Apolipoprotein E ε-4 as a genetic determinant of Alzheimer's disease heterogeneity.

Alzheimer's disease (AD) displays a high degree of heterogeneity in terms of its etiology, presentation, prognosis, and treatment response. This can partly be explained by high-penetrance mutations in the amyloid precursor protein, presenilin 1 and presenilin 2 genes causing amyloid beta aggregation, which is a major pathogenic mechanism in the development of early-onset AD in a small subgroup of patients. Late-onset AD is considered a polygenic disorder in which cumulative risk resulting from interaction with modifiable environmental risk factors may be responsible for the majority of cases. The ε-4 allele of the apolipoprotein E (APOE) gene has emerged as the most significant genetic risk factor for late-onset AD, influencing nearly every pathogenic domain affected in AD. It is a major risk factor for cerebral amyloid angiopathy, recognized as a common pathological finding in an AD subtype associated with white matter dysfunction. The APOE ε-4 allele is also a known risk factor for ischemic stroke, which can result in vascular dementia or contribute to subcortical vascular dysfunction. In this review, we evaluate the clinical relevance of APOE genotyping in relation to cholesterol metabolism and available evidence on risk reduction strategies applicable to AD.

Guideline summary: appropriate use of tigecycline.

Tigecycline, the first of a new class of broad-spectrum antibiotics (the glycylcyclines), has been licensed in South Africa for the parenteral treatment of adult patients with complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs). This article serves as a summary of the guideline on the appropriate use of tigecycline, published in mid-2010 as a collaborative effort by representatives of the Association of Surgeons of South Africa, the Critical Care Society of Southern Africa, the Federation of Infectious Diseases Societies of Southern Africa, the South African Thoracic Society and the Trauma Society of South Africa.

Guideline: appropriate use of tigecycline.

INTRODUCTION: Tigecycline, the first of a new class of antibiotics, the glycylcyclines, was licensed in South Africa for the parenteral treatment of adult patients with complicated intra-abdominal infections (cIAIs) and complicated skin and soft-tissue infections (cSSTIs). METHODS: A multidisciplinary meeting representative of the Association of Surgeons of South Africa, the Critical Care Society of Southern Africa, the Federation of Infectious Diseases Societies of Southern Africa, the South African Thoracic Society and the Trauma Society of South Africa was held to draw up a national guideline for the appropriate use of tigecycline. Background information reviewed included randomised controlled trials, other relevant publications and local antibiotic susceptibility patterns. The initial document was drafted at the meeting. Subsequent drafts were circulated to members of the working group for modification. OUTPUT: The guideline addresses several important aspects of the new agent, summarising key clinical data and highlighting important considerations with the use of the drug. The recommendations in this guideline are based on currently available scientific evidence together with the consensus opinion of the authors. CONCLUSION: This statement was written out of concern regarding the widespread misuse of antibiotics. Its primary intention is to facilitate heterogeneous use of antibiotics as a component of antibiotic stewardship and to highlight the appropriate use of tigecycline in particular.

Neonatal death in mice lacking cardiotrophin-like cytokine is associated with multifocal neuronal hypoplasia.

Mice with null mutations of ciliary neurotrophic factor (Cntf) receptor alpha (Cntf-Ralpha), or cytokine-like factor 1 (Clf), one component of Cntf-II (a heterodimeric Cntf-Ralpha ligand), die as neonates from motor neuron loss affecting the facial nucleus and ventral horn of the lumbar spinal cord. Exposure to cardiotrophin-like cytokine (Clc), the other putative Cntf-II element, supports motor neuron survival in vitro and in ovo. Confirmation that Clc ablation induces an equivalent phenotype to Clf deletion would support a role for Clc in the functional Cntf-II complex. In this study, Clc knockout mice had decreased facial motility, did not suckle, died within 24 hours, and had 32% and 29% fewer motor neurons in the facial nucleus and lumbar ventral horn, respectively; thus, Clc is essential for motor neuron survival during development. The concordance of the Clc knockout phenotype with those of mice lacking Cntf-Ralpha or Clf bolsters the hypothesis that Clc participates in Cntf-II.

Gammaherpesvirus carrier status of black wildebeest (Connochaetes gnou) in South Africa.

Malignant catarrhal fever (MCF) is an economically important disease primarily of domestic cattle with a high case fatality rate. It is caused by either alcelaphine herpesvirus type 1 (AlHV-1) or ovine herpesvirus type 2 (OvHV-2). The major reservoir host of AlHV-1 is the blue wildebeest (Connochaetes taurinus), but it is generally accepted that the black wildebeest (Connochaetes gnou) is also a reservoir host. No viral studies in the black wildebeest have been reported and the carrier status of black wildebeest has not been documented. Specimens were collected from several game farms and conservation areas in central South Africa representing the geographical area historically linked to the natural habitat of the black wildebeest. Specimens were obtained from 304 black wildebeest of different ages and sex, as well as 51 black wildebeest foetuses at different stages of gestation. Virus was isolated from a black wildebeest calf. Morphological features and antigenic characteristics suggested it to be a gammaherpesvirus closely related to AlHV-1. All serum samples tested positive with a competitive inhibition enzyme-linked immunosorbent assay (CI-ELISA) for group-specific malignant catarrhal fever virus antibody. A SYBR Green real-time PCR assay was developed for the detection of gammaherpesviral DNA. Only 15.8 % of the animals tested positive with the real-time PCR assay whereas 90 % of the foetuses tested positive. This finding suggests that, unlike OvHV-2 infection in lambs in which the infection takes place after weaning, the virus in black wildebeest is mainly transmitted in utero or soon after birth. The results suggest that black wildebeest are latent carriers of a gammaherpesvirus similar or closely related to AlHV-1 present in blue wildebeest and that it is likely that all black wildebeest are persistently infected.

Bony landmarks as an aid for intraoperative facial nerve identification.

Identification of the facial nerve trunk is essential during surgery of the parotid gland. Numerous landmarks have been researched and used. The relation between the facial nerve to two constant bony landmarks, the tip of the mastoid process and the central point of the transverse process of the atlas was investigated. Forty cadavers were dissected. A preauricular incision exposed the nerve trunk. Bony landmarks were identified and marked. The distance from the nerve trunk to the mastoid process and the atlas was measured. The mean distance between the mastoid process and nerve for the left was 9.18 +/- 2.05 mm and for the right, 9.35 +/- 1.67 mm. The mean distance between the atlas and the nerve for the left was 14.31 +/- 3.59 mm and for the right, 13.76 +/- 4.65 mm. Confidence intervals were determined. The importance of the aforementioned data revolves around minimizing the chance of injury to the facial nerve during surgery. The applicability of these landmarks needs to be studied in the clinical setting.

The Surgical Management and Speech and Swallowing Rehabilitation of Patients with Advanced Tongue Cancer in South Africa

Advanced tongue cancer may have a devastating effect on a person's ability to speak and to swallow. Very little is known about the surgical management and speech and swallowing rehabilitation of persons with advanced tongue cancer in South Africa. The aim of this study was to obtain information regarding clinical practices in treatment and rehabilitation. Questionnaires were distributed to 450 surgeons and 150 speech-language pathologists in South Africa. The response rate was 16 for the surgeons and 33 for the speech-language pathologists. Results showed that only a small number of surgeons and speech-language pathologists in South Africa are involved in the treatment of persons with advanced tongue cancer. Surgeons prefer combined modality treatment (surgery and post-operative radiotherapy) in the primary treatment of patients with advanced tongue cancer; but the use of radiochemotherapy is growing. Total glossectomy is a very radical procedure; but it is sometimes used by surgeons to treat patients with advanced disease. Total glossectomy with laryngeal preservation is preferred to total glossolaryngectomy by surgeons; in order to preserve laryngeal voice. Patients with total glossectomy form only a small part of the caseload of speech-language pathologists. Swallowing rehabilitation includes aspects such as dietary changes; compensatory swallowing techniques and airway protection mechanisms. Speech intelligibility is targeted in speech rehabilitation; but alternative communication is sometimes recommended for patients who have undergone total glosso-laryngectomy

A histomorphometric evaluation of factors influencing the healing of bony defects surrounding implants.

PURPOSE: The authors' aim was to perform a histomorphometric study of the healing of bone defects created adjacent to titanium and hydroxyapatite (HA) -coated implants and covered with either a resorbable or a nonresorbable membrane in combination with different filler materials and to evaluate to what degree coating, membrane, and/or filler influenced the healing of the defects. MATERIALS AND METHODS: Posterior teeth were extracted from the mandibles of 10 baboons, and 12 implants were placed in each animal in the edentulous areas. The implants were either titanium or HA-coated, the membranes were either Vicryl, Gore-Tex, or Resolut, and the filler was either demineralized freeze-dried bone (DFDB), autogenous bone, or Biocoral. The implants were observed for either 3, 6, 9, 12, or 18 months. The volume of newly generated tissue and the relative contribution of bone, marrow, and filler were evaluated, as was relative extension of resorption, formation, and quiescent surface. RESULTS: The results indicated that autogenous bone is still the gold standard, but both the DFDB and Biocoral compared favorably to it. Both filler materials were being gradually replaced by bone; this process was not yet finished at 18 months postsurgery. DISCUSSION: Since even the sterilization of DFDB cannot exclude the possibility of a disease transmission, it is important to find an appropriate substitute. Both filler and membranes contributed to the re-establishment of the original volume; better results were achieved with the Vicryl and Gore-Tex membranes than with the Resolut. Biocoral can be considered an effective material. CONCLUSION: A bony defect is not necessarily a contraindication for the placement of an implant. (More than 50 references.)

Mandibular landmarks as an aid in minimizing injury to the marginal mandibular branch: A metric and geometric anatomical study.

Iatrogenic injury to the marginal mandibular branch is an important reason for medicolegal actions. The aim of this study was to determine the distance of the marginal mandibular branch to the inferior border of the mandible as well as variation of nerve position in relation to this border. The marginal mandibular branch was dissected carefully in a number of 36 facial halves. Three points were identified on the inferior border of the mandibular ramus: Point A at the angle of the mandible, Point B just anterior to the facial artery, and Point C, 2 cm anterior to Point B. A metric and geometric morphometric analysis, including thin-plate spline and relative warp analysis was done to determine the variation of nerve position in relation to these three bony landmarks. The metric study indicated a median distance from Point A to the nerve 2.3 mm inferior to Point A, 2.4 mm superior to Point B, and 10.7 mm superior to Point C. The shape analysis indicated that variation in the position of the nerve occurs most commonly at Points A and B. We conclude that these mandibular landmarks may assist surgeons in minimizing marginal mandibular branch injury and patient discomfort.

CD4+CD45RBHi T cell transfer induced colitis in mice is accompanied by osteopenia which is treatable with recombinant human osteoprotegerin.

BACKGROUND AND AIMS: Transfer of CD4+CD45RBHi T cells into semi syngeneic immunodeficient mice represents a model of inflammatory bowel disease (IBD). As patients with IBD often suffer from osteopenia, we studied if this T cell transfer in mice results in osteopenia in addition to colitis, and if treatment with osteoprotegerin (OPG) has effects on the bone mineral density of T cell transferred mice. We also investigated whether osteopenia was due to malabsorption as a result of a dysregulated digestive tract or as a consequence of the inflammatory process. METHODS: CD4+CD45RBHi or CD4+CD45RBLo T cells (4 x 10(5)) were sorted from CB6F1 and transferred into C.B.17 scid/scid mice. Recipient mice were treated with human IgG1 Fc (control) or Fc-OPG three times per week in a prophylactic regimen as well as a therapeutic regimen (after 10% body weight loss) and were evaluated for osteopenia and colitis. RESULTS: Mice that received CD4+CD45RBHi T cells developed osteopenia (as indicated by decreased bone density accompanied by decreased osteoblasts and increased osteoclasts) and colitis (as indicated by histological changes in the large intestine). Mice that received CD4+CD45RBLo T cells developed neither osteopenia nor colitis. All animals consumed, on average, the same amount of food and water over the course of the study. Prophylactic treatment with Fc-OPG increased bone density in mice that received either CD4+CD45RBHi or CD4+CD45RBLo T cells but had no effects on the gastrointestinal tract. Fc-OPG treatment of osteopenic mice with established IBD caused the normalisation of bone density. Osteopenia in CD4+CD45RBHi T cell recipients was accompanied by hypoparathyroidism that was partially normalised by treatment with Fc-OPG. CD4+CD45RBHi T cell recipients also had a bone marrow inflammatory cell infiltrate expressing tumour necrosis factor alpha which was unaffected by treatment with Fc-OPG. CONCLUSIONS: CD4+CD45RBHi T cell transfer results in osteopenia in addition to colitis. Evidence suggests that this osteopenia was induced by inflammatory cell infiltration and not by malabsorption of calcium. Recombinant human osteoprotegerin effectively treated the osteopenia. OPG may be a useful therapeutic option for treating osteopenia in patients with IBD.

Appropriate use of the carbapenems.

The carbapenems are a group of broad-spectrum beta-lactam antibiotic agents of which there are three parenteral preparations currently available in South Africa, namely imimpenem/cilastatin, meropenem and ertapenem. Owing to the fact that imipenem/cilastatin and meropenem have a broad spectrum of activity that includes Pseudomonas and Acinetobacter species, they are ideal antibiotics for treatment of severe nosocomial infections. In contrast, ertapenem has limited in vitro activity against the latter non-fermentative gram-negative bacteria and is therefore more suitable for the treatment of certain severe community-acquired infections. This statement arises out of concerns about the general abuse of antibiotics such as the carbapenems, with the primary intention of highlighting the appropriate use of these agents.

Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte-Duclos disease.

Initially identified in high-grade gliomas, mutations in the PTEN tumor-suppressor are also found in many sporadic cancers and a few related autosomal dominant hamartoma syndromes. PTEN is a 3'-specific phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) phosphatase and functions as a negative regulator of PI3K signaling. We generated a tissue-specific deletion of the mouse homolog Pten to address its role in brain function. Mice homozygous for this deletion (PtenloxP/loxP;Gfap-cre), developed seizures and ataxia by 9 wk and died by 29 wk. Histological analysis showed brain enlargement in PtenloxP/loxP;Gfap-cre mice as a consequence of primary granule-cell dysplasia in the cerebellum and dentate gyrus. Pten mutant cells showed a cell-autonomous increase in soma size and elevated phosphorylation of Akt. These data represent the first evidence for the role of Pten and Akt in cell size regulation in mammals and provide an animal model for a human phakomatosis condition, Lhermitte-Duclos disease (LDD).

Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects.

AIMS: To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the 'atypical' antipsychotic clozapine and the 'classical' antipsychotic haloperidol, in healthy male volunteers. METHODS: Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective 'alertness', 'contentedness' and 'anxiety' were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05. RESULTS: Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; -3.02 [-3.56, -2.47]), salivary output (g; -0.34 [-0.60, -0.08]), mean arterial blood pressure (mm Hg; -8.7 [-14.3, -3.1]), critical flicker fusion frequency (Hz; -3.26 [-3.94, -2.58]), and subjectively-rated 'alertness' (mm; -20.94 [-29.21, -12.67]) and 'contentedness' (mm; -12.98 [-17.90, -8.06]), whereas haloperidol increased prolactin concentration (mU l(-1); 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; -0.68 [-1.23, -0.14]), mean arterial blood pressure (mm Hg; -7.0 [-12.6, -1.4]) and critical flicker fusion frequency (Hz; -1.15 [-1.83, -0.47]). CONCLUSIONS: The effects of the antipsychotics are in agreement with their receptor binding profiles: alpha(1)-adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D(2) dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug.

Purification and identification of active antibacterial components in Carpobrotus edulis L.

Very little is known about the chemical composition of Carpobrotus edulis, also known as Hotnotsfig or sourfig. However, some claims have been made in the past by traditional healers, regarding its usage as a medicinal plant. In this investigation it was initially illustrated that a crude methanolic extract of the plant exhibits strong anti-bacterial activity. Subsequently, the crude extract was fractionated by means of liquid-liquid chromatography, tannins removed by means of LH20 column chromatography and bioactive fractions with antibacterial properties isolated by means of preparative thin layer chromatography. Five bioactive compounds, individually or collectively responsible for the antibacterial property of C. edulis, were purified from an active ethyl acetate fraction. These compounds were initially identified as flavanoids using standard fingerprinting methods and eventually identified as rutin, neohesperidin, hyperoside, cactichin and ferulic acid using flavanoid standards. A sixth flavanoid with antibacterial activity was also purified but could not be identified in this way. The latter is currently isolated in larger volume for identification through nuclear magnetic resonance spectroscopy.

Penetrating cardiac injuries--current evaluation and management of the stable patient.

Patients with penetrating cardiac injuries present in a stable or only mildly shocked condition--especially if the laceration has sealed off and the patient has been adequately resuscitated. A large proportion of patients presenting to our unit are in a reasonably stable condition after resuscitation, and rapid diagnosis may be difficult. We present our experience over a 5-year period (191 patients), with particular reference to the stable patient. All patients with penetrating precordial wounds should be assessed for a possible cardiac injury, especially if a period of hypotension has occurred. Clinical signs, central venous pressure, chest radiograph, pericardiocentesis and subxiphoid window are not always helpful in the diagnosis. Cardiac ultrasound is very useful (in the absence of haemothorax), and was performed in 103 of 191 patients, with 8 false-negatives and 3 false-positives. When an unstable patient presents with an obvious diagnosis use of cardiac ultrasound should be restricted. A subxiphoid window has diagnostic value where the cardiac ultrasound is inconclusive.

Myospherulosis in renal cell carcinoma.

OBJECTIVE: To study retrospectively the identification, characteristics, and localization of myospherulosis in different types of renal cell carcinomas. DESIGN: Twenty-seven consecutive renal cell carcinomas treated by radical nephrectomy in 1 year were studied. All the tumor and nontumor slides were examined for myospherulosis. The demographic data, histological type of renal cell carcinoma, Robson stage, and Fuhrman grades were recorded. RESULTS: Myospherules were found in 10 cases. They were associated with the clear cell type and a higher nuclear grade. The cell type remained the only significant factor when these 2 factors were tested together with the tumor stage by logistic regression. Myospherulosis tended to be found in younger patients but was not associated with the sex or the side of the tumor. They were scattered within tumor cystic spaces or among sheets of tumor cells. Some of the myospherules might arise from histiocytes or even tumor cells. Compared with previous reports of myospherulosis associated with exogenous or endogenous lipid, the myospherules associated with renal cell carcinoma were smaller and more uniform in size. There is no associated fibrosis or foreign body giant cell reaction. CONCLUSION: As far as we know, this is the first report of myospherulosis occurring in malignant tumors in human, and their associated features are different from those previously described for myospherulosis related to exogenous or endogenous lipid.

Hippocampal N-methyl-D-aspartate receptor subunit mRNA levels in temporal lobe epilepsy patients.

Changes in the subunit stoichiometry of the N-methyl-D-aspartate (NMDA) receptor (NMDAR) alters its channel properties, and may enhance or reduce neuronal excitability in temporal lobe epilepsy patients. This study determined whether hippocampal NMDA receptor subunit mRNA levels were increased or decreased in temporal lobe epilepsy patients compared with nonseizure autopsy cases. Hippocampal sclerosis (HS; n = 16), non-HS (n = 10), and autopsy hippocampi (n = 9) were studied for NMDAR1 (NR1) and NR2A-D mRNA levels by using semiquantitative in situ hybridization techniques, along with neuron densities. Compared with autopsy hippocampi, non-HS and HS patients showed increased NR2A and NR2B hybridization densities per dentate granule cell. Furthermore, non-HS hippocampi showed increased NR1 and NR2B mRNA levels per CA2/3 pyramidal neuron compared with autopsy cases. HS patients, by contrast, showed decreased NR2A hybridization densities per CA2/3 pyramidal neuron compared with non-HS and autopsy cases. These findings indicate that chronic temporal lobe seizures are associated with differential changes in hippocampal NR1 and NR2A-D hybridization densities that vary by subfield and clinical-pathological category. In temporal lobe epilepsy patients, these findings support the hypothesis that in dentate granule cells NMDA receptors are increased, and excitatory postsynaptic potentials should be strongly NMDA mediated compared with nonseizure autopsies. HS patients, by comparison, showed decreased pyramidal neuron NR2A mRNA levels, and this suggests that NMDA-mediated pyramidal neuron responses should be reduced in HS patients compared with non-HS cases.

Shock absorption potential of different mouth guard materials.

STATEMENT OF PROBLEM: Clinical stresses and situations in the mouths of patients are substantially different; thus, it is not possible to make an exact in vivo comparison of the efficiency of various mouth guards. PURPOSE: This study developed a device and a method to test and quantify the potential of mouth guards to absorb shock and evaluated and compared 5 designs for mouth guards. MATERIAL AND METHODS: Strain gauges and accelerometer sensors were mounted in various positions on the maxilla and inside an artificial skull. Sensors quantified the response of several areas of the skull to inputs of force on the maxillary teeth protected by the mouth guard being investigated. Input of force was applied to the maxillary teeth with a modal hammer equipped with a load cell. Five mouth guards of each of 5 designs were manufactured and placed in position before force was applied to the maxillary teeth. All inputs were measured and analyzed and, from those results, a method was developed to quantify the relative potential of the mouth guards to absorb shock. This method was then used to quantify the shock absorption potential of the 5 types of mouth guard designs. RESULTS: All 5 types of mouth guards provided some measure of protection and were better than no protection. However, the level of protection provided by the 5 mouth guard designs differed.

Crisis phenomena among African adolescents.

This study investigated inadequate parent-child relationships, problems with regard to sexuality, and substance abuse among African university students. They reported experiencing positive aspects of the parent-child relationship, such as acceptance, love, understanding, encouragement, and guidance, as well as negative aspects, including inadequate communication and parents' authoritarian attitudes. Numerous sexual issues and the abuse of alcohol and other drugs were perceived as serious problems among teenagers in general. Although an inadequate parent-child relationship appears to contribute to substance abuse and sexuality problems, it cannot be regarded as solely responsible, as a multitude of factors also play a role. The results indicate the need for life-skills training for both adolescents and parents, particularly regarding communication.