The effect of inhaled nitric oxide on shunt fraction in mechanically ventilated patients with COVID-19 pneumonia.

Background: Studies in patients with severe acute respiratory distress syndrome (ARDS) with refractory hypoxaemia suggest that inhaled nitric oxide (iNO) can be added to ventilatory strategies as a potential bridge to clinical improvement. However, the potential role of iNO as a management strategy in severe COVID-19 pneumonia remains unclear. The authors describe their clinical findings of using iNO for severe COVID-19 pneumonia in 10 patients with refractory hypoxaemia in a tertiary respiratory intensive care unit. The results showed an improvement in shunt fraction, P/F ratio, PaO2 and arterial oxygen saturation but the improvements did not translate into a mortality benefit. This report adds to the current body of literature indicating that the correct indications, timing, dose and duration of iNO therapy and how to harness its pleiotropic effects still remain to be elucidated. What the study adds: This brief report adds to the body of literature exploring the potential use of inhaled nitric oxide as a management strategy in patients with severe COVID-19 pneumonia with refractory hypoxaemia. What are the implications of the findings: The findings of the report shows that there is a beneficial role of using inhaled nitric oxide to improve respiratory parameters, but that it does not translate to a mortality benefit. It adds to the investigation of establishing which patients, the duration and at what dose, inhaled nitric oxide should be used to gain maximum benefit for this subgroup of patients.

Comparison of patients with severe COVID-19 admitted to an intensive care unit in South Africa during the first and second wave of the COVID-19 pandemic.

Background: The second wave of coronavirus disease 2019 (COVID-19), dominated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant, has been reported to be associated with increased severity in South Africa (SA). Objectives: To describe and compare clinical characteristics, management and outcomes of COVID-19 patients admitted to an intensive care unit (ICU) in SA during the first and second waves. Methods: In a prospective, single-centre, descriptive study, we compared all patients with severe COVID-19 admitted to ICU during the first and second waves. The primary outcomes assessed were ICU mortality and ICU length of stay (LOS). Results: In 490 patients with comparable ages and comorbidities, no difference in mortality was demonstrated during the second compared with the first wave (65.9% v. 62.5%, p=0.57). ICU LOS was longer in the second wave (10 v. 6 days, p<0.001). More female admissions (67.1% v. 44.6%, p<0.001) and a greater proportion of patients were managed with invasive mechanical ventilation than with non-invasive respiratory support (39.0% v. 14%, p<0.001) in the second wave. Conclusion: While clinical characteristics were comparable between the two waves, a higher proportion of patients was invasively ventilated and ICU stay was longer in the second. ICU mortality was unchanged.

Medical practice in Graeco-roman antiquity.

The roots of modern medicine can be traced back to the 5th century BC when Hippocratic rational medicine originated on the Greek islands of Cos and Cnidos. In this study we examine the way in which practitioners conducted their profession in Graeco-Roman times, as well as their training. Medical training was by way of apprenticeship with recognized doctors, but no qualifying examinations existed and the standard of practice thus varied enormously. Even in the Roman era the vast majority of medical doctors were Greek and in private practice as itinerant physicians. Civic doctors in the paid service of local communities appeared in Greek society from the 5th century BC onwards, but much later in Rome - probably as late as the 4th century AD. Rome's unique contributions to medicine lay in public health measures (e.g. their aqueducts, public baths and sewages systems) and an excellent medical service for their armies and navy. Hospitals (valetudinaria) were established for military purposes and for slaves on large Roman estates from the 1st century BC, but civic hospitals for the general public originated as late as the 4th century AD. The Greek medical schools of Cos and Cnidos were eventually superseded by the school of Alexandria in Egypt and towards the end of the Roman Empire by that of Carthage in northern Africa. Its gradual demise in the Christian era lowered the curtain on original medical endeavours during antiquity.

Is the d an allelic gene of D in the Rh blood group system? A quantitative study using 99mTechnetium-pyrophosphate-labelled antibody (TcLA) method.

This article reports on studies of Rh antigens, such as D, Du and d, using uranyl-labelled antibody (ULA) and TcLA (99mTc-pyrophosphate-labelled antibody) methods for the first time for this purpose. TcLA method proved to be simple in labelling and very sensitive (20--100 times more so than the indirect Coombs test) in the detection of Rh antigen-antibody binding. Results of this quantitative study demonstrate convincingly that the d is not an allelic gene of D but rather the weakest of the series D less than Du less than d. Although the evidence from this study demonstrates clearly that differences between D and d are only quantitative, the authors do not think that the Rh nomenclature should be changed but they do think that the present evidence should be used in regard to the understanding of the allelism in the Rh blood group system. The c is an allelic gene of C as the e is an allelic gene of E; specific test sera detecting every one of these antigens exist and the family studies verify these statements. However, the d is not a distinct antigen as c and e are, even if the pattern of inheritance from family studies, using the existent anti-D serum, would suggest the allelism as probability. That is why in the past the anti-Du and anti-d specific test sera never incidentally found or artificially produced.

Uranyl-labelled antibody (ULA) method and its application for Rh antibodies.

The existent labelling materials for studies of antigen--antibody interaction at ultrastructural level, namely ferritin and peroxidase, because of their large molecular size do not fulfill all requirements of excellent markers for electron microscopy (EM). Uranyl acetate has a molecule 354 times smaller than IgG and its uranium atom is electron-dense. These physical characteristics of uranyl acetate make it a labelling material par excellence as described in this article. Quantitative and qualitative studies of Rh antigen-antibody interactions are for the first time presented at the ultrastructural level, and the application of the uranyl-labelled antibody (ULA) method for weak antisera (dilutions 100 to 1000 time higher than the Coombs range of sensitivity) is demonstrated. The ULA method opens a new era for studies of antigens, antibodies and their interactions because it will demonstrate visibly details of the antigen-antibody interaction and is especially suitable for studies of weak antisera.

The identification of human T and B lymphocytes by electron microscopy.

Lymphocytes of peripheral blood, bone marrow, spleen, vermiform appendix, tonsil and Mantoux skin reaction were examined by electron microscopy (EM) and classified as T, B and Null cells by E-rosette and immunoglobulin membrane-receptor characteristics. The low pH and ionic strength of the fixative solution for EM, and some other minor procedural modifications, made it possible to distinguish B and T lymphocytes morphologically. T-cells have electron-dense cytoplasm and euchromatin in the nucleus whereas B-cells constantly have electron-lucent cytoplasm and euchromatin in the nucleus. A proportion of lymphocytes were unclassifiable by their ultrastructural features. These unclassifiable cells may be Null cells as determined by the classical techniques. The specificity and simplicity of this EM technique for T and B lymphocytes is especially useful for studies of immunocompetent-cell topography and cell-to-cell interaction in lymphoid organs. It may also be utilized for diagnostic purposes in immunocytic dyscrasias.

ADPase activity of normal and atherosclerotic human aorta intima.

ADP plays a key role in platelet aggregation and the enzymatic removal of this nucleotide may be important in the pathogenesis of intravascular thrombosis and atherosclerosis. Aortic intima extracts have ADPase activity and is able to remove small quantities of ADP efficiently. ADPase activity was assayed by measuring the catabolism of 2 micrometer 14C-ADP (final concentration) by the tissue extracts. Extracts prepared from normal, moderately and severely atherosclerotic human aortic initimas showed a significant progressive decrease in ADPase activity with increasing atherosclerosis. ADPase activity of the arch, thoracic and abdominal regions of normal aortas did not vary significantly, and thus did not correlate with the anatomical distribution of atherosclerosis. Vascular ADPase activity seems relevant in thrombogenesis since it may be a link between blood platelets and blood vessel wall interaction.

Preparation of a viable population of indium-111-labelled human blood platelets.

Factors influencing labelling of human platelets with 111Indium-8-hydroxyquinoline ([111In]-oxine) in a physiological saline medium were investigated. The efficiency of labelling is influenced by time of incubation, concentration of oxine, and pH of the incubating medium. It was found that a viable platelet population could be labelled under the following conditions: (1) centrifugation of platelet rich plasma in polystyrene conical tubes at 800 g for 15 min; (2) resuspension of the platelet pellet in saline, pH 5.5; (3) incubating for 30 min at 22 degrees C with [111In]-oxine at a concentration of 6.25 mg oxine/litre platelet suspension; (4) washing once with platelet poor autologous plasma (PPP); and (5) finally resuspending the platelets in PPP. The labelled platelets aggregated normally with collagen and ADP. Electron microscopy, done immediately after labelling, showed internal organelle reorganization characteristic of activated platelets. These ultrastructural features were reversible on incubation in PPP at 37 degrees C for 30 min. The 111In is not released from aggregated platelets and the label does not elute from incubated platelets for at least five hr. We conclude that human platelets thus labelled are suitable for in vivo kinetic studies.

Folate binders in body fluids.

In normal serum, saline dialysis for 48 hours in Visking casing resulted in folate clearance closely comparable to that produced by haemoglobin-coated charcoal adsorption, except in kwashiorkor where charcoal removed a greater proportion of folate. Pre- and post-dialysis values probably represented total and bound folate, respectively. Urinary folate consisted almost exclusively of dialyzable or free folate. Folate in saliva, bile, and erythrocytes consisted of dialyzable and non-dialyzable fractions; gastric juice contained minimal amounts of folate. In spite of low serum albumin in kwashiorkor the bound folate fraction was increased rather than decreased; in myeloma with hyperglobulinaemia there was no increase in the bound folate fraction. Nephrotic urine did not contain excess folate, but pregnancy urine (third trimester) showed increased total folate.Serum, chromatographed on Sephadex G-25, produced two folate peaks, only the first being associated with serum proteins. Urine contained only a second folate peak corresponding to the elution peak of pteroyl-monoglutamic acid (PGA). Adsorption studies with charcoal coated with ;molecular sieves' of varying size suggested that the predominant serum folate binder was of molecular weight 70,000-120,000. It is unlikely to be albumin.

Platelet aggregation in chronic idiopathic thrombocytopenic purpura.

A method for washing platelets by albumin density gradient separation has been modified to prepare platelet rich plasma of thrombocytopenic patients for platelet aggregation studies. The concentration procedure, consisting of centrifuging platelets into a specific gravity gradient between plasma and 40-45% aqueous solution of bovine albumin, does not affect platelet aggregation adversely. Platelet aggregation in eight patients with chronic idiopathic thrombocytopenic purpura was determined by this method. On the basis of the results the patients could clearly be divided into two groups: four patients with normal aggregation and four with a qualitative platelet defect. In contrast to the other patients, the group with an in vitro platelet functional defect all had more prolonged bleeding times and the presence of a serum antiplatelet antibody.

Efficacy and tolerability of 20 mg pantoprazole versus 300 mg ranitidine in patients with mild reflux-oesophagitis: a randomized, double-blind, parallel, and multicentre study.

BACKGROUND AND AIM: The aim of this study was to compare the efficacy and tolerability of low dose pantoprazole (20 mg) (a gastric proton pump inhibitor) with standard dose ranitidine (300 mg) (a histamine-receptor antagonist), in their ability to relieve symptoms and heal oesophageal lesions associated with gastrooesophageal reflux disease (GORD). METHODS: Patients with endoscopically established mild GORD (stage I, modified Savary-Miller classification) were enrolled into a multicentre, randomized, double-blind, parallel-group comparison study (intention-to-treat population, n = 201; age range, 18-82 years). Patients took either oral pantoprazole 20 mg in the morning (n = 101) or ranitidine 300 mg in the evening (n = 100) once daily for 4 weeks or, if the healing was not complete, 8 weeks. Relief from key symptoms (heartburn, acid regurgitation, pain on swallowing) was assessed after 2, 4, and if applicable, 8 weeks. Healing of lesions was confirmed endoscopically after 4 and, if applicable, 8 weeks. RESULTS: Complete relief from key symptoms was noted after 2 weeks in 70/88 (80%) patients treated with pantoprazole vs 45/89 (51%) patients treated with ranitidine ('per-protocol and key-point available' populations, P < 0.001); the corresponding results after 4 weeks were 77/88 (88%) vs 51/88 (58%) (P < 0.001). Complete healing of lesions after 4 weeks of treatment was seen in 74/88 (84%) vs 49/89 (55%) in the pantoprazole and ranitidine group, respectively (P < 0.001, per-protocol); by week 8 the cumulative healing rates were 84/88 (95%) vs 69/89 (78%) in the pantoprazole and ranitidine group, respectively (P < 0.001). For the intention-to-treat populations, the corresponding values for healing after 4 and 8 weeks were 73% vs 49% (P < 0.001) and 83% vs 69% (P < 0.05), respectively. Both study medications were well tolerated. CONCLUSION: Compared to ranitidine 300 mg, the regimen with pantoprazole 20 mg provides faster relief from symptoms and is significantly more effective in healing of oesophageal lesions in patients with mild reflux-oesophagitis. Thus, the low dose of pantoprazole offers a treatment approach which minimizes drug exposure and costs while retaining high efficacy.

Aspects of folate metabolism in lactating women studied after ingestion of 14C-methylfolate.

Radioactive methylfolate (14C-5CH3H4PteGlu) (10-14 microgram/kg) was fed to four lactating women presenting with breast abscesses necessitating cessation of lactation. The appearance of radiofolate in milk, plasma and urine over the next 24 hours was investigated. In spite of a minimal postabsorption rise of plasma biofolate, plasma radiofolate (including a dialysis-resistant (bound) fraction) increased steadily to 1.26 to 5.11 microgram/l at 24 hours. Urinary radiofolate excretion was considerable. Total milk biofolate rose significantly by 15 to 28 microgram/l, in contrast with a much smaller radiofolate fraction (1.95-3.88 microgram/l) which at 24 hours was comparable with that of plasma. Milk radiofolate included a dialysis-resistant fraction rising to 0.75 to 1.15 microgram/l at 24 hours. On chromatography (Sephadex-DEAE-A50) plasma, urine and milk showed a nonbound radiofolate peak suggestive of 10-CHO.H4PteGlu. This folate may originate predominantly from the apocrine mammary glands. The in vitro labelled radiofolate milk binder could not be identified chromatographically, but it was shown that the in vitro milk binders of PteGlu and 5CH3H4PteGlu could be separated chromatographically.

The evolution of the hospital from antiquity to the end of the middle ages.

The evolution of the hospital is traced from its onset in ancient Mesopotamia towards the end of the 2nd millennium to the end of the Middle Ages. Reference is made to institutionalised health care facilities in India as early as the 5th century BC, and with the spread of Buddhism to the east, to nursing facilities, the nature and function of which are not known to us, in Sri Lanka, China and South East Asia. Special attention is paid to the situation in the Graeco-Roman era: one would expect to find the origin of the hospital in the modern sense of the word in Greece, the birthplace of rational medicine in the 4th century BC, but the Hippocratic doctors paid house-calls, and the temples of Asclepius were visited for incubation sleep and magico-religious treatment. In Roman times the military and slave hospitals which existed since the 1st century AD, were built for a specialized group and not for the public, and were therefore also not precursors of the modern hospital. It is to the Christians that one must turn for the origin of the modern hospital. Hospices, initially built to shelter pilgrims and messengers between various bishops, were under Christian control developed into hospitals in the modern sense of the word. In Rome itself, the first hospital was built in the 4th century AD by a wealthy penitent widow, Fabiola. In the early Middle Ages (6th to 10th century), under the influence of the Benedictine Order, an infirmary became an established part of every monastery. During the late Middle Ages (beyond the 10th century) monastic infirmaries continued to expand, but public hospitals were also opened, financed by city authorities, the church and private sources. Specialized institutions, like leper houses, also originated at this time. During the Golden Age of Islam the Muslim world was clearly more advanced than its Christian counterpart with magnificent hospitals in various countries.