Interview data support results. The 13 participants gained various benefits from the exercise program and functioned the same or better outside of the program. Implications for advising FMS patients relative to exercise are given for clinical nurse specialists.

HIV-1 incidence among opiate users in northern Thailand.

The incidence of human immunodeficiency virus type 1 (HIV-1) infection among opiate users was determined in a retrospective cohort of 436 patients with multiple admissions to the only inpatient drug treatment program in northern Thailand between October 1993 and September 1995. During 323.4 person-years of follow-up, 60 patients presenting for detoxification acquired HIV-1 infection, for a crude incidence rate of 18.6 per 100 person-years (95% confidence interval 14.4-23.9). All seroconverters were male. HIV-1 incidence varied by the current route of drug administration: 31.3 per 100 person-years for injectors and 2.8 per 100 person-years for noninjectors (smoking and ingestion). Significant differences were found by ethnicity: HIV-1 incidence was 29.3 per 100 person-years for Thai lowlanders and 8.5 per 100 person-years for hill tribes. Multivariate relative risk estimates showed that injecting opiates (vs. use by other routes), being unmarried, being under age 40 years, being a Thai lowlander, having a primary and secondary education, and being employed in the business sector were each independently associated with human immunodeficiency virus seroconversion. This HIV-1 incidence rate is double that reported for Bangkok and suggests that prevention and control programs for drug users need to be expanded throughout Thailand. Improved availability of more-effective treatment regimens and increased access to sterile injection equipment are needed to confront the HIV-1 epidemic among opiate users in northern Thailand.

PIP: The incidence of HIV-1 infection among opiate users was assessed in a retrospective cohort of 436 patients with multiple admissions to the only inpatient drug treatment program in northern Thailand between October 1993 and September 1995. During 323.4 person-years of follow-up, 60 patients presenting for detoxification acquired HIV-1 infection, for a crude incidence rate of 18.6/100 person-years. All seroconverters were male. HIV-1 incidence varied by the current route of drug administration: 31.3/100 person-years for injectors and 2.8/100 person-years among those who smoked or ingested the drug. HIV-1 incidence was 29.3/100 person-years for Thai lowlanders and 8.5/100 person-years for hill tribes. Multivariate analysis found that injecting opiates, being unmarried, being under age 40 years, being a Thai lowlander, having a primary and secondary education, and being employed in the business sector were each independently associated with HIV seroconversion. The HIV-1 incidence rate in this population is double that reported for Bangkok. As such, HIV prevention and control programs for drug users need to be expanded throughout Thailand. Moreover, improved availability of more effective treatment regimens and increased access to sterile injection equipment are needed to confront the HIV-1 epidemic among opiate users in northern Thailand.

NF-AT-Driven interleukin-4 transcription potentiated by NIP45.

The induction of cytokine gene transcription is mediated in part by the nuclear factor of activated T cells (NF-AT). Factors involved in the mechanisms of NF-AT-mediated transcription are not well understood. A nuclear factor that interacted with the Rel homology domain (RHD) of NF-ATp was identified with the use of a two-hybrid interaction trap. Designated NIP45 (NF-AT interacting protein), it has minimal similarity to any known genes. Transcripts encoding this factor were enriched in lymphoid tissues and testes. NIP45 synergized with NF-ATp and the proto-oncogene c-Maf to activate the interleukin-4 (IL-4) cytokine promoter; transient overexpression of NIP45 with NF-ATp and c-maf in B lymphoma cells induced measurable endogenous IL-4 protein production. The identification of NIP45 advances our understanding of gene activation of cytokines, critical mediators of the immune response.

The proto-oncogene c-maf is responsible for tissue-specific expression of interleukin-4.

The molecular basis for the distinctive cytokine expression of CD4+ T helper 1 (Th1) and T helper 2 (Th2) subsets remains elusive. Here, we report that the proto-oncogene c-maf, a basic region/leucine zipper transcription factor, controls tissue-specific expression of IL-4. c-Maf is expressed in Th2 but not Th1 clones and is induced during normal precursor cell differentiation along a Th2 but not Th1 lineage. c-Maf binds to a c-Maf response element (MARE) in the proximal IL-4 promoter adjacent to a site footprinted by extracts from Th2 but not Th1 clones. Ectopic expression of c-Maf transactivates the IL-4 promoter in Th1 cells, B cells, and nonlymphoid cells, a function that maps to the MARE and Th2-specific footprint. Furthermore, c-Maf acts in synergy with the nuclear factor of activated T cells (NF-ATp) to initiate endogeneous IL-4 production by B cells. Manipulation of c-Maf may alter Th subset ratios in human disease.

Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice.

NF-ATp is a member of a family of genes that encodes the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). In this study, we show that mice with a null mutation in the NF-ATp gene have splenomegaly with hyperproliferation of both B and T cells. They also display early defects in the transcription of multiple genes encoding cytokines and cell surface receptors, including CD40L and FasL. A striking defect in early IL-4 production was observed after ligation of the TCR complex by treatment with anti-CD3 in vivo. The transcription of other cytokines including IL-13, GM-CSF, and TNF alpha was also affected, though to a lesser degree. Interestingly, the cytokines IL-2 and IFN gamma were minimally affected. Despite this early defect in IL-4 transcription, Th2 development was actually enhanced at later timepoints as evidenced by increased IL-4 production and IgE levels in situations that favor the formation of Th2 cells both in vitro and in vivo. These data suggest that NF-ATp may be involved in cell growth, and that it is important for the balanced transcription of the IL-4 gene during the course of an immune response.

The lost laparoscopic stone. Potential for long-term complications.

Intraperitoneal gallstones left behind at laparoscopic cholecystectomy are not uncommon. Such stones have previously been thought to be harmless. We report three instances of delayed intra-abdominal infection and/or inflammation related to these misplaced gallstones. All three patients presented months postoperatively with vague abdominal complaints. Computed tomography revealed inflammatory foci involving intraperitoneal gallstones. All patients required percutaneous or operative drainage of the collections. Every effort should be made to locate and remove "spilled" gallstones at the time of laparoscopic cholecystectomy.

A common factor regulates both Th1- and Th2-specific cytokine gene expression.

Murine T helper cell clones are classified into two distinct subsets, T helper 1 (Th1) and T helper 2 (Th2), on the basis of cytokine secretion patterns. Th1 clones produce interleukin-2 (IL-2), tumor necrosis factor-beta (TNF-beta) and interferon-gamma (IFN-gamma), while Th2 clones produce IL-4, IL-5, IL-6 and IL-10. These subsets differentially promote delayed-type hypersensitivity or antibody responses, respectively. The nuclear factor NF-AT is induced in Th1 clones stimulated through the T cell receptor-CD3 complex, and is required for IL-2 gene induction. The NF-AT complex consists of two components: NF-ATp, which pre-exists in the cytosol and whose appearance in the nucleus is induced by an increase of intracellular calcium, and a nuclear AP-1 component whose induction is dependent upon activation of protein kinase C (PKC). Here we report that the induction of the Th2-specific IL-4 gene in an activated Th2 clone involves an NF-AT complex that consists only of NF-ATp, and not the AP-1 component. On the basis of binding experiments we show that this 'AP-1-less' NF-AT complex is specific for the IL-4 promoter and does not reflect the inability of activated Th2 cells to induce the AP-1 component. We propose that NF-ATp is a common regulatory factor for both Th1 and Th2 cytokine genes, and that the involvement of PKC-dependent factors, such as AP-1, may help determine Th1-/Th2-specific patterns of gene expression.

Possible hypothalamic impotence. Male counterpart to hypothalamic amenorrhea?

Twenty-one men with erectile complaints who were found to have a low level of serum testosterone without a reciprocal elevation of the serum levels of luteinizing hormone were evaluated to identify whether the defect was of hypothalamic or of pituitary origin. Patients underwent a luteinizing hormone (LH)-follicle-stimulating hormone (FSH)-releasing hormone stimulation test that showed a normal but sluggish increase in LH and FSH levels, thus ruling out a pituitary defect and suggesting a suprapituitary abnormality. This was confirmed when, in response to clomiphene, patients had a normal increase in gonadotropin and testosterone levels. Although the basal as well as clomiphene and gonadotropin releasing hormone-stimulated levels of total testosterone and gonadotropins were identical in men less than and more than fifty years old, the elevation of free testosterone levels in response to clomiphene was higher in patients younger than fifty. This suggested that although the primary abnormality found in these patients is altered secretion of gonadotropin hormone-releasing hormone from the hypothalamus, an age-related decline in the responsivity of Leydig cells to LH may make it more manifest in older patients. Elevation of testosterone levels from a subnormal to a normal range in response to clomiphene administered for seven days suggests that the defect is functional and reversible and that the drug may be useful in treatment of sexual dysfunction in this group of patients.

Amputation of the distal portion of the foot.

For 101 patients, initial amputation of 124 extremities involved some distal portion of the foot. Amputations done for atherosclerosis healed in eight of 21 cases (38%), compared with 40 of 77 extremities (52%) in diabetic patients. Presence of cellulitis (44 cases) and absence of a popliteal pulse (44 cases) had no significant effect on success of amputation, but a palpable foot pulse was significantly associated with a successful outcome (29/35 cases, or 83%) (P less than .005). Serial amputations to preserve the foot were successful for 18 of 31 extremities (58%), a success rate equal to that of the entire series, 72 of 124 (58%). Attempts to preserve viability in the distal portion of the foot were not associated with mortality. Cellulitis and absence of a distal pulse are not contraindications to attempting preservation of the extremity, although the best results occur when distal extremity pulses are palpable. In nearly six of every ten cases, amputation of the distal portion of the foot resulted in a successful outcome.

Inverse regulation of the yeast COX5 genes by oxygen and heme.

The COX5a and COX5b genes encode divergent forms of yeast cytochrome c oxidase subunit V. Although the polypeptide products of the two genes are functionally interchangeable, it is the Va subunit that is normally found in preparations of yeast mitochondria and cytochrome c oxidase. We show here that the predominance of subunit Va stems in part from the differential response of the two genes to the presence of molecular oxygen. Our results indicate that during aerobic growth, COX5a levels were high, while COX5b levels were low. Anaerobically, the pattern was reversed; COX5a levels dropped sevenfold, while those of COX5b were elevated sevenfold. Oxygen appeared to act at the level of transcription through heme, since the addition of heme restored an aerobic pattern of transcription to anaerobically grown cells and the effect of anaerobiosis on COX5 transcription was reproduced in strains containing a mutation in the heme-biosynthetic pathway (hem1). In conjunction with the oxygen-heme response, we determined that the product of the ROX1 gene, a trans-acting regulator of several yeast genes controlled by oxygen, is also involved in COX5 expression. These results, as well as our observation that COX5b expression varied significantly in certain yeast strains, indicate that the COX5 genes undergo a complex pattern of regulation. This regulation, especially the increase in COX5b levels anaerobically, may reflect an attempt to modulate the activity of a key respiratory enzyme in response to varying environmental conditions. The results presented here, as well as those from other laboratories, suggest that the induction or derepression of certain metabolic enzymes during anaerobiosis may be a common and important physiological response in yeast cells.

Surgically incurable well-differentiated thyroid carcinoma. Prognostic factors and results of therapy.

A series of 97 consecutive patients with well-differentiated thyroid carcinoma treated between 1941 and 1970 presented with distant metastatic disease or extensive nonresectable local neck disease or had residual carcinoma after thyroid resection. Men 40 years of age or younger and women 50 years of age or younger were considered at low risk for dying of disease; older patients were considered at high risk for dying of disease. Of 17 patients with distant metastatic carcinoma, 40% of younger patients in the low-risk group and 92% of older patients in the high-risk group died. Of 80 patients with unresectable or residual local neck cancer, only 13% of younger patients but 71% of older patients died. Survival related better to risk group classification as defined by age and sex than to any details of disease presentation or management. Treatment was far more successful in patients in the low-risk group.