ABSTRACT
The emerging understanding of gut microbiota as 'metabolic machinery' influencing many aspects of physiology has gained substantial attention in the field of psychiatry. This is largely due to the many overlapping pathophysiological mechanisms associated with both the potential functionality of the gut microbiota and the biological mechanisms thought to be underpinning mental disorders. In this systematic review, we synthesised the current literature investigating differences in gut microbiota composition in people with the major psychiatric disorders, major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SZ), compared to 'healthy' controls. We also explored gut microbiota composition across disorders in an attempt to elucidate potential commonalities in the microbial signatures associated with these mental disorders. Following the PRISMA guidelines, databases were searched from inception through to December 2021. We identified 44 studies (including a total of 2510 psychiatric cases and 2407 controls) that met inclusion criteria, of which 24 investigated gut microbiota composition in MDD, seven investigated gut microbiota composition in BD, and 15 investigated gut microbiota composition in SZ. Our syntheses provide no strong evidence for a difference in the number or distribution (α-diversity) of bacteria in those with a mental disorder compared to controls. However, studies were relatively consistent in reporting differences in overall community composition (ß-diversity) in people with and without mental disorders. Our syntheses also identified specific bacterial taxa commonly associated with mental disorders, including lower levels of bacterial genera that produce short-chain fatty acids (e.g. butyrate), higher levels of lactic acid-producing bacteria, and higher levels of bacteria associated with glutamate and GABA metabolism. We also observed substantial heterogeneity across studies with regards to methodologies and reporting. Further prospective and experimental research using new tools and robust guidelines hold promise for improving our understanding of the role of the gut microbiota in mental and brain health and the development of interventions based on modification of gut microbiota.
Subject(s)
Bipolar Disorder , Depressive Disorder, Major , Gastrointestinal Microbiome , Schizophrenia , Brain , Gastrointestinal Microbiome/physiology , HumansABSTRACT
BACKGROUND: There is a surgical workforce shortage in Papua New Guinea (PNG), the Pacific and Timor Leste. Previously, Pacific Island specialists who trained overseas tended to migrate. METHODS: A narrative review was undertaken of the training programmes delivered through the University of Papua New Guinea and Fiji National University's Fiji School of Medicine, and support provided through Australian Aid and the Royal Australasian College of Surgeons (RACS), including scholarships and visiting medical teams. RESULTS: The Fiji School of Medicine MMed programme, which commenced in 1998, has 39 surgical graduates. Sixteen of 22 Fijians, nine of ten Solomon Islanders and four of five in Vanuatu currently reside and/or work in-country. Surgical training in PNG began in 1975, and now has 104 general surgical graduates, 11 of whom originate from the Pacific Islands or Timor Leste. The PNG retention rate of local graduates is 97 per cent, with 80 per cent working in the public sector. Twenty-two surgeons have also undertaken subspecialty training. Timor Leste has trained eight surgical specialists in PNG, Fiji, Indonesia or Malaysia. All have returned to work in-country. The RACS has managed Australian Aid programmes, providing pro bono visiting medical teams to support service delivery and, increasingly, capacity building in the region. The RACS has funded scholarships and international travel grants to further train or sustain the surgical specialists. CONCLUSION: The local MMed programmes have been highly successful in retaining specialists in the region. Partnerships with Australian Aid and RACS have been effective in ensuring localization of the faculty and ongoing professional development.
Subject(s)
Education, Medical, Graduate/statistics & numerical data , Specialties, Surgical/education , Surgeons/education , Australia , Humans , Papua New Guinea , Surgeons/statistics & numerical data , Timor-LesteABSTRACT
BACKGROUND: Many patients who undergo a Hartmann's procedure do not have their stoma reversed. We analysed parameters and co-morbidity scales to assess their accuracy in predicting likelihood of undergoing reversal. MATERIAL AND METHODS: Retrospective analysis of 165 patients from a prospective colorectal database who were discharged home following a Hartmann's procedure at Barwon Health (Geelong, Australia), a regional centre, between 2002 and 2010. Parameters measured included age, sex, time to reversal, ICU admission and pathology results were recorded. Patients' ASA, POSSUM and Elixhauser co-morbidity scales were retrospectively analysed. RESULTS: Reversal of Hartmann's was performed in 74/165 (45%) patients after a median of 294 days (range 70-902). Age (mean 58.5 vs 72.9 years, p < 0.001), ICU stay (34/74 vs 66/91, p < 0.001), ASA (p < 0.002), Elixhauser co-morbidity count (mean 1.14 vs 1.92, p < 0.002) and a malignant diagnosis (9/74 vs 31/91, p < 0.002) were all associated with a decreased reversal rate on univariate analysis. Age was the only parameter found to be significant on multivariate analysis. The complication rate was 23/74, with 7/74 noted to have major complications (Clavian-Dindo III-IV). Reasons for not reversing patients included age and co-morbidities, patient refusal, and malignant disease progression. CONCLUSIONS: More than half the patients undergoing a Hartmann's procedure did not proceed to a closure of their stoma. Age was the only parameter significant in predicting those patients undergoing reversal.
Subject(s)
Colorectal Neoplasms/mortality , Colorectal Neoplasms/surgery , Colostomy/adverse effects , Colostomy/methods , Comorbidity , Age Factors , Aged , Cohort Studies , Colectomy/methods , Colorectal Neoplasms/pathology , Databases, Factual , Female , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness/pathology , Neoplasm Staging , Postoperative Complications/physiopathology , Postoperative Complications/surgery , Prognosis , Prospective Studies , Reoperation/methods , Reoperation/statistics & numerical data , Retrospective Studies , Risk Assessment , Survival Rate , Treatment OutcomeABSTRACT
We present a consensus document on the diagnosis and management of C1 inhibitor deficiency, a syndrome characterized clinically by recurrent episodes of angio-oedema. In hereditary angio-oedema, a rare autosomal dominant condition, C1 inhibitor function is reduced due to impaired transcription or production of non-functional protein. The diagnosis is confirmed by the presence of a low serum C4 and absent or greatly reduced C1 inhibitor level or function. The condition can cause fatal laryngeal oedema and features indistinguishable from gastrointestinal tract obstruction. Attacks can be precipitated by trauma, infection and other stimulants. Treatment is graded according to response and the clinical site of swelling. Acute treatment for severe attack is by infusion of C1 inhibitor concentrate and for minor attack attenuated androgens and/or tranexamic acid. Prophylactic treatment is by attenuated androgens and/or tranexamic acid. There are a number of new products in trial, including genetically engineered C1 esterase inhibitor, kallikrein inhibitor and bradykinin B2 receptor antagonist. Individual sections provide special advice with respect to diagnosis, management (prophylaxis and emergency care), special situations (childhood, pregnancy, contraception, travel and dental care) and service specification.
Subject(s)
Angioedema/immunology , Complement C1 Inactivator Proteins/deficiency , Adolescent , Adult , Angioedema/diagnosis , Angioedema/therapy , Animals , Child , Complement C1 Inactivator Proteins/therapeutic use , Complement C4/analysis , Complement C4/deficiency , Emergencies , Female , Humans , Male , Pregnancy , Pregnancy Complications, Hematologic/therapy , SyndromeABSTRACT
BACKGROUND: Three previous reports have shown the incidence of breast cancer in Papua New Guinea (PNG) to have risen in the 30 years between 1958 and 1987. In the present report the incidence and pathology of breast cancer in the decade 1989-1998 are described. METHODS: This was a retrospective review of all histopathology specimens in PNG from 1989 to 1998. During this period the female population grew from 1 640 000 to more than 2 000 000. RESULTS: There were 790 cases of breast cancer. The age of the patient was not known in 221 cases (26%). The age-standardized incidence was 6.9 per 100 000. The incidence of breast cancer has been steadily rising in the 40 years since cancers were recorded in PNG. The incidence has risen in all four regions, most notably in the islands. The peak incidence was in the 45-54-year-old age group (18.4/100 000); 83.9% of women with breast cancer were aged 54 or less. Fifteen per cent were under 35 years old and 55.7% were under 45. The incidence fell in the elderly. The tumours tended to be advanced. The actual size was recorded in only 163 cases (20.7%) but there were only three T1 tumours in this group. Clinical signs of advanced breast cancer were recorded in 206 cases: ulceration of skin (91 cases), peau d' orange (69 cases), nipple retraction (43 cases) and lymphoedema of the upper extremity (three cases). Axillary nodes were positive in 185 of 247 patients (75%) in whom they were sampled. CONCLUSIONS: The incidence of breast cancer in PNG women has steadily risen over the past 40 years and the highest age-specific incidence occurs in the 35-54 age group. Tumours present late at an advanced stage. Clinical information on pathology request forms is poor and a prospective clinical audit is needed. Strategies need to be developed to detect breast cancer earlier in this population of women.
Subject(s)
Breast Neoplasms/epidemiology , Adolescent , Adult , Aged , Breast Neoplasms/surgery , Child , Child, Preschool , Female , Humans , Incidence , Infant , Mastectomy , Mastectomy, Segmental , Middle Aged , Papua New Guinea/epidemiologyABSTRACT
There is evidence that ATM plays a wider role in intracellular signalling in addition to DNA damage recognition and cell cycle control. In this report we show that activation of the EGF receptor is defective in ataxia-telangiectasia (A-T) cells and that sustained stimulation of cells with EGF downregulates ATM protein in control cells but not in A-T cells expressing mutant protein. Concomitant with the downregulation of ATM, DNA-binding activity of the transcription factor Sp1 decreased in controls after EGF treatment but increased from a lower basal level in A-T cells to that in untreated control cells. Mutation in two Sp1 consensus sequences in the ATM promoter reduced markedly the capacity of the promoter to support luciferase activity in a reporter assay. Overexpression of anti-sense ATM cDNA in control cells decreased the basal level of Sp1, which in turn was increased by subsequent treatment of cells with EGF, similar to that observed in A-T cells. On the other hand full-length ATM cDNA increased the basal level of Sp1 binding in A-T cells, and in response to EGF Sp1 binding decreased, confirming that this is an ATM-dependent process. Contrary to that observed in control cells there was no radiation-induced change in ATM protein in EGF-treated A-T cells and likewise no alteration in Sp1 binding activity. The results demonstrate that EGF-induced downregulation of ATM (mutant) protein in A-T cells is defective and this appears to be due to less efficient EGFR activation and abnormal Sp1 regulation.
Subject(s)
Epidermal Growth Factor/pharmacology , Protein Serine-Threonine Kinases/genetics , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins , Cell Line , Cells, Cultured , DNA, Antisense/genetics , DNA-Binding Proteins , Down-Regulation , ErbB Receptors/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Humans , Mutation , Protein Serine-Threonine Kinases/metabolism , Radiation, Ionizing , Sp1 Transcription Factor/metabolism , Tumor Suppressor ProteinsABSTRACT
ATM, the gene mutated in the human immunodeficiency disorder ataxia-telangiectasia (A-T), plays a central role in recognizing ionizing radiation damage in DNA and in controlling several cell cycle checkpoints. We describe here a murine model in which a nine-nucleotide in-frame deletion has been introduced into the Atm gene by homologous recombination followed by removal of the selectable marker cassette by Cre-loxP site-specific, recombination-mediated excision. This mouse, Atm-DeltaSRI, was designed as a model of one of the most common deletion mutations (7636del9) found in A-T patients. The murine Atm deletion results in the loss of three amino acid residues (SRI; 2556-2558) but produces near full-length detectable Atm protein that lacks protein kinase activity. Radiosensitivity was observed in Atm-DeltaSRI mice, whereas the immunological profile of these mice showed greater heterogeneity of T-cell subsets than observed in Atm(-/-) mice. The life span of Atm-DeltaSRI mice was significantly longer than that of Atm(-/-) mice when maintained under nonspecific pathogen-free conditions. This can be accounted for by a lower incidence of thymic lymphomas in Atm-DeltaSRI mice up to 40 weeks, after which time the animals died of other causes. The thymic lymphomas in Atm-DeltaSRI mice were characterized by extensive apoptosis, which appears to be attributable to an increased number of cells expressing Fas ligand. A variety of other tumors including B-cell lymphomas, sarcomas, and carcinomas not seen in Atm(-/-) mice were observed in older Atm-DeltaSRI animals. Thus, expression of mutant protein in Atm-DeltaSRI knock-in mice gives rise to a discernibly different phenotype to Atm(-/-) mice, which may account for the heterogeneity seen in A-T patients with different mutations.
Subject(s)
Mice, Mutant Strains/genetics , Protein Serine-Threonine Kinases/genetics , Sequence Deletion , Animals , Apoptosis/genetics , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins , Base Sequence , Cell Cycle Proteins , Crosses, Genetic , DNA/genetics , DNA-Binding Proteins , Female , Humans , Lymphoma/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains/growth & development , Mice, Mutant Strains/immunology , Mutagenesis, Site-Directed , Phenotype , Thymus Neoplasms/genetics , Tumor Suppressor Proteins , Up-RegulationABSTRACT
BACKGROUND: Papua New Guinea (PNG) is a country of 4.5 million people with an annual health budget of only 96 million Kina (1K = US$0.35). There are 19 hospitals in the country and national surgeons are now staffing most of these hospitals. This review aims to describe the surgical pathology in the year 2000 and the capability of PNG surgeons to manage it. METHODS: A review of publications, reports and surgical audit data on surgery in PNG was conducted. Surgical audit has been computerized for over 5 years. The review also draws on personal experience and data from MMed theses submitted to the University of Papua New Guinea. RESULTS: Surgical pathology Surgical practice in PNG remains very general. Late presentation and advanced disease are common. Trauma, infection, malignancy and congenital anomalies dominate the surgical scene. The pattern of disease is different from what is found in the West. Western diseases are emerging with the incidence of appendicectomy rising from 5/100,000 to 75/100,000 in the past 30 years. The incidence of diabetes and gallstones has also risen. Osteoporosis, Colles' and neck of femur fractures are rare. Surgical capability The standard of surgical care is acceptable with a low wound infection rate for clean and clean-contaminated abdominal surgery of 0.9% and an anastomotic leak rate of 1.6%. Transurethral prostatectomy is also being performed to a satisfactory standard for head injuries admitted with a Glasgow Coma Score of 6-8 and a good outcome is achieved in over 70% of cases. Hospital mortality for surgical admissions is 3.7%. Subspecialties in orthopaedics, urology and head and neck surgery have been established. Neurosurgery, paediatric and cardiac surgery are being developed. Priorities for the next decade Papua New Guinea needs to continue to develop surgical subspecialties, particularly paediatric and neurosurgery, while maintaining a broad competence in general surgery. Services for burns, spinal injuries, rehabilitation and oncology need to be improved. Surgeons need to be more involved in rural health and teaching basic skills to primary health-care workers. Acquisition, maintenance and repair of surgical equipment needs to be improved so that PNG's well-trained surgeons can have the right tools for their trade. CONCLUSIONS: Papua New Guinea offers a wide range of surgical pathology. The standard of surgery in PNG is reasonable but there are many areas that need development during the period of the next national health plan, 2001-2010. Australasian surgery has many opportunities to assist surgeons in PNG to achieve their objectives.
Subject(s)
Pathology/statistics & numerical data , Specialties, Surgical/statistics & numerical data , Surgical Procedures, Operative/statistics & numerical data , Diabetes Mellitus/epidemiology , Forecasting , Humans , Infections/surgery , Medical Audit , Neoplasms/epidemiology , Papua New Guinea/epidemiology , Specialties, Surgical/trends , Surgical Procedures, Operative/mortality , Surgical Procedures, Operative/trends , Workforce , Wounds and Injuries/mortality , Wounds and Injuries/surgeryABSTRACT
Although a variety of adverse effects have been attributed to treatment with nucleoside analog reverse transcriptase inhibitors (NRTIs) for human immunodeficiency virus type 1 (HIV-1) infection, only 5 cases of ototoxicity have been reported in the literature. We describe 3 additional cases of possible NRTI-associated ototoxicity in HIV-1-infected patients, all of whom were aged >45 years, had a history of noise-induced hearing loss, and reported tinnitus and deterioration in hearing in the setting of antiretroviral therapy. Reductions in mitochondrial DNA content induced by NRTIs, as well as mitochondrial DNA mutations associated with aging and HIV-1 infection, all may contribute to auditory dysfunction in older patients with HIV-1 infection. Prospective studies are necessary to determine the incidence of tinnitus and hearing loss among HIV-1-infected patients and their relationship to the use of NRTIs.
Subject(s)
Anti-HIV Agents/adverse effects , Deoxyribonucleosides/adverse effects , HIV Infections/drug therapy , HIV-1 , Hearing Loss, Noise-Induced/physiopathology , Reverse Transcriptase Inhibitors/adverse effects , Tinnitus/physiopathology , Anti-HIV Agents/therapeutic use , Deoxyribonucleosides/therapeutic use , HIV Infections/complications , Humans , Male , Middle Aged , Reverse Transcriptase Inhibitors/therapeutic useABSTRACT
The marine toxin bistratene A (BisA) potently induces cytostasis and differentiation in a variety of systems. Evidence that BisA is a selective activator of protein kinase C (PKC) delta implicates PKC delta signaling in the negative growth-regulatory effects of this agent. The current study further investigates the signaling pathways activated by BisA by comparing its effects with those of the PKC agonist phorbol 12-myristate 13-acetate (PMA) in the IEC-18 intestinal crypt cell line. Both BisA and PMA induced cell cycle arrest in these cells, albeit with different kinetics. While BisA produced sustained cell cycle arrest in G(0)/G(1) and G(2)/M, the effects of PMA were transient and involved mainly a G(0)/G(1) blockade. BisA also produced apoptosis in a proportion of the population, an effect not seen with PMA. Both agents induced membrane translocation/activation of PKC, with BisA translocating only PKC delta and PMA translocating PKC alpha, delta, and epsilon in these cells. Notably, while depletion of PKC alpha, delta, and epsilon abrogated the cell cycle-specific effects of PMA in IEC-18 cells, the absence of these PKC isozymes failed to inhibit BisA-induced G(0)/G(1) and G(2)/M arrest or apoptosis. The cell cycle inhibitory and apoptotic effects of BisA, therefore, appear to be PKC-independent in IEC-18 cells. On the other hand, BisA and PMA both promoted PKC-dependent activation of Erk 1 and 2 in this system. Thus, intestinal epithelial cells respond to BisA through activation of at least two signaling pathways: a PKC delta-dependent pathway, which leads to activation of mitogen-activated protein kinase and possibly cytostasis in the appropriate context, and a PKC-independent pathway, which induces both cell cycle arrest in G(0)/G(1) and G(2)/M and apoptosis through as yet unknown mechanisms.
Subject(s)
Acetamides , Ethers, Cyclic/pharmacology , Intestinal Mucosa/drug effects , Isoenzymes/metabolism , Protein Kinase C/metabolism , Pyrans , Signal Transduction/drug effects , Animals , Apoptosis , Biological Transport , Cell Cycle/drug effects , Cell Membrane/drug effects , Cell Membrane/enzymology , Cells, Cultured , Enzyme Activation/drug effects , Growth Inhibitors/pharmacology , Intestinal Mucosa/cytology , Intestinal Mucosa/enzymology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Protein Kinase C-alpha , Protein Kinase C-delta , Rats , Signal Transduction/physiology , Spiro Compounds , Tetradecanoylphorbol Acetate/pharmacologyABSTRACT
Age determination and validation studies on deep-water marine fishes indicate they are difficult to age and often long-lived. Techniques for the determination of age in individual fish includes growth-zone analysis of vertebral centra, fin rays and spines, other skeletal structures, and otoliths (there are three sets of otoliths in most bony fish semicircular canals, each of which is made of calcium carbonate). Most have regular increments deposited as the fish (and its semicircular canals) grows. The most commonly used otolith for age determination is the largest one called the sagitta. Age validation techniques include: (1) tag-recapture, often combined with oxytetracycline injection and analysis in growth-zones of bone upon recapture; (2) analysis of growth-zones over time; and (3) radiometric approaches utilizing a known radioactive decay series as an independent chronometer in otoliths from bony fishes. We briefly summarize previous studies using these three validation approaches and present results from several of our radiometric studies on deep-water, bony fishes recently subjected to expanding fisheries. Radiometric age validation results are presented for four species of scorpaenid fishes (the bank, Sebastes rufus, and bocaccio, S. paucispinis, rockfishes, and two thornyhead species, Sebastolobus altivelis and S. alascanus). In addition, our analysis of scorpaenids indicates that longevity increases exponentially with maximum depth of occurrence. The reason that the deep-water forms of scorpaenid fishes are long-lived is uncertain. Their longevity, however, may be related to altered physiological processes relative to environmental parameters like low temperature, high pressures, low light levels, low oxygen, and poor food resources.
Subject(s)
Ecosystem , Fishes/growth & development , Longevity/physiology , Age Factors , Animals , Fishes/physiology , RadiometryABSTRACT
BACKGROUND: Trauma is the commonest cause of surgical admission in Papua New Guinea, accounting for around 30% of cases in Port Moresby and over 40% in the highlands. The abdomen is traumatized in about 10-15% of trauma cases. In malarial endemic areas the enlarged spleen is particularly prone to rupture although earlier studies showed that this injury can often be managed conservatively. AIM: To determine the pattern and outcome of abdominal injury in the two largest cities, Port Moresby and Lae, in the 1990s. METHODS: A retrospective study of 213 adult admissions for abdominal trauma in Port Moresby and a prospective study of 98 adult abdominal trauma patients in Lae. In both centres malaria is endemic. Statistical analysis where appropriate was made using the chi2 test. RESULTS: Abdominal trauma was more likely to affect men outside the home and women in the home. Assault was responsible for 72% of cases of abdominal trauma. Women were assaulted by their husbands in two-thirds of cases. The spleen was the most likely organ to be injured, particularly in blunt trauma. Road traffic accidents caused only 10% of admissions with abdominal trauma. Most patients were admitted with a single injury. Splenic injury was managed nonoperatively in over 60% of cases. The negative laparotomy rate was 7% in Port Moresby and 20% in Lae, but negative laparotomy did not cause any deaths or extra morbidity. 17 patients (5.5%) died, the highest case fatality rate being 29% in a group of 31 patients with an injury severity score of 25 or greater. CONCLUSION: The pattern of abdominal trauma reflects the culture of Papua New Guinea and the different spectrum of risks to men and women. Once patients reach hospital they tend to do reasonably well although there is room for improvement, particularly with early assessment of the extent of the injury. The enlarged spleen is prone to injury and in those cases requiring laparotomy it is difficult to conserve. Many cases of ruptured spleen can be treated nonoperatively.
Subject(s)
Abdominal Injuries/epidemiology , Abdominal Injuries/diagnosis , Abdominal Injuries/therapy , Adolescent , Adult , Age Distribution , Female , Humans , Incidence , Injury Severity Score , Male , Middle Aged , Papua New Guinea/epidemiology , Retrospective Studies , Risk Factors , Sex Distribution , Survival Analysis , Treatment OutcomeABSTRACT
Epidermal growth factor (EGF) has been reported to either sensitize or protect cells against ionizing radiation. We report here that EGF increases radiosensitivity in both human fibroblasts and lymphoblasts and down-regulates both ATM (mutated in ataxia-telangiectasia (A-T)) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). No further radiosensitization was observed in A-T cells after pretreatment with EGF. The down-regulation of ATM occurs at the transcriptional level. Concomitant with the down-regulation of ATM, the DNA binding activity of the transcription factor Sp1 decreased. A causal relationship was established between these observations by demonstrating that up-regulation of Sp1 DNA binding activity by granulocyte/macrophage colony-stimulating factor rapidly reversed the EGF-induced decrease in ATM protein and restored radiosensitivity to normal levels. Failure to radiosensitize EGF-treated cells to the same extent as observed for A-T cells can be explained by induction of ATM protein and kinase activity with time post-irradiation. Although ionizing radiation damage to DNA rapidly activates ATM kinase and cell cycle checkpoints, we have provided evidence for the first time that alteration in the amount of ATM protein occurs in response to both EGF and radiation exposure. Taken together these data support complex control of ATM function that has important repercussions for targeting ATM to improve radiotherapeutic benefit.
Subject(s)
Down-Regulation , Epidermal Growth Factor/physiology , Lymphocytes/radiation effects , Mutation , Protein Serine-Threonine Kinases/metabolism , Radiation Tolerance/physiology , Ataxia Telangiectasia Mutated Proteins , Base Sequence , Cell Cycle Proteins , Cell Line , DNA/metabolism , DNA Primers , DNA-Binding Proteins , Fibroblasts/metabolism , Fibroblasts/radiation effects , Granulocyte-Macrophage Colony-Stimulating Factor/physiology , Humans , Lymphocytes/metabolism , Protein Binding , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/genetics , Sp1 Transcription Factor/metabolism , Tumor Suppressor ProteinsABSTRACT
The incidence of vein-graft occlusion associated with myocardial infarction and thrombosis following the use of the plasmin inhibitor, aprotinin, to reduce blood loss during vascular surgery has prompted the isolation of an alternative kinetically distinct inhibitor of plasmin from the venom of Pseudonaja textilis. This inhibitor has been called textilinin (Txln) and two distinct forms have been isolated from the Brown-snake venom (molecular weight, 6688 and 6692). A comparison of plasmin inhibitor constants for aprotinin and the Txlns 1 and 2 indicated that the former bound very tightly (inhibitor constant, Ki approximately 10(-11) mol/l), while both of the latter bound less tightly (Ki approximately 10(-9) mol/l). Homogeneity of Txlns 1 and 2 was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and mass spectrometry. A sequence difference of six amino acids was observed between the two forms of Txln. Txln 1 and 2 showed, respectively, 45 and 43% homology with aprotinin, while there was 58 and 55% homology, respectively, with a plasmin inhibitor from the venom of eastern Taipan, Oxyuranus scutellatus. Both Txlns have six cysteines, like other inhibitors of this group, and homology was determined by alignment of these cysteines. Both have been shown to reduce blood loss by about 60% in a murine tail vein bleeding model. It is proposed that the kinetic profiles of Txln 1 and 2 for plasmin allow the arrest of haemorrhage without the possible threat of thrombosis.
Subject(s)
Elapid Venoms , Elapid Venoms/isolation & purification , Elapid Venoms/pharmacology , Fibrinolysin/antagonists & inhibitors , Hemorrhage/drug therapy , Serine Proteinase Inhibitors/isolation & purification , Serine Proteinase Inhibitors/pharmacology , Amino Acid Sequence , Animals , Aprotinin/pharmacology , Blood Loss, Surgical/prevention & control , Elapid Venoms/genetics , Mice , Molecular Sequence Data , Serine Proteinase Inhibitors/geneticsABSTRACT
Protein kinase C-delta is activated during apoptosis, following proteolytic cleavage by caspase 3. Furthermore, overexpression of the catalytic kinase fragment of PKC-delta induces the nuclear phenotype associated with apoptosis, though the molecular basis of this effect has not been determined. In these studies we have examined the role of PKC-delta in the disassembly of the nuclear lamina at apoptosis. The nuclear lamina is disassembled during mitosis and apoptosis and mitotic disassembly involves hyperphosphorylation of lamin proteins by mitotic lamin kinases. During apoptosis, lamin proteins are degraded by caspase 6 and the contribution made by phosphorylation has not been proven. We show here that protein kinase C-delta co-localized with lamin B during apoptosis and activation of PKC-delta by caspase 3 was concomitant with lamin B phosphorylation and proteolysis. Inhibition of PKC-delta delayed lamin proteolysis, even in the presence of active caspase 6, whilst inhibitors of mitotic lamin kinases were without effect. In addition recombinant human PKC-delta was able to phosphorylate lamin B in vitro suggesting that its actions are direct and not via an intermediary kinase. We propose that PKC-delta is an apoptotic lamin kinase and that efficient lamina disassembly at apoptosis requires both lamin hyperphosphorylation and caspase mediated proteolysis.
Subject(s)
Apoptosis/physiology , Isoenzymes/metabolism , Nuclear Proteins/metabolism , Protein Kinase C/metabolism , Acetophenones/pharmacology , Apoptosis/drug effects , Benzopyrans/pharmacology , Biological Transport , Caspase 3 , Caspases/metabolism , Cell Nucleus/metabolism , Cytarabine/pharmacology , Enzyme Activation , Enzyme Inhibitors/pharmacology , HeLa Cells/drug effects , HeLa Cells/metabolism , Humans , Isoenzymes/genetics , Lamin Type B , Lamins , Peptide Fragments/metabolism , Phosphorylation , Protein Kinase C/genetics , Protein Kinase C-deltaABSTRACT
Ataxia-telangiectasia (A-T) is a genetic disorder characterized by a progressive ataxia, immunodeficiency, neurological abnormalities, hypersensitivity to ionizing radiation, and predisposition to cancer. The gene responsible for A-T (ATM) has been cloned and shown to code for a 350 kDa polypeptide containing 3,056 amino acid residues. Detection of ATM mutations for laboratory diagnosis of A-T is laborious and not practical, unless there are common mutations in a population. We describe here immunoblot analysis for the detection of ATM in seven Japanese A-T patients from five families and in controls using ATM3BA antibody. ATM protein was routinely and clearly detected in Epstein-Barr virus (EBV)-transformed or phytohemagglutinin (PHA)-stimulated lymphoblasts from controls. However, it could not be detected consistently in unstimulated peripheral blood mononuclear cells (PBMCs) from controls. We also detected ATM protein in control fibroblasts, but the background was relatively higher than in control lymphoblasts. ATM protein was not detected or dramatically decreased in EBV-transformed lymphoblasts from all seven patients tested and in fibroblasts from one patient. Immunoblot analysis using EBV-transformed or PHA-stimulated lymphoblasts represents a useful approach for laboratory diagnosis for A-T. The latter is especially preferable since it takes only 3 days to obtain sufficient cells for analysis.
Subject(s)
Ataxia Telangiectasia/blood , Protein Serine-Threonine Kinases/analysis , Adult , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins , Cell Line, Transformed , Cells, Cultured , Child , DNA-Binding Proteins , Female , Herpesvirus 4, Human , Humans , Immunoblotting/methods , Laboratories , Leukocytes, Mononuclear/chemistry , Leukocytes, Mononuclear/cytology , Male , Mitogens/pharmacology , Phytohemagglutinins/pharmacology , Tumor Suppressor ProteinsABSTRACT
BACKGROUND: Health care in Papua New Guinea (PNG) throughout the 20th century has been characterized by a significant shortage of medical practitioners and surgical expertise. A number of initiatives within the country and from outside have sought to address these deficiencies of numbers and quality. The present paper seeks to review the development of surgery and surgical training in PNG. METHODS: Review of the surgical literature, reports and records in the Division of Surgery at the University of Papua New Guinea (UPNG), and personal observations are used to look critically at the content and productivity of the various training initiatives. RESULTS: For the first half of the century, PNG relied on national medical assistants who were trained, supervised and directed by expatriate doctors. Medical training of PNG doctors began in 1951 and by 1999 more than 600 doctors had graduated. Expatriate specialist surgeons arrived in 1950 and were the only surgeons until the postgraduate Master of Medicine (surgical) programme produced its first graduates in 1978. This programme has now produced 37 surgeons who are reasonably well distributed throughout the country. Higher surgical diplomas were introduced in 1994 for more specialized training of some of the general surgeons. These training developments have been supported by AusAid as well as by Australian surgeons. CONCLUSIONS: Surgical expertise has progressively improved throughout the 20th century with the most major advances being achieved in the last decade. Training programmes have provided an expanding core of expertise of considerable quality, but the numbers of doctors and surgeons remain well below requirements.