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1.  Ubiquitin-like (UBX)-domain-containing protein, UBXN2A, promotes cell death by interfering with the p53-Mortalin interactions in colon cancer cells 
Cell Death & Disease  2014;5(3):e1118-.
Mortalin (mot-2) induces inactivation of the tumor suppressor p53's transcriptional and apoptotic functions by cytoplasmic sequestration of p53 in select cancers. The mot-2-dependent cytoprotective function enables cancer cells to support malignant transformation. Abrogating the p53-mot-2 interaction can control or slow down the growth of cancer cells. In this study, we report the discovery of a ubiquitin-like (UBX)-domain-containing protein, UBXN2A, which binds to mot-2 and consequently inhibits the binding between mot-2 and p53. Genetic analysis showed that UBXN2A binds to mot-2's substrate binding domain, and it partly overlaps p53's binding site indicating UBXN2A and p53 likely bind to mot-2 competitively. By binding to mot-2, UBXN2A releases p53 from cytosolic sequestration, rescuing the tumor suppressor functions of p53. Biochemical analysis and functional assays showed that the overexpression of UBXN2A and the functional consequences of unsequestered p53 trigger p53-dependent apoptosis. Cells expressing shRNA against UBXN2A showed the opposite effect of that seen with UBXN2A overexpression. The expression of UBXN2A and its apoptotic effects were not observed in normal colonic epithelial cells and p53−/− colon cancer cells. Finally, significant reduction in tumor volume in a xenograft mouse model in response to UBXN2A expression was verified in vivo. Our results introduce UBXN2A as a home defense response protein, which can reconstitute inactive p53-dependent apoptotic pathways. Inhibition of mot-2-p53 interaction by UBXN2A is an attractive therapeutic strategy in mot-2-elevated tumors.
doi:10.1038/cddis.2014.100
PMCID: PMC3973214  PMID: 24625977
mot-2; p53; UBXN2A; colorectal cancer; apoptosis; xenograft
2.  Kinetics of DNA load predict HPV 16 viral clearance 
Introduction
While high HPV 16 viral load measured at a single time point is associated with cervical disease outcomes, few studies have assessed changes in HPV 16 viral load on viral clearance.
Objective
To measure the association between changes in HPV 16 viral load and viral clearance in a cohort of Thai women infected with HPV 16.
Study design
Fifty women (n = 50) between the ages of 18–35 years enrolled in a prospective cohort study were followed up every three months for two years. Women positive for HPV 16 DNA by multiplex TaqMan© assay at two or more study visits were selected for viral load quantitation using a type-specific TaqMan© based real-time PCR assay. The strength of the association of change in viral load between two visits and viral clearance at the subsequent visit was assessed using a GEE model for binary outcomes.
Results
At study entry, HPV 16 viral load did not vary by infection outcome. A >2 log decline in viral load across two study visits was found to be strongly associated with viral clearance (AOR: 5.5, 95% CI: 1.4–21.3). HPV 16 viral load measured at a single time point was not associated with viral clearance.
Conclusions
These results demonstrate that repeated measurement of HPV 16 viral load may be a useful predictor in determining the outcome of early endpoints of viral infection.
doi:10.1016/j.jcv.2011.01.011
PMCID: PMC3837526  PMID: 21388867
HPV; DNA; Viral load; Epidemiology; Thailand
3.  Pattern of non-fatal injuries in road traffic crashes in a hilly area: A study from Shimla, North India 
Research Question:
What are the various injuries in road traffic crash cases?
Objectives:
To study various non-fatal injuries in road traffic crash cases.
Study Design:
Hospital based Descriptive study.
Study Population:
The study population comprised of 401 consecutive cases of non- fatal injuries involved in road traffic crashes and reported at Indira Gandhi Medical College hospital, Shimla.
Study Period:
1st June 2005 to 31st May 2006.
Study Variables:
Demographic characteristics of the victims, pattern of injuries and hospital stay of the victims. Types of crashes, time, day and month of crashes, vehicles involved in crashes, use of protective gear etc.
Statistical Analysis:
Percentages, Proportions.
Results:
73% of the injured victims were young between 20-49yrs, male to female ratio being 5.3:1. Employees (34.7%) and occupants of transport vehicles (45.9%) constituted the maximum number of the victims. Major injuries (fractures and abd. injuries) were reported in 53.4% of the victims and fractures of lower limb were the commonest of the injuries (26.3%). Use of seat-belt was found to be alarmingly low (14.3%) amongst the four- wheeler users and its non-use was found to be significantly associated with the major injuries. Helmet was used by 36 cases (66.7%) out of total of 54 users of motorized two-wheelers at the time of crash. Human error was the most reported cause of crash (82%) and the most common mode of crash was skidding and/rolling down (55%).23.1% of the drivers were reported to have consumed alcohol at the time of crash.
doi:10.4103/2229-5151.119198
PMCID: PMC3883197  PMID: 24404456
Epidemiological study; injuries; road traffic crashes
4.  Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: The DRIVE UK Study 
Eye  2012;26(4):510-516.
Introduction
End-stage diabetic eye disease is an important cause of severe visual impairment in the working-age group. With the increasing availability of refined surgical techniques as well as the early diagnosis of disease because of screening, one would predict that the prevalence of this condition is decreasing and the visual outcome is improving.
Aim
To study the prevalence and visual outcome following vitrectomy for complications of diabetic retinopathy.
Materials and methods
This study identified the patients who underwent vitrectomy from January 2007 to December 2009 because of diabetes-related complications in South East London. Data collected included baseline demographics, best-corrected visual acuity, indication for the vitrectomy, complication, outcome, and duration of follow-up.
Results
The prevalence of people requiring vitrectomy who are registered in the diabetes register of this region was 2 per 1000 people with diabetes. Vitrectomy was required in 185 eyes of 158 patients during this period. These included 83 Caucasians, 51 Afro-Caribbeans, 17 South Asians, and 7 from other ethnic groups. There were 58 patients with type I diabetes and 100 with type II, with a mean duration of diabetes of 23 and 16.5 years, respectively. The reason for vitrectomy included tractional retinal detachment (TRD) in 109 eyes, non-clearing vitreous haemorrhage (NCVH) in 68 eyes, and other causes in 8 eyes. In all, 50% of the eyes with TRD and NCVH, and 87% of the eyes with NCVH improved by at least three ETDRS lines at 12 months. Poor predictors of visual success included longer duration of diabetes (OR: 0.69), use of insulin (OR: 0.04), presence of ischaemic heart disease (OR: 0.04), delay in surgery (OR: 0.59), and the failure to attend clinic appointments (OR: 0.58). Preoperative use of intravitreal bevacizumab in eyes with TRD undergoing vitrectomy showed a marginal beneficial effect on co-existent maculopathy (P=0.08) and required less laser intervention post procedure, but did not affect the number of episodes of late-onset vitreous haemorrhage post vitrectomy (P=0.81).
Conclusion
Visual outcome has improved significantly in eyes with complications due to diabetic retinopathy compared with the previously reported Diabetic Vitrectomy Study.
doi:10.1038/eye.2011.321
PMCID: PMC3325558  PMID: 22222268
pars plana vitrectomy; proliferative diabetic retinopathy; tractional retinal detachment; non-clearing vitreous haemorrhage
5.  Surgical and visual outcome following 20-gauge vitrectomy in proliferative diabetic retinopathy over a 10-year period, evidence for change in practice 
Eye  2012;26(4):576-582.
Introduction
The study reports 10-year anatomical and visual outcome in patients who underwent pars plana vitrectomy (PPV) for complications due to proliferative diabetic retinopathy (PDR).
Methods
Retrospective analysis of patients undergoing 20G PPV from January 1999 to May 2010 for tractional retinal detachment (TRD) and non-clearing vitreous hemorrhage (NCVH) secondary to PDR recorded prospectively on an electronic patient record. The primary aim was to study anatomical success and eyes with visual acuity (VA) of ≤0.3 logMAR at last follow-up.
Results
There were 346 eyes of 249 patients with mean age of 55.63 years and follow-up of 1.44 years. In all, 95.3% of eyes had a flat retina at final follow-up. Overall 136/346 (39.4%) eyes had final VA of logMAR ≤0.3 (Snellen 6/12) and 129 (37.3%) had logMAR ≥1.0 (Snellen 6/60). In all, 50/181 (27.6%) eyes with TRD and 84/165 (50.9%) with NCVH achieved final VA of ≤0.3 logMAR (Snellen 6/12). A total of 218 (63.1%) showed ≥0.3 logMAR improvement from baseline to last follow-up. Both preoperative VA and final postoperative (post-op) VA (P<0.001) improved significantly with each year from 1999 to 2010. The commonest peroperative complication was iatrogenic retinal tear formation (28.4%). This was a risk factor for the development of post-op retinal detachment, odds ratio: 3.90 (95% confidence interval: 1.91–7.97, P=0.0002). Silicone oil was used in 5.2% of patients at the primary procedure. In all, 9.2% required removal of non clearing post vitrectomy hemorrhage.
Conclusions
Outcomes from vitreoretinal surgery for complications of diabetic retinopathy have improved. In addition, the visual outcome after diabetic vitrectomy steadily improved over the 10-year period, which may in part be due to the move to operate on patients with better vision.
doi:10.1038/eye.2011.348
PMCID: PMC3325568  PMID: 22241020
diabetes; proliferative diabetic retinopathy; tractional retinal detachment; non-clearing vitreous hemorrhage; vision
6.  Allergic Broncho Pulmonary Aspergillosis Complicated by Nocardiosis 
Case Reports in Pulmonology  2012;2012:758630.
We describe a 70-year-old male with a history of diabetes mellitus, hypertension, and asthma who presented with increasing breathlessness for 5 months. He was diagnosed to have allergic bronchopulmonary aspergillosis (ABPA) by serological and radiographic criteria. He was treated with steroids and itraconazole. After initial improvement, he developed fever with cough and mucopurulent sputum. X-ray chest revealed multiple cavities with air fluid level. Patient was treated with antibiotics without any response. Sputum was negative for acid fast bacilli (AFB). Sputum culture for bacteria and fungus did not reveal any significant growth; however a delayed growth of Nocardia was noted on fungal plates. Modified Ziehl Nelsen stain was positive for AFB. Patient was treated with cotrimoxazole. We discuss the serological and radiological criteria of ABPA, presentation and treatment of nocardia pulmonary infection and other possible causes of necrotizing pneumonia in immunocompromised settings.
doi:10.1155/2012/758630
PMCID: PMC3540710  PMID: 23320238
7.  Mapping of asthma research in India: A scientometric analysis of publications output during 1999-2008 
Objective:
This study analyzes the research output of India in asthma during the period from 1999 till 2008. It analyzes the growth, rank and global publications share, citation impact, share of international collaborative papers, contribution of major collaborative partner countries and contribution of various subject fields. It also analyzes the characteristics of most productive institutions, authors and high-cited papers.
Materials and Methods:
SCOPUS database has been used to retrieve the data on publication output in asthma research.
Results:
India ranks 15th position among the top 23 countries in asthma research, with its global publication share of 1.27% (862 papers), registering an average citation per paper of 3.43 and achieved an h-index of 33 during 1999-2008.
Conclusion:
Indian research output on asthma is quite low in the global context as reflected from its publication output per thousand population (0.001) and its world publication share (1.27%) during 1999-2008. Also, the impact and quality of Indian research is low compared to select developed and developing countries.
doi:10.4103/0970-2113.85683
PMCID: PMC3213708  PMID: 22084535
Asthma; India; publication output
8.  BEHAVIOURAL AND EMOTIONAL PROBLEMS IN SCHOOL GOING ADOLESCENTS 
Background
Adolescents are highly vulnerable to psychiatric disorders. This study aimed to explore the prevalence and patterns of behavioural and emotional problems in adolescents. It was also aimed to explore associations between socioenvironmental stressors and maladaptive outcomes.
Method
A school based cross-sectional study was conducted between January and July 2008. A stratified random sampling was done. 1150 adolescents in 12 to 18 year age group in grades 7 to 12 in 10 co-educational schools (government run and private) were the subjects of the study. Behavioural and emotional problems were assessed using Youth Self-Report (2001) questionnaire. Family stressors were assessed using a pre-tested 23 item questionnaire. Univariate and multivariate analysis were performed. Multiple logistic regression analysis was also done.
Results
Prevalence of behavioural and emotional problems in adolescents was found to be 30%, with girls exceeding boys in all age groups. Internalizing syndrome was the most common (28.6%) psychiatric problem. On stepwise regression analysis, a perceived lack of emotional proximity to mother had the highest odds (3.489) followed by addiction in father (2.642) and marital discord in parents (1.402). Type of school, type of family, socioeconomic status, relationship with father, mother&s employment and educational status were not found to be significantly associated
Conclusion
An alarming number of our adolescents suffer from emotional and behavioural problems which have their roots in the family environment. These data suggest urgency in establishing a school based mental health service.
doi:10.4066/AMJ.2011.464
PMCID: PMC3448127  PMID: 23289042
Adolescents; Youth self report; behavioural and emotional problems and screening.
9.  A scientometric analysis of Indian research output in medicine during 1999–2008 
Objective:
This study analyzes the research activities of India in medicine during 1999–2008, based on the total publication output, its growth rate, quality of papers published and rank of India in the global context. Patterns of international collaborative research output and the major partner countries of India are also discussed. This study also evaluates the research performance of different types of Indian medical colleges, hospitals, research institutes, universities and research foundations and the characteristics of published literature in Indian and foreign journals. It also analyzes the medical research output by disease and organs.
Materials and Methods:
The publication data on medicine has been retrieved by using SCOPUS database.
Results:
India holds 12th rank among the productive countries in medicine research consisting of 65,745 papers with a global publication share of 1.59% and registering a growth rate of 76.68% for the papers published during 1999–2003 to 2004–2008.
Conclusion:
High quality research in India is grossly inadequate and requires strategic planning, investment and resource support. There is also a need to improve the existing medical education system, which should foster research culture.
doi:10.4103/0976-9668.82313
PMCID: PMC3312706  PMID: 22470241
India; medical research; publication output; scientometric
10.  Endovascular Management of Infective Intracranial Aneurysms with Acrylic Glue 
Interventional Neuroradiology  2009;15(4):443-447.
Summary
Cerebral mycotic aneurysms (MAs) also called infective aneurysms, are uncommon and are usually encountered in patients with infective endocarditis. These aneurysms often present with intracranial hemorrhage. MAs may resolve on treatment with antibiotics alone. However prognosis with medical management alone is unpredictable. Good prognosis with surgery has been reported for single accessible ruptured MAs. However surgery is associated with significant morbidity. Endovascular treatment of MAs along with appropriate antibiotics is emerging as an acceptable option for these patients.
We describe two cases of infective endocarditis complicated by ruptured MA treated successfully by liquid embolic glue material.
PMCID: PMC3299432  PMID: 20465872
mycotic aneurysm, infective endocarditis, endovascular treatment, liquid embolic glue material
11.  Chronic renal insufficiency among Asian Indians with type 2 diabetes: I. Role of RAAS gene polymorphisms 
BMC Medical Genetics  2006;7:42.
Background
Renal failure in diabetes is mediated by multiple pathways. Experimental and clinical evidences suggest that renin-angiotensin-aldosterone system (RAAS) has a crucial role in diabetic kidney disease. A relationship between the RAAS genotypes and chronic renal insufficiency (CRI) among type 2 diabetes subjects has therefore been speculated. We investigated the contribution of selected RAAS gene polymorphisms to CRI among type 2 diabetic Asian Indian subjects.
Methods
Twelve single nucleotide polymorphisms (SNPs) from six genes namely-renin (REN), angiotensinogen (ATG), angiotensin converting enzyme I (ACE), angiotensin II type 1 receptor (AT1) and aldosterone synthase (CYP11B2) gene from the RAAS pathway and one from chymase pathway were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and tested for their association with diabetic CRI using a case-control approach. Successive cases presenting to study centres with type 2 diabetes of ≥2 years duration and moderate CRI diagnosed by serum creatinine ≥3 mg/dl after exclusion of non-diabetic causes of CRI (n = 196) were compared with diabetes subjects with no evidence of renal disease (n = 225). Logistic regression analysis was carried out to correlate various clinical parameters with genotypes, and to study pair wise interactions between SNPs of different genes.
Results
Of the 12 SNPs genotyped, Glu53Stop in AGT and A>T (-777) in AT1 genes, were monomorphic and not included for further analysis. We observed a highly significant association of Met235Thr SNP in angiotensinogen gene with CRI (O.R. 2.68, 95%CI: 2.01–3.57 for Thr allele, O.R. 2.94, 95%CI: 1.88–4.59 for Thr/Thr genotype and O.R. 2.68, 95%CI: 1.97–3.64 for ACC haplotype). A significant allelic and genotypic association of T>C (-344) SNP in aldosterone synthase gene (O.R. 1.57, 95%CI: 1.16–2.14 and O.R. 1.81, 95%CI: 1.21–2.71 respectively), and genotypic association of GA genotype of G>A (-1903) in chymase gene (O.R. 2.06, 95%CI: 1.34–3.17) were also observed.
Conclusion
SNPs Met235Thr in angiotensinogen, T>C (-344) in aldosterone synthase, and G>A (-1903) in chymase genes are significantly associated with diabetic chronic renal insufficiency in Indian patients and warrant replication in larger sample sets. Use of such markers for prediction of susceptibility to diabetes specific renal disease in the ethnically Indian population appears promising.
doi:10.1186/1471-2350-7-42
PMCID: PMC1479320  PMID: 16672053
12.  A patient with bag of pancreatic stones 
Postgraduate Medical Journal  2002;78(922):500-505.
doi:10.1136/pmj.78.922.500-a
PMCID: PMC1742476  PMID: 12185231
13.  Tuberculosis presenting as deep vein thrombosis 
Postgraduate Medical Journal  1999;75(880):104-106.
We present two cases, women of 21 and 60 years old, who presented with deep vein thrombosis. Both cases had retroperitoneal para-aortic and iliac lymph node enlargement without any malignancy or other predisposing thrombophilic factors. Investigations revealed tubercular aetiology of the lymph nodes causing venae caval obstruction.


Keywords: retroperitoneal lymph nodes; tuberculosis; deep vein thrombosis
PMCID: PMC1741133  PMID: 10448473
14.  Recurrent acute respiratory tract infections in areas with high nitrate concentrations in drinking water. 
Environmental Health Perspectives  2000;108(4):363-366.
A review of the literature indicated an association among high nitrate ingestion, methemoglobinemia, and pathologic changes in bronchi and lung parenchyma. The present study examined a possible correlation among drinking water nitrate concentration, methemoglobin levels, cytochrome b(5) reductase activity, and acute respiratory tract infection with a history of recurrence (RRTI). Our study was conducted in five village units in the state of Rajasthan, India, with nitrate concentrations of 26, 45, 95, 222, and 459 mg NO(3) ion/L. We randomly selected 88 children. The children were up to 8 years of age, age matched, and represented 10% of the total population of these areas. We obtained detailed RRTI histories and conducted medical examinations. Methemoglobin levels and cytochrome b(5) reductase activity were estimated biochemically. The data collected were statistically analyzed using spreadsheet software on a personal computer. We observed strong interdependence between methemoglobin levels and RRTI in children up to 8 years of age. Methemoglobin levels alone explained 80% of the variation in the RRTI cases. This study indicates that methemoglobinemia, secondary to high nitrate ingestion in drinking water, causes RRTI. Increased production of methemoglobin and free radicals of nitric oxide and oxygen due to nitrate metabolism in the body lead to alveolar damage and mismatching of ventilation and perfusion, which may be the reason for high mortality in children due to RRTI.
Images
PMCID: PMC1638033  PMID: 10753096
15.  Efficacy of enalapril in essential hypertension and its comparison with atenolol. 
Postgraduate Medical Journal  1990;66(776):446-449.
The effect of enalapril was evaluated in 67 patients with essential hypertension, and its therapeutic efficacy was compared with atenolol in a placebo run-in, single-blind, cross-over trial. Enalapril significantly reduced blood pressure in all grades of essential hypertension. As monotherapy it 'normalized' blood pressure in 88%, 50% and 25% of patients with mild, moderate and severe hypertension respectively. Optimal dose for most of the patients was 20 to 40 mg/day. Comparison with atenolol revealed almost parallel efficacy of the two drugs, although enalapril produced a significantly greater reduction in systolic blood pressure in patients with mild and moderate hypertension (P less than 0.01 in each group). No serious side effects were encountered with either drug. Enalapril, therefore, has a potent and slightly superior antihypertensive effect to that of atenolol, and may be used as a 'first-step' drug in the treatment of hypertensive patients.
PMCID: PMC2429599  PMID: 2216994
16.  Pyloric obstruction due to gastric tuberculosis--an endoscopic diagnosis. 
Postgraduate Medical Journal  1990;66(771):63-65.
A 22 year old male presented with symptoms of gastric outlet obstruction. Endoscopy showed a hypertrophic nodular lesion around the pyloric opening with pyloric stenosis. The endoscopic biopsy and histopathological examination revealed tuberculosis involving the stomach, an extremely rare lesion.
Images
PMCID: PMC2429366  PMID: 2349172
17.  Direct detection of hepatitis B virus from dried blood spots by polymerase chain reaction amplification. 
Journal of Clinical Microbiology  1992;30(8):1913-1916.
The presence of hepatitis B virus DNA in the sera of individuals is the most definitive marker of an active viral infection. We have used polymerase chain reaction detection of hepatitis B virus DNA directly on whole blood dried as a spot on filter paper. The method is rapid, specific, and sensitive and has the ability to detect as little as 10 virus particles by ethidium bromide staining of the polymerase chain reaction-amplified products. The method is cost-effective, and the stability of the spots makes the collection and transportation of potentially infectious blood safe.
Images
PMCID: PMC265415  PMID: 1500493
18.  Milk protein allergy--a rare cause of pyrexia of unknown origin in an adult female. 
Postgraduate Medical Journal  1989;65(761):183-184.
Milk protein allergy is described in a young adult female patient who presented with fever and malabsorption syndrome. The patient fulfilled Goldman's criteria for the diagnosis of milk protein allergy and responded to an elimination diet.
PMCID: PMC2429255  PMID: 2813241
19.  Two-hour methyl isocyanate inhalation exposure and 91-day recovery: a preliminary description of pathologic changes in F344 rats. 
The accidental release of methyl isocyanate (MIC) in Bhopal, India, was reportedly responsible for the deaths of more than 2,000 people. To study the pathology of acute inhalation exposure to MIC, the tissues of male and female Fischer 344 rats were evaluated immediately after a single 2-hr exposure to 0, 3, 10, or 30 ppm MIC, and through day 91. Early gross pathologic changes in the 30 ppm-exposed rats included a reddish white encrustation around the mouth and nose, a small thymus, and distension of the gastrointestinal tract with gas. Lungs (middle and median lobes) showed consolidation and hemorrhage and failed to deflate when the chest cavity was opened. Microscopic changes in the upper respiratory tract 3 hr after exposure included marked erosion and separation of olfactory and respiratory epithelia from the basement membrane with accumulation of serofibrinous fluid. On day 1, acute inflammation and fibrinopurulent exudate partially blocked the nasal passages. Epithelial cells had sloughed from the nasopharynx, trachea, bronchi, and major bronchioles, leaving the basement membrane covered with fibrin and exudate. Granulomatous inflammation and intraluminal fibrosis of the airways were observed by day 3, with increased intraluminal fibrosis by day 7. Lower airways became blocked by exfoliated cells, mucous plugs, and/or intraluminal fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1474667  PMID: 3622446
20.  Effect of methyl isocyanate (MIC) gas on the eyes of Fischer 344 rats. 
The accidental release of methyl isocyanate gas in Bhopal, India, was reported to cause temporary blindness and other eye injuries in many of the exposed people. Methyl isocyanate (MIC) is known to be corrosive and to irritate intact skin and mucous membranes, but little is known about the extent of ocular damage incurred during exposure to its vapors. The eyes of male and female Fischer 344 rats were evaluated immediately after a 2-hr exposure to 0, 3, 10, or 30 ppm of MIC, and periodically thereafter during a 91-day recovery period. During exposure to 10 ppm and higher concentrations, rats kept their eyes partially closed. Copious lacrimation and occasional frothy nasal discharge were evident. Eyes were examined under ultraviolet light after topical application of sodium fluorescein, and histopathologic examination included lids, cornea, lens, retina, optic nerve, and Harderian gland. There was no significant gross or microscopic evidence of epithelial erosion or ulceration of the cornea, or of adjacent tissues immediately after, or at any time following exposures. No skin irritation was noted. It would appear that the natural protective mechanisms of the eye of rats were adequate to prevent ocular damage at these exposure levels.
Images
PMCID: PMC1474646  PMID: 3622422
21.  Ultrastructural changes in the nasal mucosa of Fischer 344 rats and B6C3F1 mice following an acute exposure to methyl isocyanate. 
Male rats and male mice received a single 2-hr exposure to 0 (control), 10, or 30 ppm of methyl isocyanate and were sacrificed after 1, 3, 14, or 90 days to assess the ultrastructural changes in the nasal mucosa by transmission electron microscopy. One day after exposure to methyl isocyanate, there were widespread areas of necrosis and degeneration of the respiratory and olfactory epithelium of rats and mice in the 10 ppm and 30 ppm groups. Qualitatively the ultrastructural findings were similar for both exposure groups and species. Degeneration followed by rapid regeneration was observed for both respiratory and olfactory epithelia but was most striking for olfactory epithelium in the dorsal meatus. Three days after the exposure, the olfactory epithelium was two to three cell layers thick due to a loss of supporting cells, olfactory neurons, and basal cells. By 14 days after exposure, the olfactory epithelium was composed of a heterogeneous cell population three to five cell layers thick. At 90 days following exposure, the epithelium was of normal thickness (eight to ten cell layers), with normal architectural arrangement, and composed of well-differentiated cells that appeared similar to those of controls. There were several findings that suggested the epithelial cells of Bowman's glands were the progenitor for the regenerating supporting cells of the olfactory epithelium. This study demonstrated that the respiratory and olfactory epithelium is capable of complete structural regeneration after an acute destruction by methyl isocyanate.
Images
PMCID: PMC1474640  PMID: 3622447
22.  Two-hour methyl isocyanate inhalation and 90-day recovery study in B6C3F1 mice. 
B6C3F1 mice were exposed by inhalation to 0, 3, 10, and 30 ppm methyl isocyanate for 2 hr followed by a 90-day recovery period. Sixteen of eighty (20%) male mice in the 30 ppm group died following exposure. There were no other unscheduled deaths in the mice. Five mice/sex/group were examined at 2 hr or at 1, 3, 7, 14, 28, 49, or 91 days following exposure. Chemical-related changes were restricted to the respiratory system. At 30 ppm there were extensive necrosis and erosion of the respiratory and olfactory epithelium in the nasal cavity. Severe necrosis and epithelial erosion were also found in the trachea and main bronchi. Regeneration of the mucosal epithelium occurred rapidly in the nasal cavity and airways. In the turbinates, mild incomplete olfactory epithelial regeneration persisted to day 91 in the male mice. Intraluminal fibrotic projections covered by respiratory epithelium and bronchial fibrosis were found in the major airways of the 30 ppm male and female mice by day 7. The intraluminal fibrosis persisted to day 91. In males with severe bronchial fibrosis, chronic alveolitis and atelectasis were found. In mice exposed to 3 or 10 ppm, persistent pulmonary changes were not found. These studies indicate that methyl isocyanate inhalation at or near lethal concentrations can cause persistent fibrosis of the major bronchi in mice.
Images
PMCID: PMC1474648  PMID: 3622445
23.  The toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. II. Repeated exposure and recovery studies. 
F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3 ppm exposures, and mice died after exposures to 6 ppm. Deaths appeared to be related to severe respiratory distress. Survivors in high dose groups lost weight initially, then gained weight at rates equal to controls throughout a 91-day recovery period. Lung weights increased significantly in male and female rats exposed to 3 ppm, but no persistent changes in brain, kidney, thymus, spleen, liver, or testis weights were seen in either mice or rats. Blood and serum from male and female rats were taken for clinical pathology and hematology assessments on day 7 of postexposure, the day prior to the first observed deaths of these animals. No changes or only slight changes were seen in measures of serum alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, or in blood and brain cholinesterase activities. However, serum creatine kinase increased with dose in both males and females. Blood urea nitrogen, creatinine, and methemoglobin were unchanged. No changes were seen in counts of red blood cells or platelets, or in red cell indices. Hemoglobin concentrations and hematocrits were slightly elevated. No changes were noted in absolute leukocyte counts, but counts of segmented neutrophils increased and lymphocytes decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1474630  PMID: 3622427
24.  Toxicity of inhaled methyl isocyanate in F344/N rats and B6C3F1 mice. I. Acute exposure and recovery studies. 
Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. During exposures, signs of restlessness, lacrimation, and a reddish discharge from the nose and mouth were evident in rats and mice. Following exposures, rats and mice were dyspneic and weak. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. No significant clinical pathology, or hematologic changes were observed in exposed rats. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results.(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1474627  PMID: 3622444
25.  Is the injection of DNA enough to cause bacteriophage P22-induced changes in the cellular transport process of Salmonella typhimurium? 
Journal of Virology  1979;32(1):98-101.
It was demonstrated earlier in this laboratory that phage P22 induces a transient depression in the cellular transport processes of the host Salmonella typhimurium immediately after infection and that an effective injection process is enough to cause the depression. By using defective phage particles that contain host DNA instead of phage DNA for infection, it has been demonstrated that the injection of phage-specific DNA is essential for this. The defective particles adsorbed to the host and injected their DNA, but the cellular transport processes of the host were not altered. Thus, the injection of host DNA by the phage fails to affect the transport process. Insensitivity of the phage DNA-induced depression in transport to chloramphenicol rules out the involvement of newly synthesized protein in this change and indirectly suggests the possible role of phage DNA-associated internal proteins of P22.
PMCID: PMC353531  PMID: 396382

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