Development of AD-Like Pathology in Skeletal Muscle.

Effective therapeutic strategy against Alzheimer's disease (AD) requires early detection of AD; however, clinical diagnosis of Alzheimer's disease (AD) is not precise and a definitive diagnosis of AD is only possible via postmortem examination for AD pathological hallmarks including senile plaques composed of Aß and neuro fibrillary tangles composed of phosphorylated tau. Although a variety of biomarker has been developed and used in clinical setting, none of them robustly predicts subsequent clinical course of AD. Thus, it is essential to identify new biomarkers that may facilitate the diagnosis of early stages of AD, prediction of subsequent clinical course, and development of new therapeutic strategies. Given that pathological hallmarks of AD including Aßaccumulation and the presence of phosphorylated tau are also detected in peripheral tissues, AD is considered a systemic disease. Without the protection of blood-brain barrier, systemic factors can affect peripheral tissues much earlier than neurons in brain. Here, we will discuss the development of AD-like pathology in skeletal muscle and the potential use of skeletal muscle biopsy (examination for Aßaccumulation and phosphorylated tau) as a biomarker for AD.

Stress responses at birth: determinants of cord arterial cortisol and links with cortisol response in infancy.

OBJECTIVE: To investigate (A) the determinants of infant stress response at delivery and (B) test the hypothesis that stress at birth, as reflected by cord arterial cortisol, influences cortisol response to vaccination at two months. DESIGN: Prospective observational study. SETTING: Tertiary referral maternity hospital. POPULATION: One hundred and seventy-two primiparous women with uncomplicated singleton pregnancies. METHODS: Women were recruited antenatally. At birth, cord arterial blood and obstetric data were collected. Saliva was collected from infants immediately before and after vaccination at two months. Cortisol was analysed from cord blood and saliva by radio-immunoassay. MAIN OUTCOME MEASURES: Stress response at birth, as demonstrated by cord arterial cortisol; association with saliva cortisol response to vaccination at two months. RESULTS: Cord arterial cortisol varied with mode of delivery, combined spinal/epidural use and pH. Salivary cortisol response at two months correlated with cord arterial cortisol (r= 0.24, P < 0.05). Infants with the highest and lowest cord arterial cortisol had markedly different cortisol responses at two months (P= 0.017). These groups had different modes of delivery with caesarean rates of <8% in the high cortisol response group and 83% in the low cortisol response group (P < 0.0001). CONCLUSION: Babies born vaginally mount greater cortisol responses at birth than those delivered by caesarean section. Stress at delivery may influence the infant HPA axis response for up to two months.

Infant cortisol response after prolonged antenatal prednisolone treatment.

Prednisolone is widely used to treat medical conditions in pregnancy, despite the lack of long-term safety studies on infants. Animal studies have shown that antenatal glucocorticoid treatment can cause in utero growth restriction and up-regulation of the offsprings' hypathalamic-pituitary-adrenal axis. We recruited women treated antenatally with prednisolone, and followed 12 of the infants up to four months, using routine infant vaccinations as a stressor. Birthweights were similar to controls (n = 289, uncomplicated, singleton term pregnancies), as were infants' baseline and stress-induced cortisol levels. Mothers rated their infants as less difficult and more adaptable than controls. This study provides initial reassurance about the safety of prednisolone in pregnancy.

The painful truth: physicians are not invincible.

Physicians are not immune to psychosocial problems but may face unique impediments to attending to them. Self-care among physicians is not a topic generally included as a part of professional training, nor is it a topic that readily receives consideration in professional practice. The stresses of professional practice can exact a great toll, however, and self-neglect can lead to tragic consequences. In some areas, particularly suicide rates, physicians have increased vulnerability, and in other areas problems may be unrecognized (depression, substance abuse, marital problems, and other stress-related concerns). Female physicians show some particular areas of risk. In this paper, we raise questions about how and why physicians may be particularly vulnerable, review the available literature about the extent and nature of such problems in physicians, discuss possible factors related to the development of these problems in physicians, and suggest a variety of solutions to improve physician self-care.

Aplastic crisis associated with parvovirus B19 in an adult with hereditary spherocytosis.

Parvovirus B19 is usually associated with an acute, self-limited disease in children. In patients with a congenital hemolytic anemia, infection with this virus can cause an aplastic crisis. We describe such a crisis in an adult with asymptomatic hereditary spherocytosis. The association between acute red blood cell aplasia and infection with parvovirus B19 is well described in patients with hereditary hemolytic anemia, particularly sickle cell anemia. This association has also been described, although less frequently, in patients with other inherited hemolytic diseases, such as hereditary spherocytosis. In children, human parvovirus B19 causes an acute self-limited illness known as erythema infectiosum (fifth disease). In immunocompromised individuals, chronic infections can occur and cause a severe, persistent anemia. In pregnant women, infection can, but usually does not, lead to fetal infection. An infected fetus can have severe anemia, congestive heart failure, generalized edema (fetal hydrops) and even death. Most cases of aplastic crises associated with parvovirus B19 in patients with hereditary spherocytosis have been reported in children and adolescents. In this paper we describe an aplastic crisis in a 28 year old man with asymptomatic hereditary spherocytosis.

Effects of some K(+)-channel inhibitors on the electrical behaviour of guinea-pig isolated trachealis and on its responses to spasmogenic drugs.

1. A study has been made of the effects of inhibitors selective among plasmalemmal K(+)-channels on the sensitivity and responsiveness of guinea-pig trachealis muscle to carbachol, histamine and KCl. The effects of the K(+)-channel inhibitors on the resting membrane potential and spontaneous electrical activity of the trachealis cells have also been examined. 2. In indomethacin (2.8 microM)-treated trachealis muscle, dofetilide (1 microM) and glibenclamide (10 microM) were each devoid of spasmogenic activity. In contrast, 4-aminopyridine (4-AP, 62.5 microM--8 mM), charybdotoxin (ChTX, 100 nM) and iberiotoxin (IbTX, 100 nM) were each spasmogenic. Spasm evoked by 4-AP, IbTX or ChTX was reduced, though not abolished, by atropine (1 microM). Spasm evoked by 4-AP (1 mM), ChTX (100 nM) or IbTX (100 nM) was unaffected by tetrodotoxin (TTX; 3.1 microM) or by tissue pretreatment with capsaicin (1 microM for 30 min). Spasm evoked by IbTX or ChTX was abolished by nifedipine (1 microM). 3. Dofetilide (1 microM) and glibenclamide (10 microM) were each without effect on the tracheal sensitivity or responsiveness to carbachol, histamine or KCl. 4-AP (1 mM) antagonized carbachol, potentiated histamine but did not affect tissue sensitivity to KCl. When the effects of 4-AP were examined in the presence of atropine (1 microM), it potentiated all the spasmogens including carbachol. IbTX and ChTX (each 100 nM) potentiated all three spasmogens. Potentiation of histamine induced by 4-AP (1 mM) or IbTX (100 nM) was also observed in tissues treated with a combination of atropine (1 microM) and TTX (3.1 microM). 4. Dofetilide (1 and 10 microM) was without effect on the resting membrane potential or spontaneous electrical activity of the trachealis cells. 4-AP (1 mM) evoked depolarization and caused a small increase in the frequency of slow wave discharge. The depolarization evoked by 4-AP was abolished by atropine (1 microM). IbTX (100 nM) and ChTX (100 nM) each evoked little or no change in resting membrane potential but converted the spontaneous slow waves into spike-like, regenerative action potentials. These electrophysiological effects of IbTX and ChTX were unaffected by atropine (1 microM). 5. It is concluded that the dofetilide-sensitive, cardiac, delayed rectifier K(+)-channel is either not expressed in trachealis muscle or is of no functional importance in that tissue. The ATP-sensitive K(+)-channel (KATP) does not moderate tracheal sensitivity to spasmogens such as carbachol, histamine and KCl. The 4-AP-sensitive delayed rectifier K(+)-channel (Kdr) and the large Ca(2+)-dependent K(+)-channel (BKCa) each moderate trachealis muscle sensitivity to spasmogens. Neither Kdr nor BKCa plays an important role in determining the resting membrane potential of guinea-pig trachealis cells. However, the BKCa channel is responsible for limiting the effects of the increase in membrane Ca2+ conductance associated with the depolarizing phase of slow waves. It is BKCa channel opening that prevents the development of a slow wave into a spike-like regenerative action potential.

The law and ethics in relation to dentists treating HIV-positive patients: two recent court cases.

Two recent Canadian judgements regarding the application of human rights legislation to dentistry and HIV-seropositive patients are summarized and discussed. In the Ontario case of Jerome v. DeMarco, the Ontario Human Rights tribunal found that seropositivity constitutes a "handicap" under human rights legislation. However, the tribunal dismissed the claim by a seropositive patient that he had been illegally discriminated against by a dentist who, on learning the patient was seropositive, delayed treating him until the end of the day. This decision served as a precedent in the lengthy Quebec small claims court judgment of Hamel v. Malaxos. In this case, the dentist was held to have violated Quebec human rights legislation by trying to refer an HIV-seropositive patient to a hospital treatment centre rather than performing the appropriate dental treatment himself. Court judgments regarding this problem are reported and discussed.

Evaluation of the "one-minute" test for detecting Helicobacter (Campylobacter) pylori infection.

The "one-minute" urease test to detect Helicobacter (Campylobacter) pylori infection was evaluated using histology and culture as the "gold standard". The test was performed in a blinded manner and compared with the conventional Christensen's urease test. Helicobacter pylori was detected in 88 of 100 consecutive patients attending the gastrointestinal clinic for upper endoscopy. Although the "one-minute" urease test was more sensitive [86% (76/88)] than the conventional Christensen's urease test [70% (62/88)], this difference was not statistically significant (P = 0.22). Histology was the most sensitive [97% (85/88)] whilst culture was 80% (70/88) sensitive. All tests exhibited specifications of 100%. The "one-minute" urease test is a simple, rapid and highly specific test to detect Helicobacter pylori which can be performed at endoscopy.

Urinary changes in ultra long-distance marathon runners.

The urine of 45 athletes, male and female, were studied after completing an ultra long-distance marathon race. Of these athletes, 24.4% were found on screening to have red blood cells in the urine. The urinary mean corpuscular volume (MCV) of red cells was used in an attempt to differentiate between lower and upper urinary tract haematuria. With the exception of 1 athlete, the red cells were not dysmorphic and had an MCV greater than 72 fl. This suggested that the haematuria had an origin from the lower urinary tract. The urinary changes disappeared within 7 days. No definite residual renal damage could be established.

Evaluation of various laboratory techniques to diagnose Helicobacter pylori in patients with upper gastro-intestinal tract symptoms.

Helicobacter (Campylobacter) pylori is strongly associated with type B gastritis. The detection of H. pylori, which entails histological examination and culture of gastric biopsy specimens, takes several days. There has been much interest in developing more rapid tests, including non-invasive ones. Using histology and/or culture as the 'gold standard', several methods to detect H. pylori were compared and evaluated. The organism was detected in 84 of 100 consecutive patients attending the Gastrointestinal Unit of King Edward VIII Hospital for upper gastrointestinal tract endoscopy. Histological examination was the most sensitive (98%) and specific (100%) method used in detecting H. pylori in gastric biopsy specimens. An enzyme-linked immunosorbent assay to detect specific IgG antibodies to whole H. pylori organisms is a moderately sensitive (82%), non-invasive method but it is nonspecific (38%). Although culture was specific (100%), it was less sensitive (68%) than histological examination. The 'conventional' urease assays must be performed under controlled conditions (37 degrees C) for optimal results (sensitivity, 71%).

Incidence of Campylobacter pylori in patients with upper gastro-intestinal symptoms.

Antral mucosal biopsy specimens were examined microbiologically and histologically for the presence of Campylobacter pylori in 224 patients with upper gastrointestinal symptoms. The gastric mucosa of 183 patients (82%) were found to harbour C. pylori. C. pylori was strongly associated with the presence of histological gastritis (93%) and was detected in only 10% of 30 patients in whom histological examination of gastric biopsy specimens was negative. Endoscopically diagnosed duodenal lesions were more strongly associated with the presence of C. pylori than gastric lesions (P less than 0.001). The histological demonstration of spiral bacteria in biopsy specimens was a more sensitive method for the diagnosis of C. pylori than culture (80% v. 65%).

Outbreak of cryptosporidiosis among young children attending a day-care centre in Durban.

During an outbreak of an enteric illness occurring among infants and toddlers in a day-care centre in Durban, Cryptosporidium was detected in 51 (73%) of 70 children. Two (10%) of 20 staff members were also found to have cryptosporidiosis. Symptoms occurred in all but 4 of the Cryptosporidium-positive infants and toddlers and lasted for 1-33 days. Oocyst excretion often persisted after cessation of symptoms and continued for up to 50 days in some children. Transmission is considered to have occurred predominantly by person-to-person spread. Measures to prevent transmission of enteric-type diseases were implemented and coincided with cessation of the outbreak.

Neuronal and neuroglial responses following retinal lesions in the neonatal rats.

Lesions were produced in the nasal-superior quadrant of rat retinas at 1 day postnatal. Both the optic fiber and ganglion cell layers were destroyed at the lesion site. Retrograde changes in the more peripherally located ganglion cell bodies, their optic fibers, and neuroglia were monitored by light and electron microscopy. No optic fibers remained in the region peripheral to the lesion site after 2 days postoperative (DPO). Neither regenerative sprouting nor axonal ingrowth from late-maturing ganglion cells in the retinal periphery was observed. Cell death of the large and the majority of medium ganglion cell bodies was very rapid as was clearing of the degeneration products. These processes peaked at 1 DPO and were complete by 2 DPO. Microglia and Mueller cell cytoplasm actively phagocytized degenerating ganglion cell bodies and their optic fibers. A stable population of cell bodies in the ganglion cell layer peripheral to the lesion remained intact from 2 DOP to 21 DPO. The surviving somata were consistently 65% of the control ganglion cell population, and they remained after their axons had degenerated. The cell bodies measured 6-12.1 micron in diameter, a range which included the small cell population and a few of the medium cells. Dendritic patterning, used to designate ganglion cell types, corroborated their classification as small and medium ganglion cells. Morphological changes in these perikarya due to axotomy were limited to a mild chromatolytic response.