Neonatal porcine islet cells induce human CD4+, but not CD8+, lymphocyte proliferation and resist cell-mediated cytolytic injury in vitro.

Xenotransplantation of porcine tissue to human recipients promises to alleviate the organ shortage. Human antibody-mediated and cell-mediated immune responses against porcine grafts, however, represent barriers to successful xenotransplantation. We compared neonatal porcine islet cells (NPICs) and neonatal porcine splenocytes for the ability to stimulate proliferation of human peripheral blood lymphocytes (PBLs), and for their susceptibility to human natural killer (NK) and cytotoxic T-lymphocyte (CTL)-mediated lysis. Human peripheral blood CD4+ lymphocytes showed strong proliferation in response to NPICs, likely because of occasional swine leukocyte antigen (SLA) class II+ cells in the NPIC preparations. In contrast, human peripheral blood CD8+ lymphocytes did not proliferate in response to NPICs, although they showed clear responses to both porcine splenocytes and endothelial cells. Both human CTL-raised-against-porcine splenocytes and endogenous NK cells lysed porcine splenocytes, but the same cells showed little or no lytic activity against NPICs. Lysis of porcine splenocyte targets was completely abrogated by pretreatment of the human NK or CTL populations with concana-mycin A, suggesting a perforin-dependent effector mechanism. Pretreatment of the NPIC targets with proinflammatory porcine cytokines to upregulate SLA class I expression failed to enhance human CTL-mediated lysis. However, lysis of NPICs by human CTLs could be elicited when a lectin was added to form stable effector:target cell conjugates. It appears that NPICs do not express sufficiently high levels of co-stimulatory and/or adhesion molecules to either activate human CD8+ T-cells or to be effective targets for activated human CTLs. These data suggest that NPICs may not be destroyed by NK- or CTL-mediated lytic mechanisms after transplantation into humans.     

Heterozygous mutations causing partial prohormone convertase 1 deficiency contribute to human obesity

Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.     

Effect of splinting and exercise on intraneural edema of the median nerve in carpal tunnel syndrome--an MRI study to reveal therapeutic mechanisms

Splinting and nerve and tendon gliding exercises are commonly used to treat carpal tunnel syndrome (CTS). It has been postulated that both modalities reduce intraneural edema. To test this hypothesis, 20 patients with mild to moderate CTS were randomly allocated to either night splinting or a home program of nerve and tendon gliding exercises. Magnetic resonance images of the wrist were taken at baseline, immediately after 10 min of splinting or exercise, and following 1 week of intervention. Primary outcome measures were signal intensity of the median nerve at the wrist as a measure of intraneural edema and palmar bowing of the carpal ligament. Secondary outcome measures were changes in symptom severity and function. Following 1 week of intervention, but not immediately after 10 min, signal intensity of the median nerve was reduced by ≈ 11% at the radioulnar level for both interventions (p = 0.03). This was accompanied by a mild improvement in symptoms and function (p < 0.004). A similar reduction in signal intensity is not observed in patients who only receive advice to remain active. No changes in signal intensity were identified further distally (p > 0.28). Ligament bowing remained unchanged (p > 0.08). Intraneural edema reduction is a likely therapeutic mechanism of splinting and exercise.     

Robotic/Laparoscopic prolapse repair and the role of hysteropexy: a urology perspective

Approximately 11% of women will undergo a surgical procedure for the treatment of pelvic organ prolapse (POP) or urinary incontinence by age 80 years. Abdominal sacrocolpopexy has been found in multiple studies to have high long-term success rates for repair of severe vault prolapse. Robotic or laparoscopic sacrocolpopexy offer similar success to an open approach. This article describes the techniques of laparoscopic sacrocolpopexy and robotic sacrocolpopexy. The role of hysteropexy for the treatment of POP is also discussed.     

Mechanical differences between lumbar and tail discs in the mouse.

The mouse lumbar and tail discs are both used as models to study disc degeneration; however, the mechanical behavior of these two levels has not been compared. The objective of this study was to compare the elastic and viscoelastic mechanical properties of lumbar and tail discs of the mouse under axial compression-tension loading. We hypothesized that tail discs would have a larger transition zone (e.g., neutral zone) and would be less stiff in compression. To test these hypotheses, lumbar and tail bone-disc-bone motion segments were loaded in axial compression and tension. The nonlinear elastic mechanical behavior was examined using a tri-linear curvefit. Elastic behavior of lumbar and tail discs was most different in the low-stiffness transition region (neutral zone), where lumbar discs were nearly twice as stiff over half the axial displacement. In addition, viscoelastic behavior, which was examined using a stretch-exponential curvefit, also showed large lumbar and tail differences, where lumbar discs compressed by 60% of their original height and tail discs by 98% after static creep compression. These results demonstrate that tail discs undergo far more axial displacement than lumbar discs under the same load. These findings are relevant to rodent tail models where chronic loads are applied in vivo to study mechanical pathways of degeneration. Furthermore, the tri-linear model, used here to curvefit the nonlinear compression-tension data, quantified stiffness in the transition zone for the first time, which may prove useful in future disc mechanical studies.     

The accuracy of diagnostic laparoscopy in trauma patients: a prospective, controlled study

BACKGROUND: Numerous studies advocate the use of diagnostic laparoscopy (DL) for abdominal trauma, but none have documented its ability to diagnose specific injuries. This study tests the hypothesis that DL can accurately identify all significant intra-abdominal injuries in trauma patients. METHODS: Of trauma patients requiring laparotomy for presumed injuries, 47 underwent DL followed by laparotomy. Injuries noted at laparoscopy were compared with those found at laparotomy. RESULTS: Of these, 14 patients had no significant injuries necessitating operative intervention noted at laparoscopy and celiotomy. The remaining 33 patients harbored 93 significant injuries at laparotomy, of which only 57.0% were found by DL. DL possessed poor sensitivity (<50%) for injuries to hollow viscera. Despite DL's poor performance in finding specific injuries, it possessed excellent sensitivity (96.2%), and specificity (100%) for determining the need for therapeutic celiotomy. CONCLUSIONS: DL offers no clear advantage over diagnostic peritoneal lavage and computed tomography in blunt trauma. Its utility lies in assessment of the need for laparotomy in patients with penetrating wounds. Currently, DL cannot consistently identify all abdominal injuries, disqualifying it as a therapeutic tool in abdominal trauma.     

Randomized, double-blind study of the analgesic efficacy of morphine-6-glucuronide versus morphine sulfate for postoperative pain in major surgery

BACKGROUND: Morphine-6-glucuronide (M6G) has promising preclinical characteristics and encouraging pharmacokinetic features for acute nociceptive pain. Early studies have produced a good safety profile when compared to morphine sulfate, although in surrogate pain models studies, a mixed picture emerged. A study to evaluate the efficacy and safety profile in a clinical setting was designed. METHODS: The authors conducted a double-blind, randomized, dose-finding study of patients scheduled to undergo major joint replacement. One hundred patients of both sexes were included, with 50 patients in each group. A loading dose of 10 mg of study medication was given intravenously at induction of anesthesia, and two further doses were allowed during surgery if required. Bolus doses via a patient-controlled analgesia system were given subcutaneously at 2 mg/dose and set at a 10-min lockout. Assessments of pain intensity and relief were recorded during the 24-h period. RESULTS: There were no statistically significant differences between the treatments for 24-h mean pain intensity. However, pain intensity was significantly higher in the M6G group than in the morphine group at 30 min and 1 h. There was no statistical difference in 24-h mean pain relief or retrospective pain scores at any time point during the 24-h period. The severity of sedation was significantly greater in the morphine group than in the M6G group at 30 min, 1 h, 2 h, and 24 h. Respiratory depression was greater in the morphine group than in the M6G group, and more patients in the morphine group withdrew from the study because of respiratory depression. CONCLUSIONS: Overall, M6G has an analgesic effect similar to that of morphine over the first 24 h postoperatively. However, M6G may be slower onset initially than morphine; therefore, a larger initial dose may be required.     

Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes

Summary  The etiology of bone fragility in individuals with type 1 diabetes is unknown. This study demonstrated that bone turnover favors resorption and that poor glycemic control is associated with low bone mineral density (BMD) and low bone turnover, in premenopausal women with type 1 diabetes. The results could inform future interventions. Introduction  Low BMD and fracture may be complications of type 1 diabetes. We sought to determine the roles of bone turnover and glycemic control in the etiology of low BMD. Methods  Premenopausal women from the Wisconsin Diabetes Registry Study and matched controls were compared (n = 75 pairs). Heel and forearm BMD were measured, and hip and spine BMD were measured in a subset. Markers of bone formation (osteocalcin) and resorption (NTx), and glycemic control (HbA1c) were determined. Results  Age ranged from 18 to 50 years with a mean of 28, and 97% were Non-Hispanic white. Among women with diabetes, mean disease duration was 16 years and current HbA1c was 8%. Compared to controls, women with diabetes had a high prevalence of previous fracture (37% vs. 24%) and low BMD for age (heel or forearm: 49% vs. 31%), low heel and forearm BMD, and low osteocalcin levels. Levels of NTx were similar, suggesting uncoupled turnover favoring resorption. Poor glycemic control was associated with low BMD at all bone sites except the spine, and with low osteocalcin and NTx levels. Conclusions  Optimal glycemic control may prevent low BMD and altered bone turnover in type 1 diabetes, and decrease fracture risk.     

Use of risk stratification to target therapies in patients with recent onset arthritis; design of a prospective randomized multicenter controlled trial

Background  

Early and intensive treatment is important to inducing remission and preventing joint damage in patients with rheumatoid arthritis. While intensive combination therapy (Disease Modifying Anti-rheumatic Drugs and/or biologicals) is the most effective, rheumatologists in daily clinical practice prefer to start with monotherapy methotrexate and bridging corticosteroids. Intensive treatment should be started as soon as the first symptoms manifest, but at this early stage, ACR criteria may not be fulfilled, and there is a danger of over-treatment. We will therefore determine which induction therapy is most effective in the very early stage of persistent arthritis. To overcome over-treatment and under-treatment, the intensity of induction therapy will be based on a prediction model that predicts patients' propensity for persistent arthritis.     

Medical action for global security (MEDACT): Founding statement

Two principles should underpin the provision of primary health care to refugees: (a) that refugees should have the same access to quality primary care services as the local population, and (b) any specialist service should have the goal of full integration of the refugee into normal general practice. The various ways in which medical care can be provided to refugees and the knowledge, skills and attitudes important to such provision are described. One way in which such a service was provided in east Kent is reported. The term ‘refugee’ encompasses newly arrived refugees who are awaiting a decision from the Home Office, as well as those who have been given permission to stay, either as recognized Refugees under the provisions of the 1951 United Nations Convention, or with Exceptional or Indefinite Leave to Remain.