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Biomedical subjects

M K Khan

Publications and source records attributed to M K Khan.

At least 19 recordsLinked to original sources
PubMed2001

Radiation therapy to a primary tumor accelerates metastatic growth in mice.

The surgical removal of a primary tumor can result in the rapid growth of metastases. The production of angiogenesis inhibitors by the primary tumor is one mechanism for the inhibition of metastatic tumor growth. The effect of curative radiotherapy to a primary tumor known to make an inhibitor of angiogenesis and the effects on distant metastases has not been studied. We here show that the eradication of a primary Lewis lung carcinoma (LLC-LM), which is known to generate angiostatin, is followed by the rapid growth of metastases that kill the animal within 18 days after the completion of radiation therapy. The right thighs of C57BL/6 mice (n = 25) were injected s.c. with 1 x 10(6) LLC-LM cells. Animals were randomized to one of five groups: no irradiation, 40 Gy in one fraction, 30 Gy in one fraction, 40 Gy in two 20 Gy fractions, or 50 Gy in five 10 Gy fractions. Tumors were clinically eradicated in each treatment group. All of the surviving animals became dyspneic and were killed within 14-18 days after the completion of radiation therapy. Examination of their lungs revealed >46 (range, 46-62) surface metastases in the treated animals compared with 5 (range, 2-8) in the untreated animals. The lung weights had increased from 0.2 g (range, 0.19-0.22 g) in the controls to 0.58 g (range 0.44-0.84) in the experimental animals. The most effective dose regimen was 10 Gy per fraction for five fractions, and serial experiments were conducted with this fractionation scheme. Complete response of the primary tumor was seen in 25 of 35 (71%) mice. The average weight of the lungs in the nonirradiated animals was 0.22 g (range, 0.19-0.24 g) and in the irradiated animals was 0.66 g (range, 0.61-0.70 g). The average number of surface metastases increased from five per lung (range, 2-13) in the control animals to 53 per lung (range, 46-62) in the irradiated animals. Both differences were statistically significant with P < 0.001. If the nontumor-bearing leg was irradiated or the animals were sham-irradiated, no difference in the number of surface metastases or lung weights was observed between the control group and the treated group. Urinary levels of matrix metalloproteinase 2, the enzyme responsible for angiostatin processing in this tumor model, were measured and correlated with the viability and size of the primary tumor. Administration of recombinant angiostatin prevented the growth of the metastases after the treatment of the primary tumor. In this model, the use of radiation to eradicate a primary LLC-LM tumor results in the growth of previously dormant lung metastases and suggests that combining angiogenesis inhibitors with radiation therapy may control distant metastases.

Angiogenesis Inhibitors↗
PubMed2001

Engineering and characterization of functional human microvessels in immunodeficient mice.

SUMMARY: Current model systems used to investigate angiogenesis in vivo rely on the interpretation of results obtained with nonhuman endothelial cells. Recent advances in tissue engineering and molecular biology suggest the possibility of engineering human microvessels in vivo. Here we show that human dermal microvascular endothelial cells (HDMEC) transplanted into severe combined immunodeficient (SCID) mice on biodegradable polymer matrices differentiate into functional human microvessels that anastomose with the mouse vasculature. HDMEC were stably transduced with Flag epitope or alkaline phosphatase to confirm the human origin of the microvessels. Endothelial cells appeared dispersed throughout the sponge 1 day after transplantation, became organized into empty tubular structures by Day 5, and differentiated into functional microvessels within 7 to 10 days. Human microvessels in SCID mice expressed the physiological markers of angiogenesis: CD31, CD34, vascular cellular adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1). Human endothelial cells became invested by perivascular smooth muscle alpha-actin-expressing mouse cells 21 days after implantation. This model was used previously to demonstrate that overexpression of the antiapoptotic protein Bcl-2 in HDMEC enhances neovascularization, and that apoptotic disruption of tumor microvessels is associated with apoptosis of surrounding tumor cells. The proposed SCID mouse model of human angiogenesis is ideally suited for the study of the physiology of microvessel development, pathologic neovascular responses such as tumor angiogenesis, and for the development and investigation of strategies designed to enhance the neovascularization of engineered human tissues and organs.

Absorbable Implants↗
PubMed2000

Interferon-dependent activation of the serine kinase PI 3'-kinase requires engagement of the IRS pathway but not the Stat pathway.

Several signaling pathways are activated by interferon alpha (IFNalpha) in hematopoietic cells, including the Jak-Stat and the insulin receptor substrate (IRS) pathways. It has been previously shown that IFNalpha activates the phosphatidylinositol (PI) 3'-kinase via an interaction of the p85 subunit of PI 3'-kinase with IRS proteins. Other studies have proposed that Stat-3 also functions as an adapter for p85. We sought to identify the major pathway that regulates IFNalpha activation of the PI3'-kinase in hematopoietic cells. Our data demonstrate that IFNalpha induces the interaction of p85 with IRS-1 or IRS-2, but not Stat-3, in various hematopoietic cell lines in which IRS-1 and/or IRS-2 and Stat-3 are activated by IFNalpha. In addition, inhibition of PI 3'-kinase activity by preincubation of cells with the PI 3'-kinase inhibitor LY294002 does not affect IFN-dependent formation of SIF complexes that contain Stat-3. To determine whether phosphorylation of tyrosine residues in the IFN receptor is required for activation of the PI 3'-kinase, we performed studies using mouse L929 fibroblasts transfected with mutated human IFNAR1 and/or IFNAR2 subunits of the Type I IFN receptor, lacking tyrosine phosphorylation sites. The serine kinase activity of the PI-3K was activated by human IFNalpha in these cells, suggesting that phosphorylation of the Type I IFN receptor is not essential for PI3K activation. We then determined whether IFNalpha activates the Akt kinase, a known downstream target for PI 3'-kinase that mediates anti-apoptotic signals. Akt was activated by insulin or IGF-1, but not IFNalpha, in the IFNalpha-sensitive U-266 myeloma cell line. Altogether, our data establish that the IRS pathway and not the Stat pathway, is the major pathway regulating engagement of PI 3'-kinase in hematopoietic cells. Furthermore, the selective activation of Akt by insulin/IGF-1 suggests the existence of distinct regulatory activities of PI3'-kinase in growth factor versus interferon signaling.

Cells, Cultured↗
PubMed2000

The efficacy and safety of cefaclor in respiratory infections amongst Pakistani children.

PURPOSE: To evaluate the efficacy and safety of Cefaclor in respiratory tract infections amongst Pakistani children. PATIENTS AND METHODS: Multicenter, open label and non-comparative study was done to evaluate the response in terms of symptoms (In vivo) and bacterial cultures (In Vitro) to Cefaclor amongst children with respiratory tract infection between the ages 2 months to 12 years. Each patient was asked to visit the doctor on three occasions i.e., Day 0 (Initial evaluation prior to commencement of study), Day 4 (During therapy assessment and confirmation of compliance) and Day 10 (End of therapy assessment and compliance evaluation). Representative swab specimens (Throat swabs, Ear swabs or Sputum) were collected from the infected site on day 0 and day 10 for culture and sensitivity. Patients were also assessed by the evaluators on each visit in terms of clinical symptomatic response and information collected was documented on a prescribed data base form. RESULTS: A total of 160 patients were enrolled in the study, of whom 15 were lost to follow-up between the first and second visit and a further 38 were lost by the 3rd visit. Thus 107 patients completed the study as per protocol. Otitis media and Upper respiratory tract infection were the predominant ailments amongst the cases enrolled. One or more bacteria were isolated in 75 (46%) instances, the maximum number of isolates being from ear swabs of Otitis media patients. Beta haemolytic Streptococcus (group A,C,F,G) seen in 18 cases was the most common pathogen reported followed by Staphylococcus aureus, H. influenzae and Streptococcus pneumoniae in 13,12 and 11 cases respectively. Sensitivity of Cefaclor for bacteria commonly seen in the respiratory tract was greater than 90% in most of the cases. Evaluation of the 42 culture proven cases for patients who completed the study showed that Cefaclor had a 93% efficacy for indicated bacteria and 54% for non-indicated bacteria. In Vivo analysis of Cefaclor (i.e. on the basis of symptomatic response) showed that 96% cases had a symptomatic response by the second visit, which improved to 97% by the third visit. Only 15 non-serious adverse events were observed in 160 patients, none of the cases necessitated discontinuation of drug. Mild gastrointestinal symptom was the most common adverse event reported. CONCLUSION: Cefaclor was found to be a safe and efficacious drug in the treatment of bacterial respiratory tract infections amongst Pakistani children.

Bacterial Infections↗
PubMed2000

A case of haemophagocytic syndrome and Kikuchi-Fujimoto disease occurring concurrently in a 17-year-old female.

An unusual case in which a young Asian female presenting with fever, lymphadenopathy and cytopaenia was found to have distinct histological features of both haemophagocytic syndrome (HS) and histiocytic necrotising lymphadenitis (Kikuchi-Fujimoto disease, KFD) is presented. We review the clinical features of each of these rare, but important, diagnoses and propose the hypothesis that they may form part of a disease continuum, rather than representing separate entities.

Adolescent↗
PubMed1999

Dystrophin expression in the mdx mouse restored by stem cell transplantation.

The development of cell or gene therapies for diseases involving cells that are widely distributed throughout the body has been severely hampered by the inability to achieve the disseminated delivery of cells or genes to the affected tissues or organ. Here we report the results of bone marrow transplantation studies in the mdx mouse, an animal model of Duchenne's muscular dystrophy, which indicate that the intravenous injection of either normal haematopoietic stem cells or a novel population of muscle-derived stem cells into irradiated animals results in the reconstitution of the haematopoietic compartment of the transplanted recipients, the incorporation of donor-derived nuclei into muscle, and the partial restoration of dystrophin expression in the affected muscle. These results suggest that the transplantation of different stem cell populations, using the procedures of bone marrow transplantation, might provide an unanticipated avenue for treating muscular dystrophy as well as other diseases where the systemic delivery of therapeutic cells to sites throughout the body is critical. Our studies also suggest that the inherent developmental potential of stem cells isolated from diverse tissues or organs may be more similar than previously anticipated.

Animals↗
PubMed1999

Manganese in gasoline. Council on Scientific Affairs, American Medical Association.

This report responds to a resolution that asked the American Medical Association (AMA) to take action to reduce potential health risks from the use of methylcyclopentadienyl manganese tricarbonyl (MMT) in gasoline. Information for this report was derived from a search of the MEDLINE database and references listed in pertinent articles, as well as through communications with medical and public health experts. Based on this information, the AMA Council on Scientific Affairs determined that there is insufficient scientific evidence to assess the public health impact of MMT use. While limited evidence indicates that general-population exposures to manganese from the use of MMT in gasoline are low, more research is needed to determine possible health effects from long-term, low-dose exposures to MMT and its combustion products. Until such data are available, educational and informational strategies should be developed to improve public awareness of the health and environmental issues surrounding MMT use.

Air Pollutants↗
PubMed1997

A wooden foreign body in the neck.

Foreign bodies in the throat and/or neck are uncommon and transpharyngeal impaction of a wooden foreign body in the neck without vascular injury is very rare. The patient presented in this communication, reported to our center five days after severe physical assault with a pharyngocutaneous fistula in the left side of the neck. Clinical examination and X-rays were unremarkable. Conservative treatment led to healing of the fistula and he was discharged. Two weeks later he was readmitted with an abscess in the right supraclavicular region. Exploration under general anaesthesia revealed a 7 cm long wooden fragment of a spear in the abscess cavity. The fragment was removed. After several days' antibiotic treatment, he recovered fully and was discharged.

Abscess↗
PubMed1997

Cut throat injury: a retrospective study of 26 cases.

Cut throat injuries and associated deaths are common in our society. Majority succumb to their injuries. In this study, the hospital records of twenty six such cases (13 M & 13 F) were reviewed. Eleven victims were in their third decade. Eighteen cases came from poor socio-economic class. Eleven had suicidal, eleven homicidal and four accidental injuries. Familial troubles, psychiatric illness and poverty were the triggering factors in suicidal attempts. The motives of homicide included political conflict, sex related crimes, dacoity, familial, land related disputes, etc. All had their hypopharynx and/or larynx exposed. Tracheostomy was done in fifteen cases. All but two had uneventful recovery. One died in the hospital due to hemorrhage, shock and asphyxia from aspirated blood. It was observed that appropriate measures could save lives in vast majority.

Accidents↗
PubMed1991

Inpatient sociodemographic and diagnostic study from a psychiatric hospital in Libya.

Sociodemographic and diagnostic characteristics of 1009 patients admitted to the Psychiatry Hospital, Benghazi (Libya) in one calendar year are reported. Five hundred and four (50%) were 'first admission' cases. There were an average of 2.05 admissions for each 'readmission' case. Eighty nine percent of patients were of Libyan origin, of whom 62% were males; 66% were between 15-34 years of age, 37% were married, 28% were unemployed and 16% were in military service. ICD-9 schizophrenic psychosis was the commonest diagnosis (39%), followed by affective psychosis (17%), neurotic disorders (12%), organic psychosis (8%) and acute psychosis (7%). Neurotic depression was the commonest type of neurotic disorder and antisocial personality was the commonest among personality disorders. Relationship of sociodemographic variables with major diagnostic categories was studied in Libyan patients. Sociodemographic profiles of 'first admission' and 'readmission' cases of Libyan origin were also compared. These findings are discussed in relation to the sociocultural context.

Adolescent↗
PubMed1988

HLA-DR4 genotype frequency and gender effect in familial rheumatoid arthritis.

We have studied HLA-A, B, C, and DR antigens in 75 unrelated white families, each with multiple cases of adult-onset definite or classical rheumatoid arthritis (RA) (by ARA criteria). There was no difference in age of onset or serological features of RA between males and females. HLA-DR4 phenotype frequency among female (68%) and male (71%) patients also did not differ significantly. The observed frequencies of HLA-DR4 genotypes (homozygous, heterozygous, and those lacking it) differed significantly (p less than 0.005) between affected and unaffected individuals. However, the observed genotype distribution did not differ from what is expected given the Hardy-Weinburg equilibrium. There is a direct correlation between the number of DR4 allele(s) carried (two, one, or zero) and the percent affected (p less than 0.026 for females and p less than 0.052 for males). These findings highlight the importance of discerning the additional genetic determinants, including those that are gender-associated, which influence susceptibility to RA.

Arthritis, Rheumatoid↗
PubMed1986

Analysis of genetic susceptibility to familial rheumatoid arthritis.

We have studied HLA-A, B, C, and DR antigens in 37 unrelated Caucasian families with multiple cases of definite or classic rheumatoid arthritis (RA). HLA-DR4 was observed in 26 of 36 probands tested (73 per cent); and six of the 10 DR4 negative probands possessed DR1. HLA haplotype sharing among affected siblings was more often observed than would be expected if RA and HLA haplotype were segregating independently (p = 0.041). In families with a DR4-heterozygous parent, the affected parent's HLA haplotype co-segregates significantly with RA among the offspring (p less than 0.005); and in families where both parents are unaffected, occurrence of RA among the offspring co-segregates significantly with DR4 haplotype (p = 0.004). Our data strongly indicate that at least one genetic determinant for susceptibility to RA resides in the HLA region, closely linked to the DR locus, or that the susceptibility determinant may be an epitope or structure that is commonly found on DR4 molecules but occasionally on other DR molecules.

Adult↗
PubMed1986

HLA studies in familial and sporadic rheumatoid arthritis.

Fifty-eight unrelated patients with familial (36) and non-familial (22) rheumatoid arthritis (RA) have been studied for HLA-A, B, C, and DR antigens. Among the 36 probands of families with multiple cases of RA (Group I) 73 per cent are DR4 positive, and 60 per cent of the DR4 negative probands possess DR1. The corresponding frequencies among the 22 patients with non-familial (sporadic) RA (Group II) are 59 per cent and 56 per cent, respectively, DR4 and/or DR1 are present in 89 per cent of patients in Group I and 82 per cent in Group II. Homozygosity for DR4 has been definitely established by family studies in six of the 26 DR4 positive patients (23 per cent) in Group I, and a further two patients are possible homozygous. Family studies have not been performed in sporadic RA patients but two of 13 DR4 positive patients in this group are possibly homozygous for DR4. HLA haplotypes A1, Cw7, B8, DR4; and A2, Cw3, B15, DR4 are shared by two or more unrelated probands of multicase families.

Arthritis, Rheumatoid↗
PubMed1985

Selection of optimal dose.

Dose and dilution levels for quantal response bioassays and dilution assays are selected rather arbitrary. Some guidelines for designing experiments for binary data arising in such fields as bioassay studies, dilution series assays, and dose-response curves are provided. It is shown that for estimation purposes, the study should be designed in such a way so that the experimental doses lie around a critical interval. Failure to do so many produce serious bias in the Maximum Likelihood estimates. This critical interval, however, depends on the unknown parameters. With the help of extensive computer simulations for the logit model ways of overcoming this difficulty are outlined.

Biological Assay↗