The epidemiology and orthopaedic burden of civilian gunshot injuries over a four-year period at a level one trauma unit in Cape Town, South Africa.

PURPOSE: The aim of this study was to quantify the overall burden of orthopaedic gunshot-related injuries at our institution over a four year period. Secondary aims included identifying complications from gunshot-related injuries and the additional burden it places on healthcare services. METHODS: A retrospective review was conducted on all patients with gunshot injuries presenting to our hospital's trauma unit between January 2014 and December 2017. Patient data was recorded, and demographic data, number and type of implants, blood products used, duration of hospital admission, duration of ICU admission, radiological studies performed, and prevalence of complications were analysed. RESULTS: A total of 1449 patients with a mean age of 28.2 ± 9.7 years (range 2.0-71.0) were included in this study. The majority of these gunshot-related orthopaedic injuries were sustained to the lower extremities and were treated non-operatively. The median duration of hospital stay was 7.0 (IQR 4.0-12.0). The most common complications identified were nerve injury (8.3%), vascular injury (6.5%), fracture-related infection (3.2%), non-union (3.1%), and compartment syndrome (1.6%). The total cost of care was ZAR 53,568,537 (USD 4,320,043) with an average cost per patient of ZAR 37,031 (USD 2986). CONCLUSION: This study highlighted the burden of gunshot injuries presenting to our hospital and the strain it places on its healthcare resources. The prevalence of complications was comparable to international studies on the subject. With improved understanding of this burden, more healthcare resources can be allocated to this problem and better prevention strategies can be planned.

Histamine-mediated potentiation of transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 signaling in submucosal neurons in patients with irritable bowel syndrome.

Previously, we showed histamine-mediated sensitization of transient receptor potential (TRP) vanilloid 1 (TRPV1) in patients with irritable bowel syndrome (IBS). Sensitization of TRP ankyrin 1 (TRPA1) and TRP vanilloid 4 (TRPV4) are also involved in aberrant pain perception in preclinical models of somatic pain. Here, we hypothesize that in parallel with TRPV1, histamine sensitizes TRPA1 and TRPV4, contributing to increased visceral pain in patients with IBS. Rectal biopsies were collected from patients with IBS and healthy subjects (HS) to study neuronal sensitivity to TRPA1 and TRPV4 agonists (cinnamaldehyde and GSK1016790A) using intracellular Ca2+ imaging. In addition, the effect of supernatants of rectal biopsies on patients with IBS and HS was assessed on TRPA1 and TRPV4 responses in murine dorsal root ganglion (DRG) sensory neurons. Finally, we evaluated the role of histamine and histamine 1 receptor (H1R) in TRPA1 and TRPV4 sensitization. Application of TRPA1 and TRPV4 agonists evoked significantly higher peak amplitudes and percentage of responding submucosal neurons in biopsies of patients with IBS compared with HS. In HS, pretreatment with histamine significantly increased the Ca2+ responses to cinnamaldehyde and GSK1016790A, an effect prevented by H1R antagonism. IBS supernatants, but not of HS, sensitized TRPA1 and TRPV4 on DRG neurons. This effect was reproduced by histamine and prevented by H1R antagonism. We demonstrate that the mucosal microenvironment in IBS contains mediators, such as histamine, which sensitize TRPV4 and TRPA1 via H1R activation, most likely contributing to increased visceral pain perception in IBS. These data further underscore H1R antagonism as potential treatment for IBS. NEW & NOTEWORTHY We provide evidence for histamine-mediated transient receptor potential (TRP) ankyrin 1 and TRP vanilloid 4 sensitization in irritable bowel syndrome (IBS) via histamine 1 receptor (H1R) activation, most likely contributing to increased visceral pain perception. Our results reveal a general role of sensory TRP channels as histamine effectors in the pathophysiology of IBS and provide novel mechanistic insights into the therapeutic potential of H1R antagonism in IBS.

Improved survival after LTx-associated acute GVHD with mAb therapy targeting IL2RAb and soluble TNFAb: Single-center experience and systematic review.

Acute graft-versus-host disease (GVHD) after liver transplant (LTx) is a rare complication with a high mortality rate. Recently, monoclonal antibody (mAb) treatment, specifically with anti-interleukin 2 receptor antibodies (IL2RAb) and anti-tumor necrosis factor-α antibodies (TNFAb), has gained increasing interest. However, evidence is mostly limited to case reports and the efficacy remains unclear. Here, we describe 5 patients with LTx-associated GVHD from our center and provide the results of our systematic literature review to evaluate the potential therapeutic benefit of IL2RAb/TNFAb treatment. Of the combined population of 155 patients (5 in our center and 150 through systematic search), 24 were given mAb (15.5%)-4 with TNFAb (2.6%) and 17 with IL2RAb (11%) ("mAb group")-and compared with patients who received other treatments (referred to as "no-mAb group"). Two-sided Fisher exact tests revealed a better survival when comparing treatment with mAb versus no-mAb (11/24 vs 27/131; P = .018), TNFAb versus no-mAb (3/4 vs 27/131; P = .034), and IL2RAb versus no-mAb (8/17 vs 27/131; P = .029). This systematic review suggests a beneficial effect of mAb treatment and a promising role for TNFAb and IL2RAb as a first-line strategy to treat LTx-associated acute GVHD.

Combined liver and lung transplantation with extended normothermic lung preservation in a patient with end-stage emphysema complicated by drug-induced acute liver failure.

Isolated lung transplantation (LuTx) and liver transplantation are established treatments for irreversible lung and liver failure. Combined liver and lung transplantation (cLiLuTx) is a less common, but approved therapy of combined organ failure, mostly applied in patients suffering from progressive cystic fibrosis and advanced liver disease. We report a patient who was listed for LuTx due to end-stage chronic obstructive pulmonary disease and who developed drug-induced acute hepatic failure. The only therapeutic option was hyper-urgent cLiLuTx. To correct the poor coagulation in order to reduce the per-operative risk of bleeding, the liver was transplanted first. In anticipation of the longer lung preservation time, cold flushed lungs were preserved on a portable lung perfusion device for ex vivo normothermic perfusion for 11 h 15 min, transplanted sequentially off-pump, and reperfused after a total ex vivo time of 13 h 32 min and 16 h for the first and second lung, respectively. Ten months later, the patient is doing well and no rejection occurred. Normothermic ex vivo lung perfusion may help to prolong preservation time, facilitating long-distance transport and combined organ transplantation.

Endoscopic therapy for Bouveret syndrome, illustrated by a case report.

Bouveret syndrome is an exceptionally rare form of gallstone ileus secondary to a bilioenteric fistula, through which a voluminous gallstone can migrate into the pylorus or duodenum, thereby causing gastric outlet obstruction. In order to increase awareness, we reviewed the clinical features, diagnostic tools and management options for this uncommon entity. We specifically focus on endoscopic therapeutic options, illustrated by a case of a 73 year old woman with Bouveret syndrome, where endoscopic electrohydraulic lithotripsy was successful in relieving gastroduodenal obstruction.

Evaluating the neutrophil-to-lymphocyte ratio as an indicator for early referral of patients with COVID-19 pneumonia to a high-care facility.

BACKGROUND: Early identification of patients at high risk of severe disease requiring referral and treatment at a high-care facility is imperative in the management of COVID-19 pneumonia in a limited-resource setting, as transfer of unstable patients can be detrimental. OBJECTIVES: To examine the value of the neutrophil-to-lymphocyte ratio (NLR) calculated on admission to a healthcare facility as a predictor of the need for early referral to a high-care facility for further treatment. METHODS: We designed a cohort analytical study of 198 patients with COVID-19 pneumonia admitted to the COVID-19 unit at Universitas Academic Hospital in Bloemfontein, South Africa, between 20 May and 30 September 2021. RESULTS: Of the 198 patients enrolled in the study, 134 (67.7%) were admitted to high care and 93 (46.9%) died. The median (interquartile range (IQR)) NLR measured on admission to the hospital was 8.09 (4.90 - 14.86), and the NLR ranged from 0.26 to 136.7. The admission NLR was statistically significantly higher in the high-care group v. the general ward group (p<0.001). After converting the NLR to log scale, to bring it closer to conditional normality, logistic regression analysis identified log NLR (odds ratio (OR) 4.089; 95% confidence interval (CI) 2.464 - 6.787; p<0.001) and age (OR 1.029; 95% CI 1.004 - 1.056; p=0.024) as significant in determining who will require high care. The area under the receiver operating characteristic curve for the combined model of NLR and age was 0.829 (95% CI 0.767 - 0.891). An NLR cut-off value of 7.5 (sensitivity 0.7462, specificity 0.7968) has been calculated as the optimal cut-off value to determine who will need high care. Admission log NLR and age were significant in determining who died (OR 2.067; 95% CI 1.404 - 3.045; p<0.001, and OR 1.043; 95% CI 1.018 - 1.068; p=0.001, respectively). CONCLUSION: The NLR measured on admission and age can be used to predict whether a patient with COVID-19 pneumonia will require high care.

Umbilical hernia repair in patients with cirrhosis: who, when and how to treat.

PURPOSE: Hernia management in patients with cirrhosis is a challenging problem, where indication, timing and type of surgery have been a subject of debate. Given the high risk of morbidity and mortality following surgery, together with increased risk of recurrence, a wait and see approach was often advocated in the past. METHODS: The purpose of this review was to provide an overview of crucial elements in the treatment of patients with cirrhosis and umbilical hernia. RESULTS: Perioperative ascites control is regarded as the major factor in timing of hernia repair and is considered the most important factor governing outcome. This can be accomplished by either medical treatment, ascites drainage prior to surgery or reduction of portal hypertension by means of a transjugular intrahepatic portosystemic shunt (TIPS). The high incidence of perioperative complications and inferior outcomes of emergency surgery strongly favor elective surgery, instead of a "wait and see" approach, allowing for adequate patient selection, scheduled timing of elective surgery and dedicated perioperative care. The Child-Pugh-Turcotte and MELD score remain strong prognostic parameters and furthermore aid in identifying patients who fulfill criteria for liver transplantation. Such patients should be evaluated for early listing as potential candidates for transplantation and simultaneous hernia repair, especially in case of umbilical vein recanalization and uncontrolled refractory preoperative ascites. Considering surgical techniques, low-quality evidence suggests mesh implantation might reduce hernia recurrence without dramatically increasing morbidity, at least in elective circumstances. CONCLUSION: Preventing emergency surgery and optimizing perioperative care are crucial factors in reducing morbidity and mortality in patients with umbilical hernia and cirrhosis.

Evaluating the accuracy of three international guidelines in identifying the risk of malignancy in pancreatic cysts: a retrospective analysis of a surgical treated population.

BACKGROUND AND STUDY AIMS: The international consensus Fukuoka guideline (Fukuoka ICG), The European evidence-based guideline on pancreatic cystic neoplasms (European EBG) and the American Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts (AGA IG) are 3 frequently cited guidelines for the risk stratification of neoplastic pancreatic cysts. The aim of this study was to assess the accuracy of detecting malignant cysts by strictly applying these guidelines retrospectively to a cohort of surgically resected pancreatic cysts. PATIENTS AND METHODS: 72 resected cysts were included in the analysis. Invasive carcinoma, high grade dysplasia and neuro-endocrine tumour were considered as "malignant cysts" for the purpose of the study. RESULTS: 32% of the resected cysts were malignant. The analysis showed that the Fukuoka ICG, European EBG and AGA IG had a sensitivity of 66,8%, 95,5%, 80%; a specificity of 26,8%, 11,3%, 43,8%; a positive predictive value of 31,8%, 35%, 47,1% and a negative predicted value of 61,1%, 83,3%, 77,8% respectively. The missed malignancy rate was respectively 11,3%, 1,5%, 7,7% and surgical overtreatment was respectively 48,4%, 59,1%, 34,6%. CONCLUSION: In this retrospective analysis, the European EBG had the lowest rate of missed malignancy at the expense of a high number of "unnecessary" resections. The Fukuoka ICG had the highest number of missed malignancy. The AGA IG showed the lowest rate of unnecessary surgery at the cost of a high number of missed malignancy. There is need to develop better biomarkers to predict the risk of malignancy.

Zero-order and prolonged release of atenolol from microporous FAU and BEA zeolites, and mesoporous MCM-41: Experimental and theoretical investigations.

The potential of microporous zeolites FAU and BEA, and mesoporous MCM-41, for prolonged release of atenolol in drug delivery systems was investigated both experimentally, using drug release studies, and theoretically using classical molecular dynamics simulations. Remarkably, zero-order release of atenolol was achieved from FAU (SiO2:Al2O3 = 80:1) into phosphate buffer for 24 h followed by prolonged release for at least another 48 h. Experimental data also demonstrate the ability for all of the drug-zeolite combinations investigated to achieve prolonged release of atenolol, with the release rates determined by the combination of framework topology, aluminium content and drug release study media. Molecular dynamics simulations give an insight into the reasons for the different release rates observed for FAU and BEA. The results of this work emphasise the need for sophisticated models in order to explain subtle differences in release, such as those observed at different SiO2:Al2O3 ratios.

Nutritional supplements for people being treated for active tuberculosis: A technical summary.

Tuberculosis and nutrition are intrinsically linked in a complex relationship. Altered metabolism and loss of appetite associated with tuberculosis may result in undernutrition, which in turn may worsen the disease or delay recovery. We highlight an updated Cochrane review assessing the effects of oral nutritional supplements in people with active tuberculosis who are receiving antituberculosis drug therapy. The review authors conducted a comprehensive search (February 2016) for all randomised controlled trials comparing any oral nutritional supplement, given for at least 4 weeks, with no nutritional intervention, placebo or dietary advice only in people receiving antituberculosis treatment. Of the 35 trials (N=8 283 participants) included, seven assessed the provision of free food or high-energy supplements, six assessed multi-micronutrient supplementation, and 21 assessed single- or dual-micronutrient supplementation. There is currently insufficient evidence to indicate whether routinely providing free food or high-energy supplements improves antituberculosis treatment outcomes (i.e. reduced death and increased cure rates at 6 and 12 months), but it probably improves weight gain in some settings. Plasma levels of zinc, vitamin D, vitamin E and selenium probably improve with supplementation, but currently no reliable evidence demonstrates that routine supplementation with multi-, single or dual micronutrients above the recommended daily intake has clinical benefits (i.e. reduced death, increased cure rate at 6 and 12 months, improved nutritional status) in patients receiving antituberculosis treatment. In South Africa, most provinces implement a supplementation protocol based on nutritional assessment and classification of individuals rather than on disease diagnosis or treatment status.

A large-scale automated method for hepatocyte isolation: effects on proliferation in culture.

Large-scale sterile methods for isolating hepatocytes are desirable for the development of bioartificial liver support systems. In this study the traditional centrifuge method was compared with the use of a Baylor Rapid Autologous Transfusion (BRAT) machine for isolating large quantities of porcine hepatocytes. After isolating hepatocytes, the methods were evaluated in terms of cell viability and yield per liver, proliferation over 7 days, and the effects on the cell cycle using the trypan blue exclusion test, conventional phase-contrast light microscopy, the lactate to pyruvate ratio, the leakage of lactate dehydrogenase (LD) and aspartate aminotransferase (AST), lidocaine clearance, albumin production, and flow cytometry. With the centrifuge method the mean cell viability was 92.5%, while with the BRAT method the viability was 95.9%. The minimal cell yields with the BRAT procedure were 7.3 x 10(9) for 250-ml centrifuge bowls and 2.8 x 10(9) for 165-ml bowls, which compares well with that found by other authors. Because the same initial procedures were employed in both methods the total hepatocyte yield per liver was comparable. Flow cytometry confirmed that the proliferation of hepatocytes was facilitated by oxygenation during the isolation procedure. The recovery of hepatocytes in culture following isolation was similar after either method. Daily microscopic investigation indicated that cytoplasmic vacuolization and granularities were present after either procedure and these disappeared following 3-4 days of culturing. Flow cytometry indicated that the hepatocyte cell cycle was similar after either method; at 7 days the profile indicated that the cells were still proliferating. Trends in the lactate to pyruvate ratio and the leakage of LD and AST indicated that the functional polarity of hepatocytes was regained after approximately 3 days. Lidocaine clearance at 4 days indicated that the cytochrome P450 system was active, while significant albumin production was apparent at day 5. The benefit of using BRAT technology in hepatocyte isolation lies in guaranteed sterility, convenience, speed, and the ability to oxygenate media and cell suspensions during the procedure.

Electrohydrodynamic Preparation of Nanomedicines.

The preparation of nanomedicines can be achived using a host of methods ranging from wet-chemical approaches to more engineering related techniques. As a maturing branch of nanotechnology, nanomedcines are being tailored to serve multiple pharmaceutic and biomedical related funcitons (e.g. targeted delivery, imaging, healing, sensing which may require the utilisaiton of one or more actives or excipients. In some instances, handling of materials (such as sensitive biomolecules or active pharmaceutical ingredient) becomes a limiting factor along with issues related to fabrication steps (loss or degradation of active components and functional materials, deposition location & procedure (removal of formed structures, process environment sensitivity and scale-up potential. This short review focuses on the electrohydrodynamic preparation of emerging nanomedicines that have potential to serve as therapeutic platforms. An insight into the underpinning process (jet-formation, related paramerts (material and process and strucutral outcomes (particles and fibres is given in relation to highlighted research. The ambient temperature processing, user friendly preparation and present industrial scale up potential (now in kg/hr make such processes valuable in the preparation of future nano-scaled and sensitive dosage forms.

Budd-Chiari syndrome: reassessment of a step-wise treatment strategy.

BACKGROUND AND STUDY AIMS: The Budd-Chiari syndrome is a rare disorder characterized by hepatic venous outflow obstruction. A step-wise management was recently proposed. The aim of this study is to reassess our treatment approach and long-term outcome. PATIENTS AND METHODS: The data of 37 Budd-Chiari patients, seen in our unit, were critically analyzed and compared with the ENVIE (European Network For Vascular Disorders of the Liver) data. RESULTS: Most patients had multiple prothrombotic conditions (41%), of which an underlying myeloproliferative neoplasm was the most frequent (59%). The JAK2V617F mutation was associated with more complete occlusion of all hepatic veins (JAK2 mutation +: 70% vs JAK2 mutation -: 23% and a higher severity score. The step-wise treatment algorithm used in our unit, in function of the severity of the liver impairment and the number and the extension of hepatic veins occluded, resulted in the following treatments: only anticoagulation (n = 7.21%), recanalization procedure (n = 4.21%), portosystemic shunts (n = 9.26%) and liver transplantation (n = 14.44%). This resulted in a 10 year survival rate of 90%. Treatment of the underlying hemostatic disorder offered a low recurrence rate. None of the 21 patients with a myeloproliferative neoplasm died in relation to the hematologic disorder. CONCLUSIONS: An individualized treatment regimen consisting of anticoagulation and interventional radiology and/or transplantation when necessary and strict follow-up of the underlying hematologic disorder, provided an excellent long-term survival, which confirm the data of the ENVIE study.

Effects of a prudent diet containing either lean beef and mutton or fish and skinless chicken on the plasma lipoproteins and fatty acid composition of triacylglycerol and cholesteryl ester of hypercholesterolemic subjects.

In this two-phase crossover study, 39 hypercholesterolemic subjects followed a prudent diet with either lean red meat or fish and skinless chicken (treatment groups), and 13 subjects (reference group) followed their habitual diet. Fasting blood samples were analyzed for plasma total cholesterol, triacylglycerol (TAG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein one- and two-cholesterol, apolipoprotein-B, very low density lipoprotein cholesterol, and very low density lipoprotein TAG, and fatty acid composition of plasma TAG and cholesteryl ester (CE). Body mass and blood pressure were determined. Seven-day dietary records were kept once at baseline and twice during the treatment periods. Significant differences were observed in dietary intake between the baseline and treatment diets and between the two treatment diets. HDL-C (P < 0.05) and diastolic blood pressure (P < 0.01) were higher in patients on the red meat diet than in those on the chicken-fish diet. No other significant differences in lipoproteins were observed between the effects of the two treatment diets. The linoleic acid (%), eicosapentaenoic acid (%), and the eicosapentaenoic acid/arachidonic acid ratios in TAG and CE were higher (P < 0.01) in subjects on the chicken-fish diet than in those on the red meat diet. In conclusion, this study showed that the effect of two lipid-lowering diets containing either lean red meat or skinless chicken and fish on the atherogenic lipoproteins did not differ significantly. A prudent diet with skinless chicken and fish, however, had a more favorable effect on the fatty acid composition of the plasma TAG and the CE than did the lean red meat diet.

Quantitation of hydroxyproline in bone by gas chromatography-mass spectrometry.

A validated gas chromatography (GC)-mass spectrometric (MS) method for the analysis of hydroxyproline in rat femur is reported. Hydroxyproline in bone hydrolysates was extracted with an anion exchange resin and the N(O)-tert-butyldimethylsilyl derivatives analyzed by GC-MS. The hydroxyproline concentration was estimated relative to pipecolic acid, 3,4-dehydroproline and n-tetracosane as internal standards. The mass-to-charge ratios (m/z) for the ions used for quantitation by single ion monitoring were 314 m/z for hydroxyproline, 198 m/z for pipecolic acid, 256 m/z for dehydroproline and 57 m/z for n-tetracosane. A coefficient of variation of 5.8% was achieved and the limit of detection was calculated to be 0.233 micromol/l bone hydrolysate.

N-trimethyl chitosan chloride as absorption enhancer in oral peptide drug delivery. Development and characterization of minitablet and granule formulations.

In this study, minitablet and granule formulations were developed as solid oral dosage forms for the delivery of peptide drugs with the absorption enhancer N-trimethyl chitosan chloride (TMC). Minitablets were deemed suitable as a dosage form due to their ability, as components of multiple unit dosage forms (MUDFs), to disperse from each other, before disintegration, effectively increasing the area in which the polymer can assert its absorption-enhancing effect. The polymer should be released from the dosage forms prior to the release of the peptide, which was, together with achieving maximum release of both ingredients, the main focus of this study. Desmopressin (1-(3-mercaptopropionic acid)-8-D-arginine vasopressin monoacetate (DDAVP) was used as model peptide drug. The optimized minitablet formulation consisted of two types of granules, namely DDAVP and TMC granules. DDAVP granules, containing tetraglycerol pentastearate (TGPS), were specifically aimed at delaying the release of the peptide from the dosage form. Burst release of TMC was attempted with TMC granules. Both these granule types were included in the granule formulation. Release profiles for both the optimized minitablet formulation as well as the granule formulation showed that the release of DDAVP was effectively delayed from the formulation compared to the formulation where no attempt at delaying the release was made. In comparison, more TMC was released, and at a faster rate, from the granule formulation than the optimized minitablet formulations. Both the optimized minitablet formulation and the granule formulation show suitable release profiles for the delivery of peptide drugs with TMC as absorption enhancer in solid oral dosage forms.

Trimethylated chitosan as polymeric absorption enhancer for improved peroral delivery of peptide drugs.

The absorption enhancing effects of chitosan and its derivatives have been intensively studied in recent years. It has been shown that these compounds are potent absorption enhancers. Chitosan is only soluble in acidic environments and is therefore incapable of enhancing absorption in the small intestine, the main absorption area in the gastrointestinal tract. Special emphasis has been placed on the absorption enhancing properties of N-trimethyl chitosan chloride (TMC), a partially quaternised derivative of chitosan, due to its solubility in neutral and basic environments. TMC is prepared by the reductive methylation of chitosan. The degree of quaternisation can be altered by increasing the number of reaction steps or by increasing the reaction time. Although the molecular weight of the polymer increases with addition of the methyl groups, a net decrease in the molecular weight is observed due to a decrease in the chain length of the polymer. TMC, like chitosan, possesses mucoadhesive properties. In vitro studies performed on Caco-2 cell monolayers showed a pronounced reduction in the transepithelial electrical resistance (TEER). TMC is also able to increase the permeation of hydrophilic compounds such as [14C]-mannitol and [14C] polyethylene glycol 4000 ([14C] PEG 4000, MW4000) across the cell monolayers. It was also shown that the degree of quaternisation of the polymer plays an important role on its absorption enhancing properties, especially in neutral environments where chitosan is ineffective as an absorption enhancer. The reduction in TEER is an indication of the opening of the tight junctions located between epithelial cells. Opening of the tight junctions will result in enhancement of absorption via the paracellular route. Confocal laser scanning microscopy confirmed transport of large hydrophilic compounds via the paracellular route as well as the mechanism of action of the polymer in which redistribution of the cytoskeletal F-actin is provoked, which leads to the opening of the tight junctions. Various in vivo studies in different animal models confirmed the ability of TMC to increase the absorption of the peptide drugs buserelin and octreotide after intraduodenal or -jejunal administration. However, TMC has always been administered as a solution in these studies. The impracticality of administering a solution, as well as the fact that most peptides are unstable in the presence of water, have led to the need for a solid oral dosage form with which TMC can be administered together with peptide drugs. Recent studies have focused on the development and in vivo evaluation of solid oral dosage forms.

Hepatic osteodystrophy: the influence of liver disease and portal hypertension on cytokine activation.

Chronic liver disease is frequently complicated by bone disease. The mechanisms leading to bone-loss are unknown but are probably not related to abnormal vitamin D metabolism. The effects of portal hypertension and porto-systemic shunting on bone-loss have not been studied. It is postulated that liver disease, or the complications of liver disease (portal hypertension or porto-systemic shunting), might be responsible for the activation of cytokines. It is further postulated that these cytokines might be the final common pathway leading to bone-loss in both parenchymal and cholestatic liver disorders by modifying osteoblast or osteoclast function.

The effect of Senecio latifolius a plant used as a South African traditional medicine, on a human hepatoma cell line.

A number of traditional remedies used in South Africa contain pyrrolizidine alkaloids, some of which are hepatotoxic. We investigated the effect on human HuH-7 cells of Senecio latifolius DC., a plant that is a component of some traditional remedies and which is known to contain toxic pyrrolizidine alkaloids. Cells were also treated with extracts of a standard pyrrolizidine, retrorsine. The changes in the gross morphology of the cells were studied using light microscopy after haematoxylin and eosin staining. The cytoskeleton was investigated using fluorescence-labelled anti-beta-tubulin antibody and the nuclear organisation was studied using fluorescence-labelled antinuclear antibodies. The plant extracts gave rise to dose-dependent gross morphological changes. At high doses, we observed necrosis and at lower doses, destruction of the cytoskeleton, nuclear fragmentation and apoptosis. Doses of less than the equivalent of 330 ng/ml retrorsine led to multinucleated cells with failure in spindle formation and clumping of nuclear chromatin. This latter finding suggests that chronic low-dose treatment with such traditional remedies could give rise to teratogenic and/or carcinogenic effects.