South Africa's male homicide epidemic hiding in plain sight: exploring sex differences and patterns in homicide risk in a retrospective descriptive study of postmortem investigations.

Background: South Africa has homicide rates six times the global average, predominantly among men, but little is known about male victims. As part of the country's first ever study of male homicide we compared 2017 male and female victim profiles for selected covariates, against global averages and previous estimates for 2009. Methods: We conducted a retrospective descriptive study of routine data collected through postmortem investigations, calculating age-standardised mortality rates for manner of death by age, sex and province and male-to-female incidence rate ratios with 95% confidence intervals. We then used generalised linear models and linear regression models to assess the association between sex and victim characteristics including age and mechanism of injury (guns, stabs and blunt force) within and between years. Findings: 87% of 19,477 homicides in 2017 were males, equating to seven male deaths for every female, with sharp force and firearm discharge the most common external causes. Rates were higher among males than females at all ages, and up to eight times higher among males aged 15-44 years. Provincial rates varied overall and by sex, with the highest comparative risk for men vs. women in the Western Cape Province (11.4 males for every 1 female). Male homicides peaked during December and were highest on weekends, underscoring the prominent role of alcohol as a risk factor. Significantly more males tested positive for alcohol than females. Interpretation: The massive, disproportionate and enduring homicide risk borne by adult South African men highlights the negligible prevention response. Only through challenging the normative perception of male invulnerability can we begin to address the enormous burden of violence impacting men. There is an urgent need to address the insidious effect of such societal norms alongside implementing structural interventions to overcome the root causes of poverty and inequality and better control alcohol and firearms. Funding: South African Medical Research Council and Ford Foundation.

Pain management in peripheral arterial obstructive disease: oral slow-release oxycodone versus epidural l-bupivacaine.

OBJECTIVES: To compare the effectiveness of oral slow-release oxycodone (group OX, n=18) with that of epidural l-bupivacaine (group LRA, n=13) for the control of moderate/severe pain of advanced-stage peripheral arterial obstructive disease (PAOD) patients. DESIGN: Observational and retrospective analysis of advanced stage and hospitalised PAOD patients treated for pain management for at least 7 days prior to surgery or discharged from the hospital without surgery. METHODS: The outcome measures were pain intensity using the visual analogue scale under static, (VASs) and dynamic (VASd) conditions; vital signs, treatment side effects and patient satisfaction. RESULTS: In both groups, pain control was satisfactory and VAS scores median were VASs<3 and VASd<4; under dynamic conditions, pain control was better in the LRA group (p<0.01). Against few and transient side effects, most patients (n=30) found both pain treatments good or excellent. Results should be confirmed by studies with larger samples. CONCLUSIONS: In the perioperative setting, the epidural infusion of local anaesthetics, such as l-bupivacaine, is an effective technique for pain control in PAOD patients; for patients with contraindication for this technique or for non-surgical or outpatients, slow-release oxycodone is suggested as a possible alternative for the control of severe pain in these patients.

Major abdominal surgery and postoperative pain control: are protocols enough?

Suitable postoperative pain control (POPC) requires both the application of appropriate pain therapy and the continuous supervision of its therapeutic effects. In our hospital, POPC was, until recently, limited to the first 48 postoperative hours. The purpose of this retrospective study was to assess, the evolution of POPC at the end of the first postoperative 48 hours among major abdominal surgery patients using the Acute Pain Service (APS) database. Further we sought to establish the indications to extend POPC to the entire postoperative period. Regardless of the type of protocol applied after surgery, 79.6% of cases showed pain control was still needed after the 48(th) hour. In about half of the cases, POPC was perpetuated with only the drug category or by dosage modifications, while in roughly one third of the cases we adopted both drug and administration route changes. These changes were made by the APS after a thorough evaluation of the patients' conditions and needs in terms of analgesia. Interestingly, in approximately 5% of cases the surgeon decided to interrupt pain therapy. When applying evidence-based guideline protocols, organizational issues are important as well as a better definition of the APS role in POPC, at least from the timing point of view.

Autologous T cells control B-chronic lymphocytic leukemia tumor progression in human-->mouse radiation chimera.

B-chronic lymphocytic leukemia (B-CLL) is characterized by the clonal accumulation of CD5+ B cells. It has been suggested that CLL cells may be regulated by inhibitory and growth-promoting signals exerted by autologous T cells. We have recently described a model for human B-CLL in which peripheral blood mononuclear cells (PBMCs) are transplanted into the peritoneal cavity of lethally irradiated mice radioprotected with bone marrow from mice with severe combined immunodeficiency. In this model, adoptive transfer of low-stage PBMCs leads to marked engraftment of T cells or combined T and CLL cell engraftment, whereas infusion of high-stage PBMCs leads to dominance of CLL cells with a miniscule level of T-cell engraftment. This mutual exclusive pattern of engraftment indicated that T cells might control the expansion of tumor cells in the peritoneum of recipient BALB/c mice. In the present study, we further investigated this question and we demonstrate that in vivo T-cell depletion, using OKT3 antibody, markedly enhances the engraftment of B-CLL cells from patients with early-stage disease. In mice receiving PBMCs from 11 donors with advanced-stage disease, the results were more heterogeneous. In five patients the results were similar to those observed in early stage, whereas in two cases no CLL cell engraftment was found in the absence of T cells. The addition of purified T cells to PBMCs led to a substantial decrease of CLL engraftment in three advanced-stage cases. These results strengthen the working hypothesis that autologous T cells can actively suppress the expansion of the pathological cells in human-->mouse radiation chimera. This effect is prominent in early-stage disease, whereas in advanced stage suppressive and/or stimulatory effects may occur in different patients. The interaction of T cells with tumor cells and the potential of autologous T cell/immune-therapy in CLL can be further explored in this model.

Human/mouse radiation chimera generated from PBMC of B chronic lymphocytic leukemia patients with autoimmune hemolytic anemia produce anti-human red cell antibodies.

Previous studies performed in our laboratory have shown that B-CLL cells are involved in the production of anti-red cell auto-antibodies, providing a possible mechanism for the autoimmune hemolytic anemia occurring during the course of B-CLL. In order to confirm this hypothesis, we attempted to transfer human B-CLL with AIHA to immunodeficient mice. Peripheral blood mononuclear cells (PBMC) from 11 B-CLL patients suffering from AIHA were transplanted into the peritoneal cavity of lethally irradiated Balb/c mice reconstituted with SCID bone marrow. Chimeric mice generated from PBMC of these patients (in stage III-IV of the disease) exhibited an engraftment profile with dominance of tumor cells and minuscule levels of T cells. Eighty-five percent of the chimeric mice generated from 10 out of the 11 B-CLL patients with Coombs'-positive AIHA, produced human Ig with anti-human red cell specificity as detected by indirect anti-globulin test. In addition, anti-red cell auto-antibodies were produced in 36% of chimeric mice generated from PBMC of Coombs'-negative B-CLL. In contrast, control experiments in which splenic cells from idiopathic AIHA or PBMC from normal donors were transplanted, failed to produce anti-RBC. This in vivo model further supports the relationship between the B cell expansion and the autoimmune hemolytic process.

Pressure support ventilation.

The field of ventilatory support has changed dramatically with the introduction of improvements in technology and new ventilatory modes. The most recent ventilators are characterized by microprocessor technology, making the interaction between patient and ventilator more sophisticated than ever before. This technology has enabled the development of pressure support ventilation, which has gained extensive popularity during the past 10 years. Pressure support ventilation is different from controlled mechanical ventilation or intermittent mandatory ventilation; pressure support ventilation is characterized by a unique combination of simultaneous spontaneous and mechanical breathing, so that the ventilatory and flow rates and tidal volume depend on the patient's breathing pattern and the set level of pressure support. Pressure support ventilation can be used as a stand-alone ventilatory support mode and alternative to volume-controlled ventilation, and it can be used in weaning patients from mechanical ventilation.

Engraftment of human kidney tissue in rat radiation chimera: I. A new model of human kidney allograft rejection.

BACKGROUND: We have recently shown that lethally irradiated normal strains of mice and rats, reconstituted with bone marrow from severe combined immune deficiency (SCID) mice, can be engrafted with human peripheral blood mononuclear cells (PBMC). METHODS: The feasibility of transplanting human renal tissue under the kidney capsule of the SCID/Lewis and SCID/nude radiation chimera and the effects of intraperitoneal infusion of allogeneic human PBMC on the human renal implants were investigated by histology, electron microscopy, immunohistochemistry, and fluorescence-activated cell sorter analysis. RESULTS: Sequential evaluation of the human renal implants from 10 days to 2 months after transplantation showed that human parenchymal elements survive in the implants up to 2 months after transplantation. The overall architecture of the transplanted kidney tissue and the normal structure of individual cells in the glomeruli and tubuli were preserved. Infusion of allogeneic human PBMC after kidney implantation resulted in patchy cellular infiltrates, composed mainly of activated human T cells, and led to prompt rejection of the human renal tissue, whereas no signs of inflammation were observed in human renal implants of chimeric rats that did not receive human PBMC. Treatment with OKT3 antibody, anti-human CD25 antibody, or CTLA4Ig fusion protein in vivo ameliorated the rejection process. CONCLUSIONS: Human adult kidney fragments transplanted into SCID-like rats transiently retain competent parenchymal structures. When these grafts are combined with allogeneic human PBMC, acute cellular rejection develops. We suggest that this chimeric model might be useful for the investigation of the effects of experimental manipulation on the kinetics of the inflammatory response during human renal allograft rejection.

Engraftment of human kidney tissue in rat radiation chimera: II. Human fetal kidneys display reduced immunogenicity to adoptively transferred human peripheral blood mononuclear cells and exhibit rapid growth and development.

BACKGROUND: Transplantation of human kidney tissue under the kidney capsule of immunodeficient animals (severe combined immunodeficiency [SCID]/Lewis and SCID/nude chimeric rats), and the subsequent intraperitoneal infusion of allogeneic human peripheral blood mononuclear cells (PBMC), results in a rapid and consistent human renal allograft rejection. We investigated the consequences of grafting human fetal kidney fragments instead of the adult tissue. METHODS: The development of human fetal kidney tissue and its interaction with allogeneic human PBMC in chimeric rats were analyzed by histology, immunohistochemistry, and in situ hybridization. RESULTS: We report successful establishment of human fetal kidney to SCID/Lewis and SCID/nude chimeric rats. The intrarenal human fetal renal implants displayed rapid growth and maintained numerous developing glomeruli and tubular structures up to 4 months after transplantation. In contrast to the adult human kidney, infusion of allogeneic human PBMC resulted in either minimal human T-cell infiltration or abundant nonrejecting T-cell infiltrates, characterized by a reduced number of T cells of the CD45RO+ or HLA-DR+ subsets, both leading to less tissue destruction as well as to continued growth of the human fetal renal tissue. This observation was found to be related to the reduced protein expression of tissue HLA class I and II, intercellular adhesion molecule 1, and vascular adhesion molecule 1 in the fetal grafts compared with the adult grafts. Lack of tissue expression of Fas ligand in the fetal grafts suggests that the latter does not contribute to the delayed rejection of human fetal kidneys. CONCLUSIONS: Our model should be useful for the study of human fetal renal development and the human alloresponse against fetal tissue.

In vivo modulation of the allogeneic immune response by human fetal kidneys: the role of cytokines, chemokines, and cytolytic effector molecules.

BACKGROUND: We have recently demonstrated that human fetal renal tissue, implanted under the kidney capsule of severe immunodeficient rats, escapes early destruction by intraperitoneal infusion of allogeneic human peripheral blood mononuclear cells, compared with the rapid rejection of implants of human adult kidney tissue. Variable amounts of human mononuclear infiltrates were seen in the transplanted fetal kidney, however, prolonged survival of the fetal tissue (maintenance of graft architecture and significant growth) was independent of the cellular infiltrate. METHODS: We have used this experimental model to sequentially analyze transcript levels of interferon-gamma and interleukin (IL)-2 (T helper 1 cytokines), IL-4 and IL-10 (T helper 2 cytokines), RANTES, MIP1beta (beta chemokines) and their receptor CCR5, and Fas ligand (cytolytic effector molecule). Analysis was performed by reverse transcriptase-polymerase chain reaction, in both fetal and adult kidney grafts, after infusion of allogeneic human peripheral blood mononuclear cells. RESULTS: Transcript levels of interferon-gamma and IL-2 in the fetal grafts were markedly reduced throughout follow-up, compared with those observed in the adult implants. Peak levels of these cytokines appeared late in the rejection process. Concomitant with these findings, IL-4 mRNA was up-regulated during the early phase, whereas IL-10 mRNA persisted throughout the rejection process, indicating that a T helper 2 bias occurred in the fetal grafts. In addition, RANTES (after an early peak), MIP1beta, CCR5, and Fas ligand mRNA levels were suppressed in the fetal grafts compared with those in the adult grafts. CONCLUSIONS: These findings indicate that the immune response of kidney rejection is dependent on whether the target organ is of fetal or adult origin, and suggest that an allogeneic immune system mounts a T helper 2-biased response when the target organ is of fetal origin.

Engrafted human T and B lymphocytes form mixed follicles in lymphoid organs of human/mouse and human/rat radiation chimera.

BACKGROUND: We recently described a new approach that enables the generation of human/mouse chimera by adoptive transfer of human peripheral blood mononuclear cells into lethally irradiated normal strains of mice or rats, radioprotected with bone marrow from donors with severe combined immune deficiency. In such human/mouse chimera, a marked humoral response to recall antigens, as well as a significant primary response to keyhole limpet hemocyanin, has been generated. METHODS: In the present study, the organ distribution of the engrafted human cells in the human/mouse and human/rat chimera was investigated by immunohistochemistry. RESULTS: Our results show that the T cells seem to be distributed throughout the reticular endothelial system, almost behaving like particles without any homing specificity. The B cells, however, can barely be found in internal organs, such as the liver or the pancreas, and are concentrated in the secondary lymphoid system (e.g., spleen, lymph node, and nonencapsulated lymphoid tissue). The B cells, together with the engrafted human T cells, form mixed lymphoid follicles. CONCLUSIONS: The different homing patterns exhibited by the T and B lymphocytes indicate that the homing receptors on human B cells might be cross-reactive with their mouse counterparts, in contrast to the human T cells, which seem to be unable to interact with the mouse homing receptors. The presence of human B and T lymphocytes in close proximity to each other in the lymphoid tissues is in accordance with the ability of human/BALB radiation chimera to mount significant primary human antibody responses.

Corticocortical connections between frontal periarcuate regions and visual areas of the superior temporal sulcus and the adjoining inferior parietal lobule in the macaque monkey.

In macaque monkeys, corticocortical connections between distinct parietotemporal visual areas (areas MST-FST, DP, and 7a) and frontal periarcuate areas are studied using tritiated aminoacids and WGA-HRP. While labeling within the banks of the principal sulcus, the dorsal part of the arcuate concavity, and the banks of the upper arcuate limb were present in both 7a and MST-FST injected animals; in the latter cases, additional projections were found towards frontal regions including the dorsomedial frontal cortex and the posterior bank of the arcuate ventral limb. Our results point to widespread frontal connections of the MST-FST complex, involving both prefrontal and premotor cortical regions.

Laceration of the phrenic artery. A life-threatening complication after repair of pectus excavatum.

We report a case of life-threatening hemothorax three months after surgical repair of pectus excavatum. Angiography revealed the hemorrhage to originate from a laceration of the phrenic artery secondary to dislodgment of the metal strut used for the repair. Awareness of this rare complication in patients after repair of pectus excavatum is required.

Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.

Wilms' tumor (WT), the most frequent renal solid tumor in children, has been linked to aberrant Wnt signaling. Herein, we demonstrate that different WTs can be grouped according to either sensitivity or resistance to an antibody (Ab) specific to frizzled7 (FZD7), a Wnt receptor. In the FZD7-sensitive WT phenotype, the Ab induced cell death of the FZD7(+) fraction, which in turn depleted primary WT cultures of their clonogenic and sphere-forming cells and decreased in vivo proliferation and survival on xenografting to the chick chorio-allantoic-membrane. In contrast, FZD7-resistant WT in which no cell death was induced showed a different intra-cellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of ß-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of ß-catenin or WTX mutations. The addition of exogenous DKK1 and sFRP1 to the tumor cells enabled the sensitization of FZD7-resistant WT to the FZD7 Ab. Finally, although extremely difficult to achieve because of dynamic cellular localization of FZD7, sorting of FZD7(+) cells from resistant WT, showed them to be highly clonogenic/proliferative, overexpressing WT 'stemness' genes, emphasizing the importance of targeting this fraction. FZD7 Ab therapy alone or in combination with Wnt pathway antagonists may have a significant role in the treatment of WT via targeting of a tumor progenitor population.

Organ-injury-induced reactivation of hemangioblastic precursor cells.

Early in mammalian development, the stem cell leukemia (SCL/TAL1) gene and its distinct 3' enhancer (SCL 3'En) specify bipotential progenitor cells that give rise to blood and endothelium, thus termed hemangioblasts. We have previously detected a minor population of SCL (+) cells in the postnatal kidney. Here, we demonstrate that cells expressing the SCL 3'En in the adult kidney are comprised of CD45+CD31- hematopoietic cells, CD45-CD31+ endothelial cells and CD45-CD31- interstitial cells. Creation of bone marrow chimeras of SCL 3'En transgenic mice into wild-type hosts shows that all three types of SCL 3'En-expressing cells in the adult kidney can originate from the bone marrow. Ischemia/reperfusion injury to the adult kidney of SCL 3'En transgenic mice results in the intrarenal elevation of SCL and FLK1 mRNA levels and of cells expressing hem-endothelial progenitor markers (CD45, CD34, c-Kit and FLK1). Furthermore, analysis of SCL 3'En in the ischemic kidneys reveals an increase in the abundance of SCL 3'En-expressing cells, predominantly within the CD45 (+) hematopoietic fraction and to a lesser extent in the CD45 (-) fraction. Our results suggest organ-injury-induced reactivation of bone marrow-derived hemangioblasts and possible local angioblastic progenitors expressing SCL and SCL 3'En.

Biological consequences of long-term intrathecal administration of opioids.

The intrathecal administration of opioids produces a powerful analgesia through the activation of the spinal opioid receptors. The long term administration of opioids by this route is a valid technique for the treatment of chronic pain of malignant or non-malignant origin. Little is known about the effects of opioids administered by spinal route on various body systems which are not purely tied up to the nociception. It is known that exogenous opioids can interact with their receptors outside the classical nociceptive system. In this context, opioids can modulate the activity of various biological systems such as the immune and the endocrine one. The knowledge of the effects of opioids on these systems is of primary clinical importance. The modulation of the biological systems by exogenous opioids modifies the homeostasis of the body and the clinician should be aware of these modifications in order to be able to anticipate them, to monitor or to use them to improve the therapeutic plan. The knowledge of the influence of the administration route on the variability of these modifications is also important. A survey of the most important knowledge on this topic is presented.

Graded-index mid-infrared planar optical waveguides made from silver halides.

Since the index of refraction of AgCl(x)Br(1-x) (x<1) is higher than that of AgCl, by diffusing Br(-) ions into AgCl it was possible to control the index and thus obtain planar waveguides made from silver chlorobromide (AgClBr) on a AgCl substrate. Silver halides are transparent in the mid IR, and it was therefore possible to characterize the waveguides by transmission of 10.6-mum CO(2)-laser radiation through them. In a typical case, the thickness was optically measured and was found to be 65mum , and the propagation loss was 16 dB/cm. The output-beam profile distribution was determined experimentally and found to be well correlated with a numerical analysis simulation based on a ray-tracing model of the eikonal equation. Planar waveguides that are transparent in the mid IR will likely be useful in numerous applications.

Middle ear effusion IL-6 concentration in bacterial and non-bacterial acute otitis media.

BACKGROUND: The pathogenesis of acute otitis media is complex and multifactorial. It is characterized by inflammation of the middle ear with an infiltration of leukocytes, macrophages and mast cells. The resulting effusion contains a large amount of inflammatory mediators, among which are cytokines. OBJECTIVES: To test the role of IL-6 in the inflammatory process associated with acute otitis media. METHODS: We analyzed 20 middle ear fluid (MEF) sample pairs, obtained by aspiration before initiating antibiotic therapy (day 1) and during treatment (days 4-5), for the presence of IL-6. IL-6 concentrations were assayed with an ELISA kit (detection limit 5 pg/ml) and were correlated with bacterial etiology and bacterial eradication from the middle ear. RESULTS: IL-6 was detected in all middle ear effusions analyzed. We found decreased IL-6 concentrations in culture negative MEF compared to culture positive MEF on both days I and 4-5 (day 1, 1752.20+/-1001.31 pg/ml vs 1216.20+/-1015.44 pg/ml, p = 0.19; days 4-5, 1049.36+/-472.40 pg/ml vs 800.33+/-676.00 pg/ml, p = 0.23); however, differences did not achieve statistical significance. Overall, a marked and significant decrease in IL-6 concentration occurred following 72-96 h of antibiotic therapy (1618.15+/-1004.88 pg/ml vs 936.85+/-581.05 pg/ml, p = 0.04). While MEF IL-6 concentrations decreased in ears where bacteria persisted (1468.20+/-858.48 pg/ml vs 1044.80+/-514.16 pg/ml, p = 0.167) or were eradicated (2320.20+/-866.16 pg/ml vs 767.40+/-522.88 pg/ml, p = 0.029), a more prominent decline was demonstrated in the latter. CONCLUSIONS: These results strongly suggest the involvement of IL-6 in the ongoing inflammatory process in both bacterial and non-bacterial acute otitis media. Resolution of inflammation in the middle ear, especially where bacteria were eradicated, is reflected by low IL-6 levels.