Comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of three highly pathogenic human coronaviruses (MERS-CoV, SARS-CoV, and SARS-CoV-2).

The last two decades have witnessed the emergence of three deadly coronaviruses (CoVs) in humans: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There are still no reliable and efficient therapeutics to manage the devastating consequences of these CoVs. Of these, SARS-CoV-2, the cause of the currently ongoing coronavirus disease 2019 (COVID-19) pandemic, has posed great global health concerns. The COVID-19 pandemic has resulted in an unprecedented crisis with devastating socio-economic and health impacts worldwide. This highlights the fact that CoVs continue to evolve and have the genetic flexibility to become highly pathogenic in humans and other mammals. SARS-CoV-2 carries a high genetic homology to the previously identified CoV (SARS-CoV), and the immunological and pathogenic characteristics of SARS-CoV-2, SARS-CoV, and MERS contain key similarities and differences that can guide therapy and management. This review presents salient and updated information on comparative pathology, molecular pathogenicity, immunological features, and genetic characterization of SARS-CoV, MERS-CoV, and SARS-CoV-2; this can help in the design of more effective vaccines and therapeutics for countering these pathogenic CoVs.

Incidence and predictors of infection in patients undergoing primary isolated coronary artery bypass grafting: a report from a tertiary care hospital in a developing country.

AIM: Infection following coronary artery bypass grafting (CABG) is a leading cause of morbidity, mortality, and increased length of hospital stay. Many studies have investigated the predictive value of known risk factors for infection in patients following CABG and conclusions have been variable and may reveal regional or institution-specific influence. The purpose of this prospective study was to determine the pre- and peri-operative risk factors for infection in patients undergoing coronary artery bypass surgery in a developing country. METHODS: A prospective study was undertaken to collect data on 12 reported risk factors for all patients undergoing CABG during a five-year period at The Aga Khan University Hospital, Pakistan. The relationship of these risk factors to infection following CABG was evaluated. RESULTS: Out of 767 consecutive patients admitted for CABG, a total of 73 (9.51%) developed 92 infections following surgery. Sternal Surgical Site Infection (SSI) developed in 30 patients (3.91%), of which 29 (96.7%) were superficial and 1 (3.33%) was deep. There were 37 leg wound infections at the site of conduit harvest, and 2 cases of infection at the intra-aortic balloon pump. There were 12 cases of sepsis and 11 urinary tract infections. There were 26 cases (35.6%) of leukocytosis and 17 patients (23.3%) showed elevated erythrocyte sedimentation rate (ESR). Staphylococcus aureus was the most frequently isolated pathogen (39.7%). Bacteremia data was not collected. Of the total cases of infection following CABG, 59 required prolonged hospitalization or readmission. Univariate analysis was performed using a p-value of <0.2 as the inclusion criteria for further analysis using logistic regression. Multivariate analysis with adjusted Relative Risk (RR) showed that diabetes (P=0.002, RR=2.3, 95% CI=1.4-4.0), obesity (P=0.036, RR=2.2, 95% CI=1.0-4.4), use of an intra-aortic balloon pump (P=0.001, RR=3.6, 95% CI=1.7-7.7), female gender (P=0.004, RR=2.5, 95% CI=0.2-0.8) and prolonged mechanical ventilation (P=<0.0001, RR=6.7, 95% CI=2.8-15.5) were independent predictors of infection in the study population. CONCLUSION: This study suggests that diabetes, obesity, use of an intra-aortic balloon pump and female gender are independent predictors of infection in patients undergoing CABG. Early and strict diabetic control and pre-operative weight reduction may reduce the incidence of infection following CABG. Contamination of these patients may occur before, during and after the operation and efforts to curb such contamination must be intensive. Further prospective studies need to be undertaken to identify and establish these and other risk factors for infection in the region and elsewhere.

Secondary tasks impair adaptation to step- and gradual-visual displacements.

Motor adaptation is impaired by the performance of a secondary task which divides cognitive resources. Additionally, we previously reported slowed adaptation when participants were required to switch from one visual displacement adaptation task to another. Here, we examined whether a dividing secondary task had a similar effect on adaptation as switching between opposing visual displacements. The resource-dividing task involved simultaneously adapting to a step-visual displacement whilst vocally shadowing an auditory stimulus. The switching task required participants to adapt to opposing visual displacements in an alternating manner with the left and right hands. We found that both manipulations had a detrimental effect on adaptation rate. We then integrated these tasks and found the combination caused a greater decrease in adaptation rate than either manipulation in isolation. A second set of experiments showed that adaptation to a gradually imposed visual displacement was influenced in a similar manner to step adaptation. In summary, step adaptation slows the learning rate of gradual adaptation to a large degree, whereas gradual adaptation only slightly slows the learning rate of step adaptation. Therefore, although gradual adaptation involves minimal awareness it can still be disrupted with a cognitively demanding secondary task. We propose that awareness and cognitive resource can be regarded as qualitatively different, but that awareness may be a marker of the amount of resource required. For example, large errors are both noticed and require substantial cognitive resource. However, a lack of awareness does not mean an adaptation task will be resistant to interference from a resource-consuming secondary task.

CapA, an autotransporter protein of Campylobacter jejuni, mediates association with human epithelial cells and colonization of the chicken gut.

Two putative autotransporter proteins, CapA and CapB, were identified in silico from the genome sequence of Campylobacter jejuni NCTC11168. The genes encoding each protein contain homopolymeric tracts, suggestive of phase variation mediated by a slipped-strand mispairing mechanism; in each case the gene sequence contained frameshifts at these positions. The C-terminal two-thirds of the two genes, as well as a portion of the predicted signal peptides, were identical; the remaining N-terminal portions were gene specific. Both genes were cloned and expressed; recombinant polypeptides were purified and used to raise rabbit polyclonal monospecific antisera. Using immunoblotting, expression of the ca.116-kDa CapA protein was demonstrated for in vitro-grown cells of strain NCTC11168, for 4 out of 11 recent human fecal isolates, and for 2 out of 8 sequence-typed strains examined. Expression of CapB was not detected for any of the strains tested. Surface localization of CapA was demonstrated by subcellular fractionation and immunogold electron microscopy. Export of CapA was inhibited by globomycin, reinforcing the bioinformatic prediction that the protein is a lipoprotein. A capA insertion mutant had a significantly reduced capacity for association with and invasion of Caco-2 cells and failed to colonize and persist in chickens, indicating that CapA plays a role in host association and colonization by Campylobacter. In view of this demonstrated role, we propose that CapA stands for Campylobacter adhesion protein A.

Cortical changes to experimental sensitization of the human esophagus.

Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.

Cerebral processing of painful oesophageal stimulation: a study based on independent component analysis of the EEG.

BACKGROUND AND AIMS: Independent component analysis (ICA) of the electroencephalogram (EEG) overcomes many of the classical problems in EEG analysis. We used ICA to determine the brain responses to painful stimulation of the oesophagus. METHODS: Twelve subjects with a median age of 41 years were included. With a nasal endoscope, two series of 35 electrical stimuli at the pain threshold were given to the distal oesophagus and the EEG was subjected to ICA. The sessions were separated by 30 minutes. For each component head models, event related images, spectral perturbation, coherence analysis, and dipoles were extracted. The most valid components were found according to time/frequency information and reliability in both experiments. RESULTS: Reliable components with the most valid dipoles were found in the thalamus, insula, cingulate gyrus, and sensory cortex. Time locked activities were consistent with upstream activation of these areas, and cross coherence analysis of the sources demonstrated dynamic links in the beta(14-25 Hz) and gamma(25-50 Hz) bands between the suggested networks of neurones. The thalamic components were time and phase locked intermittently, starting around 50 ms. In the cingulate gyrus, the posterior areas were always firstly activated, followed by the middle and anterior regions. Components with dipoles in the sensory cortex were localised in several regions of the somatosensory area. CONCLUSIONS: The method gives new information relating to the localisation and dynamics between neuronal networks in the brain to pain evoked from the human oesophagus, and should be used to increase our understanding of clinical pain.

Post-coronary artery bypass surgery pericardial abscess: Salmonella paratyphi B.

Endemic enteric fever is one of the major health problems in South Asia where focal pyogenic infections with salmonella are being increasingly reported. A pericardial abscess following coronary artery bypass surgery with Salmonella paratyphi B was successfully treated, the first reported case so far.

Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans.

Tocotrienols exert hypocholesterolemic action in humans and animals. Lovastatin is widely used for that purpose. Both agents work by suppressing the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase through different mechanisms, post-transcriptional vs competitive inhibition. A human study with 28 hypercholesterolemic subjects was carried out in 5 phases of 35 days each, to check the efficacy of tocotrienol-rich fraction (TRF(25)) of rice bran alone and in combination with lovastatin. After placing subjects on the American Heart Association (AHA) Step-1 diet (phase II), the subjects were divided into two groups, A and B. The AHA Step-1 diet was continued in combination with other treatments during phases III to V. Group A subjects were given 10 mg lovastatin, 10 mg lovastatin plus 50 mg TRF(25), 10 mg lovastatin plus 50 mg alpha-tocopherol per day, in the third, fourth, and fifth phases, respectively. Group B subjects were treated exactly to the same protocol except that in the third phase, they were given 50 mg TRF(25) instead of lovastatin.The TRF(25) or lovastatin plus AHA Step-1 diet effectively lower serum total cholesterol (14%, 13%) and LDL-cholesterol (18%, 15% P < 0.001), respectively, in hypercholesterolemic subjects. The combination of TRF(25) and lovastatin plus AHA Step-1 diet significantly reduces of these lipid parameters of 20% and 25% (P < 0.001) in these subjects. Substitution of TRF(25) with alpha-tocopherol produces insignificant changes when given with lovastatin. Especially significant is the increase in the HDL/LDL ratio to 46% in group (A) and 53% (P < 0.002) in group (B). These results are consistent with the synergistic effect of these two agents. None of the subjects reported any side-effects throughout the study of 25-weeks. In the present study, the increased effectiveness of low doses of tocotrienols (TRF(25)) as hypocholesterolemic agents might be due to a minimum conversion to alpha-tocopherol. The report also describes in vivo the conversion of gamma-[4-3H]-, and [14C]-desmethyl (d-P(21)-T3) tocotrienols to alpha-tocopherol.

Non-small cell lung cancer: disease spectrum and management in a tertiary care hospital.

OBJECTIVES: To review the spectrum of presentation and the surgical management of Non Small Cell Lung Cancer (NSCLC) and the role of various diagnostic modalities in predicting the post-operative stage and the correlation of the post-operative stage with the chances of recurrence. SETTINGS: The Aga Khan University Hospital, Karachi--a tertiary care referral center in Paksitan. METHODS: This is a retrospective study of medical records of all the patients who were managed at the Aga Khan University Hospital (AKUH) between 1988 and 1998. The patients with a diagnosis of lung cancer were identified using the ICD-9-CM coding system and the data was analyzed for patients with NSCLC only. RESULTS: A total of 773 patients were admitted with a diagnosis of lung cancer at AKUH over 10 years period. Out of these 21 (2.71%) underwent staging mediastinoscopy and 20 (2.58%) patients underwent exploratory thoracotomy and biopsy without any resection, as the disease was found to be unresectable. Only 18 (2.32%) patients underwent surgical resection. There were 15 males and 3 females and the mean age was 53 years. Mean duration of symptoms was 12 months and cough and haemoptysis were the main presenting symptoms. Most of the tumors were located on the right side. CT scan and mediastinoscopy were mainly used to stage the disease. Complete surgical resection including en-bloc resection of adjacent structures was attempted, when possible. Median follow up was 24 months and the recurrence rate was 39%. There was no significant correlation between post-op stage and recurrence. CONCLUSION: It is concluded that most of the patients present at the advanced stage and resection is possible only in a small number of patients. The size of primary tumor and local extension should not contra-indicate surgery in patients with negative mediastinal nodes and without distant metastasis as it can be performed safely. All pulmonary lesion in the adults must be thoroughly investigated as early diagnosis and complete resection is the only key to cure and long term survival.

Should coronary artery bypass grafting be performed at the same time as repair of a post-infarct ventricular septal defect?

OBJECTIVE: The value of coronary artery bypass grafting (CABG) at the time of repair of a post-infarct ventricular septal defect (VSD) remains controversial. The aim of this study was to analyse the effect of CABG on early mortality and survival following repair of an acquired VSD. METHODS: Over 23 years, 179 patients, 118 male, 61 female, mean age 66 years (range 43-80), have undergone repair of a post-related VSD in our unit. A total of 29 patients, who predominantly form the earlier part of the series, were operated on greater than 1 month after the infarct and are, therefore, excluded. Coronary angiography was performed in 98 (65.3%) of the remaining 150 patients. Of these, 41 had coronary artery disease (CAD) limited to the infarct-related vessel and 57 had additional significant CAD. Those with CAD limited to the infarct-related vessel were not grafted (Group A). Of those, 40 with significant CAD underwent CABG at the time of VSD repair (Group B) and 17 did not (Group C). In 52 patients the coronary anatomy was not documented (Group D). Risk factors for early mortality were evaluated using logistic regression. Actuarial survival was compared using log rank and Wilcoxon tests. Cox's proportional hazards method was used to determine factors affecting survival. RESULTS: Overall, 30 day mortality was 32%. CABG did not significantly decrease operative mortality (logistic regression). There was no statistically significant difference in early mortality or actuarial survival between the four groups. CABG was not associated with an increased survival (Cox's method). CONCLUSIONS: Concomitant CABG at the time of VSD repair does not affect early mortality nor confer survival benefits. There seems to be no demonstrable benefit in revascularisation at the time of repair and, therefore, it may be unnecessary to perform CABG or coronary angiography in these patients.