The effect of small molecule inhibitor NSC348884 on nucleophosmin 1-mutated acute myeloid leukemia cells.

OBJECTIVE: Nucleophosmin 1 (NPM1) is a common shuttling protein. Mutation in the NPM1 gene is the most frequent gene alteration in acute myeloid leukemia (AML). This study aims to explore the inhibitory effects of small molecule NSC348884 on wild-type and NPM1-mutated AML cells. MATERIALS AND METHODS: Immunofluorescence was used to determine the intracellular localization of NPM1 protein in wild-type (OCI-AML2) and NPM1-mutated (OCI-AML3) AML cell lines. The oligomerization state of NPM1 was assessed by Western blot analysis, and the inhibitory effect of NSC348884 on the proliferation of AML cells was evaluated by Cell-counting kit-8 (CCK-8). Flow cytometry was used to detect the proapoptotic effect of NSC348884 on AML cells. RESULTS: Western blot results showed a significant reduction in the levels of the oligomeric NPM1 protein after the treatment with NSC348884. NSC348884 had an inhibitory effect on the proliferation of both wild-type and NPM1-mutant AML cells. The inhibitory effect on OCI-AML3 cells was stronger, compared to OCI-AML2 cells. Flow cytometry showed that NSC348884 could significantly induce AML cell apoptosis and had a stronger proapoptotic effect on OCI-AML3 cells. CONCLUSIONS: NSC348884 had inhibitory and proapoptotic effects on both wild-type and NPM1-mutated AML cells. The effect of NSC348884 on AML cells, carrying NPM1 mutation was significantly stronger.

[Clinical characteristics of 272 437 patients with different histopathological subtypes of primary esophageal malignant tumors].

Objective: To characterize the histopathological subtypes and their clinicopathological parameters of gender and onset age by common, rare and sparse primary esophageal malignant tumors (PEMT). Methods: A total of 272 437 patients with PEMT were enrolled in this study, and all of the patients were received radical surgery. The clinicopathological information of the patients was obtained from the database established by the State Key Laboratory of Esophageal Cancer Prevention & Treatment from September 1973 to December 2020, which included the clinical treatment, pathological diagnosis and follow-up information of esophagus and gastric cardia cancers. All patients were diagnosed and classified by the criteria of esophageal tumor histopathological diagnosis and classification (2019) of the World Health Organization (WHO). The esophageal tumors, which were not included in the WHO classification, were analyzed separately according to the postoperative pathological diagnosis. The χ2 test was performed by the SPSS 25.0 software on count data, and the test standard α=0.05. Results: A total of 32 histopathological types were identified in the enrolled PEMT patients, of which 10 subtypes were not included in the WHO classification. According to the frequency, PEMT were divided into common (esophageal squamous cell carcinoma, ESCC, accounting for 97.1%), rare (esophageal adenocarcinoma, EAC, accounting for 2.3%) and sparse (mainly esophageal small cell carcinoma, malignant melanoma, etc., accounting for 0.6%). All the common, rare, and sparse types occurred predominantly in male patients, and the gender difference of rare type was most significant (EAC, male∶ female, 2.67∶1), followed with common type (ESCC, male∶ female, 1.78∶1) and sparse type (male∶ female, 1.71∶1). The common type (ESCC) mainly occurred in the middle thoracic segment (65.2%), while the rare type (EAC) mainly occurred in the lower thoracic segment (56.8%). Among the sparse type, malignant melanoma and malignant fibrous histiocytoma were both predominantly located in the lower thoracic segment (51.7%, 66.7%), and the others were mainly in the middle thoracic segment. Conclusion: ESCC is the most common type among the 32 histopathological types of PEMT, followed by EAC as the rare type, and esophageal small cell carcinoma and malignant melanoma as the major sparse type, and all of which are mainly occur in male patients. The common type of ESCC mainly occur in the middle thoracic segment, while the rare type of EAC mainly in the lower thoracic segment. The mainly sparse type of malignant melanoma and malignant fibrous histiocytoma predominately occur in the lower thoracic segment, and the remaining sparse types mainly occur in the middle thoracic segment.

Global genetic diversity of Spirometra tapeworms.

Spirometra larvae are etiological agents of human sparganosis. However, the systematics of spirometrid cestodes has long been controversial. In order to determine the current knowledge on the evolution and genetic structure of Spirometra, an exhaustive population diversity analysis of spirometrid cestodes using the mitochondrial gene: cytochrome c oxidase subunit 1 (cox1) was performed. All publicly available cox1 sequences available in the GenBank and 127 new sequencing genes from China were used as the dataset. The haplotype identify, network, genetic differentiation and phylogenetic analysis were conducted successively. A total of 488 sequences from 20 host species, representing four spirometrid tapeworms (S. decipiens, S. ranarum, S. erinaceieuropaei and Sparganum proliferum) and several unclassified American and African isolates from 113 geographical locations in 17 countries, identified 45 haplotypes. The genetic analysis revealed that there are four clades of spirometrid cestodes: Clade 1 (Brazil + USA) and Clade 2 (Argentina + Venezuela) included isolates from America, Clade 3 contained African isolates and one Korean sample, and the remainders from Asia and Australia belonged to Clade 4; unclassified Spirometra from America and Africa should be considered the separate species within the genus; and the taxonomy of two Korea isolates (S. erinaceieuropaei KJ599680 and S. decipiens KJ599679) was still ambiguous and needs to be further identified. In addition, the demographical analyses supported population expansion for the total spirometrid population. In summary, four lineages were found in the spirometrid tapeworm, and further investigation with deeper sampling is needed to elucidate the population structure.

Global genetic diversity of Spirometra tapeworms

@#Spirometra larvae are etiological agents of human sparganosis. However, the systematics of spirometrid cestodes has long been controversial. In order to determine the current knowledge on the evolution and genetic structure of Spirometra, an exhaustive population diversity analysis of spirometrid cestodes using the mitochondrial gene: cytochrome c oxidase subunit 1 (cox1) was performed. All publicly available cox1 sequences available in the GenBank and 127 new sequencing genes from China were used as the dataset. The haplotype identify, network, genetic differentiation and phylogenetic analysis were conducted successively. A total of 488 sequences from 20 host species, representing four spirometrid tapeworms (S. decipiens, S. ranarum, S. erinaceieuropaei and Sparganum proliferum) and several unclassified American and African isolates from 113 geographical locations in 17 countries, identified 45 haplotypes. The genetic analysis revealed that there are four clades of spirometrid cestodes: Clade 1 (Brazil + USA) and Clade 2 (Argentina + Venezuela) included isolates from America, Clade 3 contained African isolates and one Korean sample, and the remainders from Asia and Australia belonged to Clade 4; unclassified Spirometra from America and Africa should be considered the separate species within the genus; and the taxonomy of two Korea isolates (S. erinaceieuropaei KJ599680 and S. decipiens KJ599679) was still ambiguous and needs to be further identified. In addition, the demographical analyses supported population expansion for the total spirometrid population. In summary, four lineages were found in the spirometrid tapeworm, and further investigation with deeper sampling is needed to elucidate the population structure.

MiR-223-3p promotes the growth and invasion of neuroblastoma cell via targeting FOXO1.

OBJECTIVE: MicroRNAs (miRNAs) have been demonstrated to have crucial roles in cancer development. We investigated the involvement of miR-223-3p in neuroblastoma (NB). MATERIALS AND METHODS: MiR-223-3p expression in NB cell lines and normal cell line was analyzed with real-time quantitative PCR method. Cell proliferation, cell invasion, and cell apoptosis were assessed by cell counting kit-8 (CCK-8), transwell invasion assay, and flow cytometry assay, respectively. Bioinformatics analysis, Dual-Luciferase reporter assays, and Western blot analysis were conducted to identify the connection of miR-223-3p and forkhead box O1 (FOXO1). RESULTS: MiR-223-3p level was found highly expressed in NB cell lines compared with normal cell line. Knockdown miR-223-3p expression decreased cell growth and invasion but increased cell apoptosis. MiR-223-3p was able to bind with the 3'-untranslated region of FOXO1, and thereby resulting in a reduction of FOXO1 expression. The knockdown of FOXO1 increased the malignant capacity of NB cells. CONCLUSIONS: Therefore, given the fact that miR-223-3p suppressed FOXO1 expression to promote NB progression, targeting miR-223-3p may be an effective method for NB treatment.

[Association of fibroblast growth factor 23 with age-related cardiac diastolic function subclinical state in a healthy Chinese population].

Objective: To determine the association of serum fibroblast growth factor-23 concentrations with age-related cardiac diastolic function subclinical state and whether this association differs by sex. Methods: Seven hundred sixteen healthy subjects (aged 35-89 years, 68.4% female) were selected from National Basic Research Program of China (973 Program-China Medical University subsection) between January 2014 and February 2015 and assigned into 4 groups according to sex and age:< 60 years old male and female group, ≥ 60 years old male and female group. Blood biochemical indicators and general clinical data of the subjects were measured. The glomerular filtration rate (eGFR) were estimated using the Modified Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI-ASIA) equation. The fibroblast factor 23 (FGF-23), C-reactive protein (CRP) and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Cardiac structure and function parameters including left atrial diameter (LAD), inter-ventricular septum thickness (IVST), left ventricle posterior wall thickness (LVPWT), left ventricle mass index (LVMI),left atrial mass index (LAVI) and the ratio of peak velocity of early filling to the septal early peak diastolic mitral annulus velocity(E/e') were measured by echocardiography. Association between serum FGF-23 and aging-related diastolic function subclinical status was analyzed by binary Logistic regression analysis. Results: (1) Serum log-transformed FGF-23 levels were significantly higher in males than in females [(2.0±0.3) ng/L vs (1.9±0.4) ng/L, P<0.05]. (2) Cardiac diastolic function gradually decreased with age, and age related cardiac diastolic function decline of female was significantly higher than males[E/e':<60 years old male group (7.6±2.6), ≥ 60 years old male group (8.6±2.7), P<0.01;<60 years old female group (8.3±2.3), ≥ 60 years old female group (9.5±3.1), P<0.01; LAVI:<60 years old female group (14±5) ml/m(2), ≥ 60 years old female group (16±5) ml/m(2), P<0.01]. (3) Serum FGF-23 was significantly positively correlated with age (r=0.089, P<0.05) and LAVI (r=0.084, P<0.05) in total study population while with E/e' (r=0.149, P<0.05) only in males. There was no significant correlation between serum FGF-23 and cardiac diastolic function parameters in females. (4) Binary Logistic regression analysis showed that median and high FGF-23 were independently associated with age-related cardiac diastolic function decline (OR=2.831, 95% CI: 1.144-7.009, P=0.024; OR=2.548, 95% CI: 1.053-6.163, P=0.038) in males. Conclusions: Serum FGF-23 concentrations are associated with age-related cardiac diastolic function subclinical state in a healthy Chinese population. High levels of FGF-23 are independently associated with age-related cardiac diastolic function decline in males.

[Prevalence of high-risk HPV and its distribution in cervical precancerous lesions among 35-64 years old women who received cervical cancer screening in Beijing].

Objective: To study the prevalence of high-risk HPV (HR HPV) in women who accepted cervical cancer screening in Beijing and its distribution in cervical precancerous lesions. Methods: From January 2014 to March 2015, all women aged 35-64 years old and received free screening in institutions of cervical cancer in Beijing were recruited. Stratified cluster random sampling method was used in selecting 31 091 women for gynecological examination and genotyping of HR-HPV. Those positive for HR-HPV (except for HPV 16/18) were examined for cervical cell. For those atypical squamous cells of uncertain significance (ASCUS) and above, who were positive for HPV 16/18 and with uncertain results for cervical cell, were transferred for colposcopy examination. For those with suspicious or abnormal results for colposcopy, were transferred for histopathology. The prevalence of HR-HPV, cervical cancer and precancerous lesions among the participants were analyzed. Results: Totally 31 091 women aged from 35-year-old to 64-year-old, with 44.3% (13 780 women) in the 35-49 age group and 55.7% (17 311 women) in the 50-64 age group. 66.1% (20 536 women) were rural women. The infection rate of HR-HPV was 7.4%(2 305 cases) among the women. High-risk infection rates of HPV except HPV 16/18 were 5.7% (1 758 cases), and multi-infection rate was 1.5% (477 cases). The highest infection rate was 7.9% (1 044 cases) among the 45-49 year-old and 50-54 year-old age groups (χ(2)=14.07, P=0.015). The rate in rural women was significantly higher than that of the urban women (6.2%, 507 cases; 7.9%, 1 798 cases) (χ(2)=25.75, P<0.001). The proportion of HPV16, HPV18, HPV52, HPV51, HPV58 was 17.0% (391 cases), 6.9% (161 cases), 8.6% (20 cases), 5.2% (12 cases) and 7.7% (18 cases), respectively. The detection rate of cervical cancer and precancerous lesions in the population was 395.6/100 000 (123 cases). In high-grade squamous intraepithelial lesions (HSIL), HPV16 and 18 infections accounted for 60.5% (72 cases) of all. HPV16 infection rate and detection rate of HSIL were the highest in 50-54 year-old group which were 1.5% (107 cases) and 25.2% (30 cases) (χ(2)=11.54, P=0.042). Conclusion: Top five types of HR-HPV infection in women who accepted cervical cancer screening in Beijing were HPV16, 18, 52, 51 and 58. The infection rate of HPV16 and 18 increased significantly in HSIL women. HPV16 infection rate and detection rate of HSIL were the highest in 50-54 year-old age group.

[Effect of nutrition quality of breakfast on satiety among young white-collar workers].

Objective: To analyze the effect of breakfast nutrition quality on the satiety among young white-collar workers. Methods: A total of 278 subjects were recruited from two cities, Shenyang and Chongqing, in June 2015. The inclusion criteria: white-collar workers aged 25-45 years involved mainly in office work, who did not experience major changes, and individuals who should follow the study protocol and sign the informed consent form. The study employed a three-phase crossover design trial. Each participant received nutritional-adequate breakfast, nutritional-inadequate breakfast, and no breakfast treatment on the basis of assignment to one of three sequences. The breakfast time was once a week and then changed, all participants underwent the tests for three successive weeks. At last, we compared the effect of participants to consume different nutritional quality on satiety sense and hunger sense. Results: A total of 232 participants completed three successive breakfast intervention studies, the age of participants was (35.2 ± 7.9) years, comprised of 48.7% male (n=113). The numbers of participants of aged 25-35 year-old and aged 36-45 were 118 and 114, respectively. Satiety scores of nutrition-adequate breakfast group, nutrition-inadequate breakfast group and no breakfast group were 63.5±14.7, 53.1±10.2 and 36.4±7.2, respectively (P<0.05). In nutrition-inadequate breakfast group and no breakfast group, male subjects scored significantly higher than female subjects (50.9±10.5 vs 46.6±9.4, 35.2±8.3 vs 31.8±5.4) (P<0.05). And, participants aged 25-35 year-old. got satiety score significantly higher than aged 36-45 (51.3±11.0 vs 45.6±12.1, 34.1±6.8 vs 32.5±7.9), the difference was statistically significant (P<0.05). The scores of hunger in the group of nutrition-adequate breakfast, nutrition-inadequate breakfast and no breakfast were 26.3 ± 8.0, 35.1 ± 11.2 and 57.3 ± 17.0, respectively (P<0.05). Conclusion: The nutrition quality of breakfast affects the satiety of young white-collar workers. The better the nutrition quality of breakfast is, the higher the satiety score and the lower the hunger score become. Compared with women and participants aged 36-45 year-old, men and those aged 25-35 year-old get satiety sense more easily.

[The impact of goal directed analgesia on mechanical ventilated patients's outcomes in intensive care unit: a clinical observational study].

To investigate the impact of goal directed analgesia on the outcome of patients with mechanical ventilation in intensive care unit.A total of 126 patients who needed mechanical ventilation were recruited.With a method of before and after paired comparison, they were divided into two group: (1) analgesia with empirical administration or control group; (2) goal directed analgesia based on critical-care pain observation tool (CPOT). Compared with the control group, after goal directed analgesia was applied, the consumption of midazolam significantly dropped from (368.47±27.41) mg to (151.27±29.31) mg(P<0.05), whereas the consumption of dexmedetomidine significantly increased from (623.62±20.91) µg to (812.34±22.57) µg(P<0.05). The median score of Richmond agitation-sedation scale increased from -3 to -1.The incidence of delirium significantly reduced from 23.81% to 17.46%(P<0.05). The mean ventilator duration was significantly shortened from (168.49±11.41) h to (142.38±13.24) h(P<0.05). ICU length of stay was significantly shortened from (23.64±9.26) d to (19.63±8.46) d(P<0.05). Due to the mild sedation, patients receiving goal directed analgesia report less delirium, less ventilation time and shorter ICU length of stay, suggesting that the general outcome is improved.

Sofosbuvir plus ribavirin for the treatment of patients with chronic genotype 1 or 6 hepatitis C virus infection in Hong Kong.

BACKGROUND: In Hong Kong, most patients with hepatitis C virus (HCV) have either genotype 6a or 1b infection. AIM: To evaluate the efficacy and safety of sofosbuvir with ribavirin in treatment-naïve patients in Hong Kong with HCV genotype 1 or 6. METHODS: In an open-label study, patients were randomised to sofosbuvir 400 mg once daily plus ribavirin 1000-1200 divided twice daily for 12 (n = 10), 16 (n = 11) or 24 (n = 10) weeks. The primary endpoint was the percentage of patients with HCV RNA < LLOQ (lower limit of quantification, 25 IU/mL) 12 weeks after cessation of therapy (SVR12). RESULTS: All 31 patients (20 HCV genotype 1 and 11 genotype 6) had HCV RNA < LLOQ by Week 4 of treatment and at their last on-treatment visit. SVR12 rates were high in all treatment groups: 100% (10/10) for 12 weeks, 100% (11/11) for 16 weeks and 90% (9/10) for 24 weeks of therapy. The only patient who did not reach SVR12 had genotype 1 HCV and relapsed at post-treatment Week 4. Sofosbuvir with ribavirin was generally well tolerated. The most common adverse events were malaise (13%) and upper respiratory tract infection (13%), followed by anaemia (10%). No patients experienced serious adverse events. One patient discontinued treatment at Week 16 because of an adverse event. The event, upper respiratory tract infection, was not considered treatment related by the investigator. This subject achieved SVR12. CONCLUSIONS: The all-oral regimen sofosbuvir plus ribavirin is effective in treatment-naïve patients in Hong Kong with genotype 1 or 6 HCV. TRIAL REGISTRATION NUMBER: NCT02021643.

Validation of a rapid method for detection of M. tuberculosis resistance to isoniazid and rifampin in Lima, Peru.

SETTING: Treatment of multidrug-resistant tuberculosis (MDR-TB) is often based on drug susceptibility testing (DST) results; for this reason, rapid, simple DST methods are sought which could be applied in resource-poor countries. One such method is a nitrate reductase colorimetric assay known as the Griess method. In Peru, where the incidence rate of TB is among the highest in South America, the National Institute of Health recently undertook the validation and implementation of the direct Griess method. OBJECTIVE: To describe the process of validation and implemention of the direct Griess method at the Peruvian National Institute of Health. DESIGN: Prospective study comparing the sensitivity and specificity of the direct Griess method with the Löwenstein-Jensen proportion method in determining resistance to isoniazid (INH) and rifampin (RMP) among clinical isolates. RESULTS: Among 192 specimens, the sensitivity and specificity of the Griess method for detection of INH resistance was 99.1% and 100%, respectively. For identification of RMP resistance, the sensitivity and specificity was 93.5% and 100%, respectively. CONCLUSIONS: In addition to its high sensitivity and specificity and rapid turn around time, the Griess method uses simple, inexpensive reagents and requires minimal laboratory space and technical expertise, thus providing an ideal screening tool for resource-poor settings with high rates of MDR-TB.

Acquisition of drug resistance in multidrug-resistant Mycobacterium tuberculosis during directly observed empiric retreatment with standardized regimens.

The risk of acquiring additional drug resistance in strains of multidrug-resistant tuberculosis (MDR-TB) during failure of empiric standardized retreatment regimens is poorly defined. We sought to estimate this risk by comparing drug susceptibility profiles and RFLP patterns of paired MDR-TB isolates collected from 27 patients before and after retreatment failure. Among 23 patients with paired isolates with concordant RFLP patterns, 19 (83%) had become resistant to at least one additional drug after failed retreatment. In this limited group of MDR-TB patients, acquisition of resistance was common during failure of empiric drug regimens. Further study is needed to confirm these findings.

Drug resistance profiles of Mycobacterium tuberculosis isolates: five years' experience and insight into treatment strategies for MDR-TB in Lima, Peru.

SETTING: Lima, Peru. OBJECTIVE: To describe drug resistance profiles of TB isolates from patients at risk for multidrug-resistant tuberculosis (MDR-TB), and to consider the implications of these findings for treatment. DESIGN: Descriptive study of drug susceptibility testing (DST) results for TB isolates from 1680 patients referred for suspicion of MDR-TB between 1996 and 2001. RESULTS: Of 1680 isolates tested, 1144 (68%) were resistant to at least one anti-tuberculosis drug and 926 (55%) were MDR-TB strains. Of 926 MDR isolates, 50 (5%) were resistant to INH and RMP alone, while 367 (40%) were resistant to at least five first-line drugs. We identified 146 unique drug resistance profiles, the most common of which accounted for 11% of drug-resistant isolates. The annual prevalence of isolates with resistance to at least five first-line drugs rose significantly during the study period, from 29% to 37% (P = 0.00086). CONCLUSIONS: This is a group of patients with TB disease among whom the prevalence of a broad spectrum of often highly drug-resistant strains appears to be increasing over time. A single standardized retreatment regimen may be inadequate to cure most patients. Capacity for drug sensitivity testing is essential for development of multiple standardized retreatment or individualized treatment regimens and epidemiological surveillance for planning.

New method for detection of Mycobacterium tuberculosis Direct Test inhibitors in clinical specimens.

Existing protocols for the detection of Mycobacterium tuberculosis Direct Test (MDT) inhibitors require substantial quantities of specimen and cannot distinguish Mycobacterium tuberculosis complex from other mycobacteria if inhibitors are present. We describe a preliminary evaluation of a simple and practical protocol for MTD inhibitor testing that circumvents these difficulties.

Practical strategies for performance optimization of the enhanced gen-probe amplified mycobacterium tuberculosis direct test.

The enhanced Gen-Probe Amplified Mycobacterium Tuberculosis Direct (MTD) test was evaluated using a combined set of 338 acid-fast smear-positive and smear-negative, respiratory and nonrespiratory clinical specimens received by the Massachusetts State Tuberculosis Laboratory from September 1999 through March 2002. Microbiological culture was used as the reference method; therefore, the sensitivity and specificity of the MTD test were calculated for culture-positive specimens only. The initial assessment indicated that the overall sensitivity, specificity, and positive and negative predictive values of the MTD test for all specimens grouped together were 62, 98, 99, and 68%, respectively. A detailed discrepancy analysis revealed that two major factors causing negative MTD results in specimens that were culture positive for M. tuberculosis complex were patient treatment with antituberculosis drugs prior to testing and the presence of inhibitory substances in the specimen. Based on these findings, a protocol for optimizing MTD test performance in this setting is proposed in which (i) specimens from patients taking antituberculosis medications are excluded from testing and (ii) all initially MTD-negative or MTD-equivocal specimens are subjected to testing for inhibitors. If this strategy was followed, the MTD test sensitivity would be at least 91%, a significant improvement over the initial sensitivity of 62%. Accordingly, the negative predictive value would increase from 68 to 91%.

Deaths of children during an outbreak of hand, foot, and mouth disease in sarawak, malaysia: clinical and pathological characteristics of the disease. For the Outbreak Study Group.

From April through June 1997, 29 previously healthy children aged <6 years (median, 1.5 years) in Sarawak, Malaysia, died of rapidly progressive cardiorespiratory failure during an outbreak of hand, foot, and mouth disease caused primarily by enterovirus 71 (EV71). The case children were hospitalized after a short illness (median duration, 2 days) that usually included fever (in 100% of case children), oral ulcers (66%), and extremity rashes (62%). The illness rapidly progressed to include seizures (28%), flaccid limb weakness (17%), or cardiopulmonary symptoms (of 24 children, 17 had chest radiographs showing pulmonary edema, and 24 had echocardiograms showing left ventricular dysfunction), resulting in cardiopulmonary arrest soon after hospitalization (median time, 9 h). Cardiac tissue from 10 patients showed normal myocardium, but central nervous system tissue from 5 patients showed inflammatory changes. Brain-stem specimens from 2 patients were available, and both specimens showed extensive neuronal degeneration, inflammation, and necrosis, suggesting that a central nervous system infection was responsible for the disease, with the cardiopulmonary dysfunction being neurogenic in origin. EV71 and possibly an adenovirus, other enteroviruses, or unknown cofactors are likely responsible for this rapidly fatal disease.

Unequal exchange at the Charcot-Marie-Tooth disease type 1A recombination hot-spot is not elevated above the genome average rate.

An increasing number of human diseases and syndromes are being found to result from micro-duplications or microdeletions arising from meiotic recombination between homologous repeats on the same chromosome. The first microduplication syndrome delineated, Charcot-Marie-Tooth disease type 1A (CMT1A), results from unequal crossing over between two >98% identical 24 kb repeats (CMT1A-REPs) on chromosome 17. In addition to its medical significance, the CMT1A region has features that make it a unique resource for detailed analysis of human unequal recombination. Previous studies of CMT1A patients showed that the majority of unequal crossovers occurred within a small region (<1 kb) of the REPs suggesting the presence of a recombination hot-spot. We directly measured the frequency of unequal recombination in the hot-spot region using sperm from four normal individuals. Surprisingly, unequal recombination between the REPs occurs at a rate no greater than the average rate for the male genome (approximately 1 cM/Mb) and is the same as that expected for equally aligned REPs. This conclusion extends to humans the findings in yeast that recombination between repeated sequences far apart on the same chromosome may occur at similar frequencies to allelic recombination. Finally, the CMT1A hot-spot stands in sharp contrast to the human MS32 mini-satellite-associated hot-spot that exhibits highly enhanced recombination initiation in addition to positional specificity. One possibility is that the CMT1A hot-spot may consist of a region with genome average recombination potential embedded within a recombination cold-spot.

Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden.

Respiratory syncytial virus (RSV) is an important cause of acute lower respiratory tract disease among the elderly, but national estimates of the burden of this disease have not been made. To estimate the morbidity, mortality, and medical costs of RSV-associated pneumonia among US elderly, national hospital discharge data, vital statistics, etiologic studies of adult pneumonia hospitalizations, and Medicare cost data were reviewed. In the United States, 687,000 hospitalizations and 74,000 deaths caused by pneumonia occur annually among the elderly; approximately 2%-9% of these are caused by RSV. At a cost of $11,000 per RSV pneumonia hospitalization, the estimated annual cost of RSV pneumonia hospitalizations is $150-$680 million. Exacerbations of congestive heart failure and other chronic conditions may also contribute substantially to RSV disease burden among the elderly. The total RSV disease burden is probably great enough to justify development of an RSV vaccine for use in this group.

Risk factors for West Nile virus infection and meningoencephalitis, Romania, 1996.

In 1996, an epidemic of 393 cases of laboratory-confirmed West Nile meningoencephalitis occurred in southeast Romania, with widespread subclinical human infection. Two case-control studies were performed to identify risk factors for acquiring infection and for developing clinical meningoencephalitis after infection. Mosquitoes in the home were associated with infection (reported by 37 [97%] of 38 asymptomatically seropositive persons compared with 36 [72%] of 50 seronegative controls, P<.01) and, among apartment dwellers, flooded basements were a risk factor (reported by 15 [63%] of 24 seropositive persons vs. 11 [30%] of 37 seronegative controls, P=.01). Meningoencephalitis was not associated with hypertension or other underlying medical conditions but was associated with spending more time outdoors (meningoencephalitis patients and asymptomatically seropositive persons spent 8.0 and 3.5 h [medians] outdoors daily, respectively, P<.01). Disease prevention efforts should focus on eliminating peridomestic mosquito breeding sites and reducing peridomestic mosquito exposure.

B lymphocytic lymphoma (large cell) of possible splenic marginal zone origin presenting with prominent splenomegaly and unusual cordal red pulp distribution.

Two cases of large cell lymphoma, B-cell type, primarily involving the red pulp of the spleen rather than the white pulp are described. A number of unusual features suggest that this may be a lymphoma originating from a distinct splenic B-cell lymphocyte whose origin may be the marginal zone of the spleen or the splenic cords. The patients presented with splenomegaly, cytopenias, and no peripheral lymphadenopathy. The gross appearance of the spleens was beefy red without tumor nodules. The tumor cells were primarily in the splenic cords and surrounding residual normal white pulp. There was a minimal hemic phase. The tumor cells had abundant cytoplasm, surface IgM, IgD, kappa, and FC receptors, tartrate-resistant acid phosphatase, but no alkaline phosphatase or interleukin-2 receptors. They had a similar DNA aneuploidy. The most unusual feature was that tumor cells in both cases had phagocytic properties. These lymphomas may be clinically more indolent than their follicular center counterparts.