Antibiotics and the Wasting Disease in Neonatally Thymectomized Rats

The administration of the antibiotic, Chloramphenicol, to pregnant rats just prior to, and for four days after delivery, diminishes the incidence of the so-called Wasting Disease in neonatally thymectomized rats. A total of 50 rats were divided into the following groups: Thymectomy only---nonmedicated 17 rats Thymectomy only---medicated 12 rats Thymectomy-adrenalectomy---nonmedicated 5 rats Thymectomy-adrenalectomy---medicated 8 rats Controls---nonmedicated 4 rats Controls---medicated 4 rats Chloramphenicol was administered in the drinking water to the mothers of groups 2, 4 and 6 for about 2 days prior to delivery and 4 days after. On the day of birth or within three days after birth, the male progeny were thymectomized. Approximately 2 weeks after thymectomy adrenalectomies were carried out on some of the progeny (groups 3 and 4). Growth rate and weight records were kept of all groups. At the 12th week white blood cell counts were made on all groups expect 1 and 3. At the end of the 24th week, all survivors were autopsied for presence of thymus and adrenal tissue and those with evidence of such were excluded. Routine tissue sections were made of various organs of all groups and search made for any evidence of hormonal deprivation or infection. The medicated control animals exhibited a higher growth rate than all other groups. The medicated thymectomized rats showed an average weight just slightly under that of the nonmedicated controls. The thymectomized-adrenalectomized animals appeared to show the same average weight at the end of the experiment but the medicated group had a faster growth rate and weight gain during the early weeks of the experiment. The medicated animals of groups 2 and 4 showed a 20 percent wasting incidence while wasting occurred in 40 percent of group 1 and 50 percent in group 3. The lowest white blood counts were 8,800 for the medicated thymectomized animals and 9,200 for the thymectomized-adrenalectomized animals, probably due to the lymphopenia reported by others. The white blood count of the nonmedicated control group was 12,000. The administration of antibiotic to a pregnant rat just prior to and for few days after birth of the young appears to lessen the incidence of the wasting disease in its progeny thymectomized within three days after birth leading to the conclusion that the wasting disease is primarily a pre-occupation of the immunologic system during the early weeks of life with infections acquired in the immediate post-operative period, These results corroborate the conclusions of Azar (1964) relative to the efficacy of antibiotic administration in preventing the wasting disease, and also are in accord with the findings of Miller (1964) that germ free thymectomized mice do not evidence the wasting syndrome

The role of drug resistance in poor viral suppression in rural South Africa: findings from a population-based study.

BACKGROUND:Understanding factors driving virological failure, including the contribution of HIV drug resistance mutations (DRM), is critical to ensuring HIV treatment remains effective. We examine the contribution of drug resistance mutations for low viral suppression in HIV-positive participants in a population-based sero-prevalence survey in rural South Africa. METHODS:We conducted HIV drug resistance genotyping and ART analyte testing on dried blood spots (DBS) from HIV-positive adults participating in a 2014 survey in North West Province. Among those with virologic failure (> 5000 copies/mL), we describe frequency of DRM to protease inhibitors (PI), nucleoside reverse transcriptase inhibitors (NRTI), and non-nucleoside reverse transcriptase inhibitors (NNRTI), report association of resistance with antiretroviral therapy (ART) status, and assess resistance to first and second line therapy. Analyses are weighted to account for sampling design. RESULTS:Overall 170 DBS samples were assayed for viral load and ART analytes; 78.4% of men and 50.0% of women had evidence of virologic failure and were assessed for drug resistance, with successful sequencing of 76/107 samples. We found ≥1 DRM in 22% of participants; 47% were from samples with detectable analyte (efavirenz, nevirapine or lopinavir). Of those with DRM and detectable analyte, 60% showed high-level resistance and reduced predicted virologic response to ≥1 NRTI/NNRTI typically used in first and second-line regimens. CONCLUSIONS:DRM and predicted reduced susceptibility to first and second-line regimens were common among adults with ART exposure in a rural South African population-based sample. Results underscore the importance of ongoing virologic monitoring, regimen optimization and adherence counseling to optimize durable virologic suppression

The application of the Johns Hopkins Hospital Template on urine cytology

Background To evaluate the utility of the Johns Hopkins Hospital (JHH) template in detection of high-grade urothelial carcinoma (HGUC). Methods A computerized search of our laboratory information system was performed for all urine cytology cases from 2009 to 2011 processed by the SurePath™. We included only cases with correlating surgical pathology within 6 months after the urinary samples were obtained. The original cytologic diagnoses were reclassified according to the JHH template, and these cytolog ic diagnoses were then correlated with the follow-up surgical pathology diagnoses. Results A total of 273 urine samples with histopathologic follow-up were identified. The reclassified cytologic diagnoses included negative for urothelial atypia or malignancy (NUAM) 110; atypical urothelial cells of undetermined significance (AUC-US) 83; atypical urothelial cells, cannot exclude high-grade urothelial carcinoma (AUC-H) 49; HGUC 29; and low-grade urothelial carcinoma (LGUC) 2. More than one-half of patients (58%) who had biopsy-confirmed high-grade urothelial lesions had a preceding cytologic diagnosis of AUC-H or HGUC. AUC-H and HGUC are associated with high-grade urothelial lesions in 80% and 90% of the cases and show statistical significance when compared with AUC-US or NUAM (P < 0.05). Conclusion The JHH template is useful and effective in identifying patients with high-grade urothelial lesions who need to undergo cystoscopy. Diagn. Cytopathol. 2015;43:593–597. © 2015 Wiley Periodicals, Inc

Improvements in the South African HIV care cascade: findings on 90-90-90 targets from successive population-representative surveys in North West Province.

IntroductionTo achieve epidemic control of HIV by 2030, countries aim to meet 90-90-90 targets to increase knowledge of HIV-positive status, initiation of antiretroviral therapy (ART) and viral suppression by 2020. We assessed the progress towards these targets from 2014 to 2016 in South Africa as expanded treatment policies were introduced using population-representative surveys.MethodsData were collected in January to March 2014 and August to November 2016 in Dr. Ruth Segomotsi Mompati District, North West Province. Each multi-stage cluster sample included 46 enumeration areas (EA), a target of 36 dwelling units (DU) per EA, and a single resident aged 18 to 49 per DU. Data collection included behavioural surveys, rapid HIV antibody testing and dried blood spot collection. We used weighted general linear regression to evaluate differences in the HIV care continuum over time.ResultsOverall, 1044 and 971 participants enrolled in 2014 and 2016 respectively with approximately 77% undergoing HIV testing. Despite increases in reported testing, known status among people living with HIV (PLHIV) remained similar at 68.7% (95% Confidence Interval (CI)&nbsp;=&nbsp;60.9-75.6) in 2014 and 72.8% (95% CI&nbsp;=&nbsp;63.6-80.4) in 2016. Men were consistently less likely than women to know their status. Among those with known status, PLHIV on ART increased significantly from 80.9% (95% CI&nbsp;=&nbsp;71.9-87.4) to 91.5% (95% CI&nbsp;=&nbsp;84.4-95.5). Viral suppression (&lt;5000 copies/mL using DBS) among those on ART increased significantly from 55.0% (95% CI&nbsp;=&nbsp;39.6-70.4) in 2014 to 81.4% (95% CI&nbsp;=&nbsp;72.0-90.8) in 2016. Among all PLHIV an estimated 72.0% (95% CI&nbsp;=&nbsp;63.8-80.1) of women and 45.8% (95% CI&nbsp;=&nbsp;27.0-64.7) of men achieved viral suppression by 2016.ConclusionsOver a period during which fixed-dose combination was introduced, ART eligibility expanded, and efforts to streamline treatment were implemented, major improvements in the second and third 90-90-90 targets were achieved. Achieving the first 90 target will require targeted and improved testing models for men

DOG1 immunohistochemical staining of testicular biopsies is a reliable tool for objective assessment of infertility

Testicular biopsy may be a component of the work-up of male infertility. However, no reliable diagnostic tools are available for objective quantitative assessment of spermatogenic cells. It is well known that MAGE-A4 is selectively expressed in spermatogonia and our group has previously demonstrated that DOG1 differentially stains germ cells. Therefore, we performed DOG1 and a double stain cocktail (DOG1 and 57b murine monoclonal anti-MAGE-A4) immunohistochemical stains on 40 testicular infertility biopsies (10 each with active spermatogenesis, Sertoli cell-only, hypospermatogenesis, and maturation arrest), 25 benign seminiferous tubules from radical orchiectomies, and 5 spermatocytic tumors (ST). In biopsies/resections with active spermatogenesis, DOG1 stained spermatocytes and spermatids and was absent in spermatogonia, while MAGE-A4 stained spermatogonia and primary spermatocytes (weak). In hypospermatogenesis, DOG1 highlighted decreased spermatocytes/spermatids and MAGE-A4 highlighted decreased spermatogonia. DOG1 staining confirmed decreased to absent spermatocytes in maturation arrest and MAGE-A4 staining established the presence of preserved spermatogonia in all cases. All STs were negative for DOG1 and positive for MAGE-A4, while all Sertoli cell-only cases were negative for DOG1 and the double stain cocktail. In conclusion, we confirmed that DOG1 is expressed in spermatocytes and spermatids and MAGE-A4 highlights primarily spermatogonia. Usage of these stains facilitates confirmation of maturation arrest, assessment of the percentage of testis involvement in hypospermatogenesis and identification of mixed patterns. Finally, this study supports that the differentiation of STs is more closely related to spermatogonia than the more mature spermatocytes

Morphologic Spectrum of Renal Cell Carcinoma, Unclassified: An Analysis of 136 Cases

Aims Renal cell carcinoma, unclassified (RCCU) is a category that includes a morphologically and biologically heterogeneous group of tumors that are unable to be diagnosed as other well-defined entities. We aim to describe the morphologic findings of tumors within this category and to determine the most frequent morphologic features leading to classification difficulty. Methods and results One hundred and thirty-six cases of RCCU were examined. Patients ranged in age from 23 to 87 years. Seventy-seven patients were men and 59 were women. International Society of Urological Pathology (ISUP) grade was most commonly 3 (n=66), followed by 2 (n=42) and 4 (n=28). Tumor size ranged from 0.6 cm to 24.9 cm. The AJCC pathologic T categories included pT1a (n=50), pT1b (n=14), pT2a (n=7), pT2b (n=4), pT3a (n=50), and pT4 (n=9). Forty-four cases included lymph node(s), of which 41% (n=18) had metastases. Tumors were assessed for a variety of histologic features and assigned to the following morphologic groups: predominantly oncocytoma/chromophobe RCC-like; clear cell RCC-like; papillary RCC-like; collecting duct-like; and pure sarcomatoid differentiation. The majority of the oncocytoma/chromophobe and clear cell RCC-like phenotypes were low stage (pT1 or pT2). The papillary RCC-like, collecting duct-like, and pure sarcomatoid phenotypes were mostly high stage (pT3 or pT4). Conclusions RCCU is a term that encompasses tumors with a variety of morphologic features and a wide biologic spectrum. The most common source of diagnostic difficulty was tumors composed of predominantly eosinophilic cells

Mémoires sur la métallurgie

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Using time-use diaries to track changing behavior across successive stages of COVID-19 social restrictions

How did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time-use diary surveys are unique in providing a complete chronicle of daily behavior: 24-h continuous records of the populations’ activities, their social context, and their location. We present results from four such surveys, collected in real time from representative UK samples, both before and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK population’s behavior relating to activities, locations, and social context. We assign different levels of risk to combinations of activities, locations, and copresence to compare risk-related behavior across successive “lockdowns.” We find evidence that during the second lockdown (November 2020), there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in the workplace. At a time when capacity is still limited both in respect of immunization and track–trace technology, governments must continue to rely on changes in people’s daily behaviors to contain the spread of COVID-19 and similar viruses. Time-use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy makers with information to assess and quantify changes in daily behaviors and the impact they are likely to have on overall behavioral-associated risks

Mild motor impairment as prodromal state in amyotrophic lateral sclerosis:A new diagnostic entity

Amyotrophic lateral sclerosis, when viewed as a biological entity rather than a clinical syndrome, probably evolves along a continuum, with the initial clinically silent phase eventually evolving into clinically manifest amyotrophic lateral sclerosis. Since motor neuron degeneration is incremental and cumulative over time, it stands to reason that the clinical syndrome of amyotrophic lateral sclerosis is probably preceded by a prodromal state characterized by minor motor abnormalities that are initially insufficient to permit a diagnosis of amyotrophic lateral sclerosis. This prodromal period, however, is usually missed, given the invariably long delays between symptom onset and diagnostic evaluation. The Pre-Symptomatic Familial ALS Study, a cohort study of pre-symptomatic gene mutation carriers, offers a unique opportunity to observe what is typically unseen. Here we describe the clinical characterization of 20 pre-symptomatic mutation carriers (in SOD1, FUS and C9orf72) whose phenoconversion to clinically manifest disease has been prospectively studied. In so doing, we observed a prodromal phase of mild motor impairment in 11 of 20 phenoconverters. Among the n = 12 SOD1 A4V mutation carriers, phenoconversion was characterized by abrupt onset of weakness, with a short (1–3.5 months) prodromal period observable in a small minority (n = 3); the observable prodrome invariably involved the lower motor neuron axis. By contrast, in all n = 3 SOD1 I113T mutation carriers, diffuse lower motor neuron and upper motor neuron signs evolved insidiously during a prodromal period that extended over a period of many years; prodromal manifestations eventually coalesced into a clinical syndrome that is recognizable as amyotrophic lateral sclerosis. Similarly, in all n = 3 C9orf72 hexanucleotide repeat expansion mutation carriers, focal or multifocal manifestations of disease evolved gradually over a prodromal period of 1–2 years. Clinically manifest ALS also emerged following a prodromal period of mild motor impairment, lasting >4 years and ∼9 months, respectively, in n = 2 with other gene mutations (SOD1 L106V and FUS c.521del6). On the basis of this empirical evidence, we conclude that mild motor impairment is an observable state that precedes clinically manifest disease in three of the most common genetic forms of amyotrophic lateral sclerosis (SOD1, FUS, C9orf72), and perhaps in all genetic amyotrophic lateral sclerosis; we also propose that this might be true of non-genetic amyotrophic lateral sclerosis. As a diagnostic label, mild motor impairment provides the language to describe the indeterminate (and sometimes intermediate) transition between the unaffected state and clinically manifest amyotrophic lateral sclerosis. Recognizing mild motor impairment as a distinct clinical entity should generate fresh urgency for developing biomarkers reflecting the earliest events in the degenerative cascade, with potential to reduce the diagnostic delay and to permit earlier therapeutic intervention

A New Perspective from Time Use Research on the Effects of Lockdown on COVID-19 Behavioral Infection Risk

We present findings from the first two waves of an innovative, population-representative, UK time-use diary survey conducted both pre- and mid-lockdown, using an online diary instrument that proved both reliable and quick-to-field. Combining diary information on activity, location, and co-presence to estimate infection risks associated with daily behavior, we show clear changes in such behavior related to infection risk between the pre- and mid-lockdown periods: a substantial reduction of time spent in those behaviors with the highest levels of risk, accompanied by an equivalent increase in low-risk behavior. Because, in general, a populations' time use changes relatively slowly, the behavioral changes revealed may be interpreted directly as a consequence of the UK COVID-19 'lockdown' regulations. Subsequent waves will reveal the behavioral consequences of future changes in regulation