The potential role of microvascular pathology in the neurological manifestations of coronavirus infection.

Human coronaviruses are highly pathogenic viruses that pose a serious threat to human health. Examples include the severe acute respiratory syndrome outbreak of 2003 (SARS-CoV-1), the Middle East Respiratory Syndrome (MERS-CoV) outbreak of 2012, and the current SARS-CoV-2 (COVID-19) pandemic. Herein, we review the neurological manifestations of coronaviruses and discuss the potential pathogenic role of blood-brain barrier dysfunction. We present the hypothesis that pre-existing vascular damage (due to aging, cardiovascular disease, diabetes, hypertension or other conditions) facilitates infiltration of the virus into the central nervous system (CNS), increasing neuro-inflammation and the likelihood of neurological symptoms. We also discuss the role of a neuroinflammatory cytokine profile in both blood-brain barrier dysfunction and macrovascular disease (e.g. ischemic stroke and thromboembolism). Future studies are needed to better understand the involvement of the microvasculature in coronavirus neuropathology, and to test the diagnostic potential of minimally-invasive screening tools (e.g. serum biomarkers, fluorescein retinal angiography and dynamic-contrast MRI).

Abnormal IL-2 receptor levels in non-pregnant women with a history of recurrent miscarriage.

BACKGROUND: Immunological abnormalities have been found in pregnant women with a history of recurrent miscarriage. This study compared interleukin-2 receptor (IL-2R) levels in non-pregnant women with a history of recurrent miscarriage with those found in serum from a non-pregnant group with no such history. METHODS: Group 1 comprised 49 non-pregnant women with a history of recurrent miscarriage (at least three consecutive miscarriages). Group 2 comprised 22 non-pregnant women with no history of miscarriage. Serum IL-2R levels were measured in all patients. RESULTS: The results obtained showed that although all women were not pregnant at the time of sampling, IL-2R levels were significantly higher in women in Group 1 compared with those in Group 2 (1589 +/- 1289 versus 1082 +/- 823 pg/ml; P < 0.05). Follow-up data were available for 21 women from Group 1. The next pregnancy ended successfully for 14 of these women, while seven miscarried again. The IL-2R levels obtained pre-pregnancy were not significantly different between the two groups (1480 +/- 910 versus 1356 +/- 716 pg/ml). CONCLUSION: This study has shown that non-pregnant women with a history of recurrent miscarriage have raised IL-2R levels. These increased pre-pregnancy IL-2R levels did not necessarily predict miscarriage for the next pregnancy.

Interleukin-2 receptor concentrations in pregnant women with a history of recurrent miscarriage.

BACKGROUND: The mechanism by which the maternal immune system tolerates the fetus during pregnancy is unclear. METHODS: This study measured interleukin-2 receptor (IL-2R) concentrations in the serum of non-pregnant women (Group 1); healthy first trimester pregnant women (Group 2); pregnant women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester (Group 3); and first trimester pregnant women with a history of recurrent miscarriage but whose pregnancies on this occasion went successfully to term (Group 4). An initial sample was obtained from all women in Groups 1, 2, 3 and 4. A further sample was obtained 4 weeks later from women in Groups 1, 2 and 4. RESULTS: The initial sample showed no significant difference in IL-2R concentrations between Groups 1 and 2. Concentrations were significantly higher in Groups 3 (667 +/- 244 U/ml; P < 0.003) and 4 (730 +/- 360 U/ml; P < 0.05) compared with healthy pregnant women (425 +/- 94). When the second sample was obtained concentrations in Group 4 were found to have fallen so that they no longer differed from Group 2. CONCLUSIONS: Our results confirm earlier findings that a successful pregnancy is associated with significantly lower concentrations of IL-2R.

Abnormal immunoglobulin subclass patterns in women with a history of recurrent miscarriage.

OBJECTIVE: To determine whether IgG subclass patterns differed between nonpregnant women, healthy pregnant women, and pregnant women with a history of recurrent miscarriage. DESIGN: Controlled clinical study. SETTING: An academic setting. PATIENT(S): Group 1 was comprised of 10 nonpregnant women, group 2 of 10 healthy pregnant women, group 3 of eight pregnant women with a history of recurrent miscarriage and whose pregnancies on this occasion went to term, and group 4 of 10 women with a history of recurrent miscarriage whose pregnancies again failed later in the first trimester. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Serum levels of total IgG and IgG 1, 2, 3, and 4. RESULT(S): The results obtained showed that normal pregnancy was associated with a significant increase in total IgG production and an increase in IgG subclasses 1, 2, and 3. Women with a history of miscarriage, but who had a successful pregnancy on this occasion, showed a similar pattern of IgG subclasses. Women with a history of miscarriage and whose pregnancy again ended in miscarriage showed a different IgG subclass pattern. CONCLUSION(S): Pregnancies that ended in miscarriage showed a different pattern of IgG subclasses than those that continued to term. The changes seen in immunoglobulin patterns could be linked to changes in cytokine production.

A simple procedure to secure an indwelling jugular vein catheter to the neck of cattle for repeated blood sampling.

A procedure to secure a jugular vein catheter system to the neck of cattle is described. A wide-mouthed polypropylene bottle attached to a halter strap provided a secure container for the catheter. This device allowed convenient access to the catheter for repeated sampling and, apparently, reduced discomfort to the cattle.

Evidence of a T(H) 1 type response associated with recurrent miscarriage.

OBJECTIVE: To determine whether the T(H) 1 cytokine interferon (IFN)-gamma is associated with miscarriage whereas the T(H) 2 cytokine interleukin (IL)-10 is associated with successful pregnancy. DESIGN: Controlled clinical study. SETTING: Healthy volunteers in an academic setting. PATIENT(S): Group 1 comprised 10 nonpregnant women; group 2, 10 first-trimester primigravid women; group 3, 10 first-trimester primigravid women suffering spontaneous abortion; and group 4, 10 first-trimester pregnant women with a history of miscarriage. All women were pregnant at the time of sampling, but 5 miscarried later in the first trimester. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Serum levels of IL-10 and IFN-gamma. RESULT(S): Levels of IL-10 were significantly raised in normal pregnancy. Levels of IFN-gamma were raised in the recurrent-miscarriage group as compared with normal pregnancy. When patients in group 4 were divided into those whose pregnancies went to term and those who miscarried, we found that successful pregnancy was associated with a statistically significant increase in IL-10, whereas miscarriage was associated with significantly increased levels of IFN-gamma. CONCLUSION(S): These results support the view that miscarriage is associated with a T(H) 1 type response.

Thyroid antibody titer and avidity in patients with recurrent miscarriage.

OBJECTIVE: To determine whether the titer and avidity of the thyroid peroxidase antibody differs between pregnant women in their first trimester who have a history of recurrent miscarriage and whose pregnancies continue to term and those whose pregnancies fail again later in the first trimester. DESIGN: Controlled clinical study. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Pregnant women in their first trimester who had a history of recurrent miscarriage (> or = 3 miscarriages) and who were known to be positive for the thyroid peroxidase antibody. INTERVENTION(S): None of the patients received any medication. MAIN OUTCOME MEASURE(S): Thyroid peroxidase antibody titer and avidity (i.e., the net binding strength between antibody and antigen). RESULT(S): At the time of presentation, thyroid peroxidase antibody titer and avidity was significantly higher in those women who later miscarried compared with those whose pregnancies continued. In those whose pregnancies continued to term, titer and avidity declined as the pregnancy progressed. CONCLUSION(S): Autoimmunity plays a role in recurrent miscarriage. Among a group of patients who had had recurrent miscarriages, there appeared to be differences in the humoral response to the pregnancy between those whose pregnancies continued to term and those whose pregnancies failed again.

1H NMR as a non-invasive probe of amniotic fluid in insulin dependent diabetes mellitus.

Ten amniotic fluid samples obtained from third trimester pregnant women suffering from insulin dependant diabetes mellitus were analysed by 1H-NMR and compared to ten samples from a group of normal volunteers. A subset of the metabolites identified; valine, lactate, alanine, acetate, citrate and glucose were quantitated using standard addition methods. Apart from valine and citrate, a general diminution in the concentration of each of these species was found, especially glucose, in the diabetic group. The abnormally low glucose levels in the diabetic group are suggestive of infection in the patient group. However, the depressed lactate levels in the diabetic group suggest that in these cases the fetus was not subjected to stress.

Recurrent miscarriage is associated with increased numbers of CD5/20 positive lymphocytes and an increased incidence of thyroid antibodies.

The aim of this study was to determine whether recurrent miscarriage (three or more miscarriages, no live children) was associated with an increased incidence of autoantibodies. Five groups were enrolled into the study; healthy non-pregnant women, healthy first-trimester pregnant women, women suffering spontaneous abortion, those undergoing termination of pregnancy and those with a previous history of miscarriage. The number of total B cells and the numbers of the antibody producing B cell subset CD5+/CD20+ were determined for each group. Samples were tested for anticardiolipin antibodies, antinuclear antibodies and thyroid microsomal and thyroglobulin antibodies. The results showed that compared to normal pregnancy or spontaneous abortion, recurrent miscarriage was associated with a significant increase in the number of CD5+/20+ positive cells (0.8 +/- 0.3 vs 0.5 +/- 0.1 vs 1.1 +/- 0.3 x 10(8)/l; p < 0.001). These women were also found to have a higher incidence of thyroid antibodies, with four out of the 11 patients being positive for thyroid microsomal antibodies. These results suggest that there may be an association between autoimmunity and recurrent miscarriage.

PIP: The aim of this study was to determine whether recurrent miscarriage (three or more miscarriages, no live children) was associated with an increased incidence of autoantibodies. Five groups were enrolled into the study: healthy nonpregnant women, healthy first-trimester pregnant women, women suffering spontaneous abortion, those undergoing termination of pregnancy, and those with a previous history of miscarriage. The number of total B cells and the numbers of the antibody-producing B cell subset CD5+/20+ were determined for each group. Samples were tested for anticardiolipin antibodies, antinuclear antibodies, and thyroid microsomal and thyroglobulin antibodies. The results showed that compared to normal pregnancy or spontaneous abortion, recurrent miscarriage was associated with a significant increase in the number of CD5+/20+ cells (0.8 +or- 0.3 vs. 0.5 +or- 0.1 vs. 1.1 +or- 0.3 x 108/L: p 0.001). These women were also found to have a higher incidence of thyroid antibodies, with 4 of the 11 patients being positive for thyroid microsomal antibodies. These results suggest that there may be an association between autoimmunity and recurrent miscarriage.

The prevalence of lupus anticoagulant and anticardiolipin antibodies in women with a history of first trimester miscarriages.

OBJECTIVE: To determine the prevalence of lupus anticoagulant and raised anticardiolipin antibodies in women with a history of two or more miscarriages in the first trimester of pregnancy. DESIGN: A prospective study of lupus anticoagulant and anticardiolipin antibody levels in unselected women with a history of two or more first trimester miscarriages. SETTING: The prepregnancy clinic and miscarriage antenatal clinic in a tertiary referral centre. SUBJECTS: Two hundred and forty-three women, of whom 113 (47%) had a past history of two miscarriages, and 130 (53%) had three or more miscarriages. MAIN OUTCOME MEASURES: Quantitative detection of lupus anticoagulant and anticardiolipin antibodies; number of miscarriages in women in the normal and the abnormal groups. RESULTS: Of the 243 women tested, 41 (16.8%) had an abnormality of lupus anticoagulant or anticardiolipin antibodies. This was significantly different from the normal population as previously reported. Sixteen women (6.6%) were positive for lupus anticoagulant, 20 (8.2%) had elevated anticardiolipin antibodies, and five (2%) had both abnormalities. The most frequently positive test for lupus anticoagulant was the dilute Russel viper venom time, and IgG was the most frequently elevated anticardiolipin antibody. Of the women with a history of only two miscarriages, 15% had an abnormality of lupus anticoagulant or anticardiolipin antibodies, compared with 18.5% of those with a history of three or more miscarriages. This did not reach statistical significance. There were 117 (48%) primary miscarriers and 126 (52%) secondary miscarriers. Of the primary miscarriers, 17% had an abnormality, compared to 18% of the secondary miscarriers. CONCLUSIONS: These findings provide further evidence of an association between lupus anticoagulant and anticardiolipin antibodies and early pregnancy loss. It is not known if these are the cause of miscarriage, markers for miscarriage, or if antiphospholipid antibodies develop as a result of a noncontinuing pregnancy. Further studies comparing various treatments are required before women with these antibodies can be optimally managed.

Providing for women following miscarriage.

It is apparent that an increased awareness amongst health care workers of the need for parents to grieve the loss of their baby, regardless of the gestation, is essential. It should also be noted that this time of coming to terms with the loss can be quite lengthy. This healing may be aided by support groups such as the Miscarriage Association, and also through pre-pregnancy counselling clinics. Support in the next pregnancy appears to improve the chance of a successful pregnancy outcome in women with a history of recurrent miscarriages. It is important that the current interest in bereavement counselling does not lead to every miscarriage being 'magnified into a catastrophe'. For some women the event will pass with little trauma. In seeking to improve the management of this distressing condition we must be careful to take into consideration the individual's requirements. In a recent publication by SANDS, guidelines for the management of patients who have experienced the loss of a baby are given. This book can be commended for all involved in the care of women at the time of pregnancy loss.

Immunological changes in normal pregnancy.

During pregnancy the mother must tolerate intra-uterine allogenic fetal tissue. Failure of this tolerance may cause spontaneous abortion. The immunological changes occurring in normal pregnancy are poorly understood. The aim of this study was to investigate the immunological changes occurring in pregnancy. Thirty women in the first trimester; 10 in the second and 10 in the third trimester of pregnancy were studied and compared to age matched non-pregnant controls. In normal pregnancy there was an increase in the total white cell count with no change in the lymphocyte count. There was a fall in total T cell numbers and activated T cell numbers, with no change in helper/inducer or suppressor/cytotoxic T cell numbers. [3H]Thymidine uptake in response to three different mitogens was increased. This implies an increase in potential for the cells to respond to mitogens. There was no change in interleukin-2 receptor levels, suggesting that despite this increased potential there was no general activation of the immune system. A rise in IgM and IgG was found after mitogen stimulation of peripheral blood lymphocytes, suggesting an increase in potential antibody production. These results demonstrate that lymphocytes from pregnant women have an increased potential rather than an increased activity.

Changes in immunologic parameters in normal pregnancy and spontaneous abortion.

To study the immunologic characteristics of miscarriage, 40 nonpregnant control subjects, 40 primigravid women in the first trimester of pregnancy, and 18 patients admitted with a spontaneous abortion were investigated. The total white blood cell count was raised significantly in normal pregnancy and spontaneous abortion (p less than 0.0005). The lymphocyte count was unchanged. The total T-cell number fell significantly in normal pregnancy and abortion (p less than 0.01). No change was seen in the cytotoxic suppressor or helper/inducer T-cell numbers. The number of activated T cells fell significantly in both groups of patients (p less than 0.0005). The response to mitogens was greatly increased in both normal patients and those with miscarriage. A marked rise in interleukin-2 receptor levels was noted in patients with spontaneous abortion (p less than 0.005). The changes in white blood cell count, total T-cell number, activated T-cell number, and mitogen activity were thought to be a direct result of pregnancy. The rise in interleukin-2 receptor levels was seen only in the miscarriage group. Although it is not known if these changes are cause or effect, it would appear that immunologic abnormalities are associated with spontaneous abortion.

Modifications in the technique of gastric lavage.

A simple experimental model was used to demonstrate the effects of water temperature and mechanical agitation in removing pills during gastric lavage. It was nearly impossible to remove pills from an artificial stomach using room temperature water and no mechanical agitation, Using warm tap water and repetitive compressions of the artificial stomach, the pills were consistently removed with ease. We recommend that gastric lavage for poisoning victims include two phases, the first using traditional lavage technique, and the second using larger aliquots, warm lavage fluid, and massage of the epigastrium.