Rapid seroconversion and persistent functional IgG antibodies in severe COVID-19 patients correlates with an IL-12p70 and IL-33 signature.

Despite ongoing efforts to characterize the host response toward SARS-CoV-2, a major gap in our knowledge still exists regarding the magnitude and duration of the humoral response. Analysis of the antibody response in mild versus moderate/severe patients, using our new developed quantitative electrochemiluminescent assay for detecting IgM/IgA/IgG antibodies toward SARS-CoV-2 antigens, revealed a rapid onset of IgG/IgA antibodies, specifically in moderate/severe patients. IgM antibodies against the viral receptor binding domain, but not against nucleocapsid protein, were detected at early stages of the disease. Furthermore, we observed a marked reduction in IgM/IgA antibodies over-time. Adapting our assay for ACE2 binding-competition, demonstrated that the presence of potentially neutralizing antibodies is corelated with IgG/IgA. Finally, analysis of the cytokine profile in COVID-19 patients revealed unique correlation of an IL-12p70/IL33 and IgG seroconversion, which correlated with disease severity. In summary, our comprehensive analysis has major implications on the understanding and monitoring of SARS-CoV-2 infections.

Improving the quality of the intensive care follow-up of ventilated patients during a national registration program.

OBJECTIVES: The Belgian Public Health Organization is concerned with rates of hospital-acquired infections like ventilator-associated pneumonia (VAP). Implementing best practice guidelines for these nosocomial infections has variable success in the literature. This retrospective study was undertaken to see whether implementation of the evidence-based practices as a bundle was feasible, would influence compliance, and could reduce the rates of VAP. STUDY DESIGN: We utilized easily collectable data about regular care to rapidly assess whether interventions already in place were effectively successfully applied. This avoided cumbersome data collection and review. METHODS: Retrospective compliance rates and VAP ratios were compared using z tests with P-values < 0.05 considered statistically significant. This data review attempted to examine the impact of education campaigns, staff meetings, in-services, physician checklist, nurse checklist, charge nurse checklist implementation, systematic VAP bundle application, and systematic protocols for oral care and sedation protocols. Additionally, VAP ratio could be registered by the participating centers. RESULTS: A total of 10,211 intensive care unit (ICU) patients were included in the study which represents 66,817 ICU days under artificial ventilation with an endotracheal tube. The general compliance for VAP bundle raised from VAP was 61% in February 2012 and 74.16% in December 2012 (P < 0.001). The incidence rate of VAP went from 8.34 occurrences/1000 vent days in 2009 to 4.78 occurrences/1000 vent days in 2012 (P < 0.001-Pearson test). CONCLUSIONS: Efforts to improve physician and staff education, and checklist implementation resulted in an increase in compliance for VAP bundle and a decrease in VAP ratio. This study confirms the applicability of best practice guidelines about regular care but results on VAP incidence have to be confirmed.

Severe ASIA syndrome associated with lymph node, thoracic, and pulmonary silicone infiltration following breast implant rupture: experience with four cases.

Silicone has been considered biologically inert; thus it has been employed in many medical devices and nowadays is commonly used in plastic surgery for mammary prosthesis. It is well tolerated in most cases. However, autoimmune disorders and siliconomas with granulomatous reactions after silicone implant rupture have been described. We report cases of four women who developed systemic disorders following rupture of silicone breast implants resulting in lymph node and thoracic silicone infiltration. The symptoms in these cases, including arthralgia, myalgia, generalized weakness, severe fatigue, sleeping disturbances, cognitive impairment, memory loss, irritable bowel syndrome, and weight loss, clearly match the criteria of the recently defined autoimmune/inflammatory syndrome induced by adjuvants (ASIA).

The changing face of internal medicine: patient centred care.

Patient centred care is now considered the gold standard and there should be 'no decision about me, without me'. Internists who treat patients with complex multi-morbidities should consider patients' preferred outcomes, following a 'goal-oriented' principle. Perhaps the most important barrier to goal-oriented care is that medicine is deeply rooted in a disease-outcome-based paradigm. Rather than asking what patients want, the culture of modern medicine has prioritised optimal disease management according to guidelines and population goals. Doing what is right for the patient should be based on trust. Patients and internists must therefore meet as equals: 'I' and 'you' should be replaced by 'we'.

Dipeptidyl peptidase-4 inhibitors and their effects on the cardiovascular system.

It is well known that patients with type 2 diabetes mellitus (T2DM) are at increased risk of cardiovascular (CV) disease. Elevated plasma glucose levels that independently lead to increased cardiovascular risk, combined with associated co-morbidities such as obesity, hypertension, and dyslipidemia, further contribute to the development of CV complications. Dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors) are a relatively new class of drugs used for the treatment of diabetes and recently have been widely used in clinical practice. They exert their actions through degradation inhibition of endogenous glucagon-like peptides (GLP-1) and glucose-dependent insulinotropic peptides (GIP), with a resulting increase in glucose mediated insulin secretion and a suppression of glucagon secretion. Since GLP-1 is known to have an impact not only on plasma glucose levels but also to have cardiovascular protective effects there is increased speculation of whether DPP-4 inhibitors will have similar effects. Though many short-term studies have been encouraging, ongoing long-term clinical trials on humans are needed to provide further clarity to the complete safety profiles of these agents in terms of cardiovascular risk, and whether they may exert potential cardiovascular benefit. This review includes available data on the cardiovascular effects of DPP-4 inhibitors as well as their overall safety profile.

Does treatment of hypertension decrease the incidence of atrial fibrillation and cardioembolic stroke?

Hypertension is the most common disease affecting humans. Statistical surveys indicate that approximately one billion individuals worldwide suffer from this serious condition. The spotlight of the present review is on the cardiac involvement in patients with hypertension and especially on the possibility that treatment of increased blood pressure may abolish the incidence of cardiac arrhythmia and particularly atrial fibrillation. Modern therapeutic approach based on the electrical and structural remodeling process in the hypertensive heart with a consequent administration of ACE inhibitors and AT1 receptor blockers represent new and more efficient option compared to other antihypertensive drugs, such as calcium channel blockers, beta-blockers and thiazide-type diuretics and might be useful in the prevention of atrial fibrillation and incidence of stroke.

Emergency hysteroscopic treatment of acute severe uterine bleeding.

The aim of this pilot feasibility study was to investigate the efficacy and safety of hysteroscopy in the diagnosis and treatment of acute severe uterine bleeding. Forty-one women (mean age, 54 years) who underwent emergency hysteroscopy were assessed. In 40 women, a benign organic cause was found. In one postmenopausal patient, endometrial carcinoma was detected in endometrial chips and was managed with hysterectomy. None of the women with benign lesions required further surgery within the first postoperative year. One underwent hysterectomy at 18 months for new-onset fibromyomas. Hysteroscopy was found to be an effective tool for treating heavy uterine bleeding. It also prevented future episodes of severe bleeding in more than half the patients during 20 months of follow-up.

The Ashkelon Hypertension Detection and Control Program (AHDC Program): a community approach to reducing cardiovascular mortality.

BACKGROUND: Blood pressure (BP) reduction is crucial in reducing cardiovascular (CV) morbidity and mortality in the community. Subjects aged 20-65 seldom visit the primary care clinics, so they are unlikely to be detected without an active outreach screening program. The aim of the project was to prepare a professional doctor-nurse screening team, who will instruct those found to be at high risk in control of their risk factors, in order to reduce CV morbidity and mortality. METHODS: During a 10-year period (1980-1990), teams examined 12,202 subjects, (mean age 51 +/- 7 years, range 20-65 years) accounting for 23.4% of the total regional population. High risk subjects underwent an intensive CV risk factor control program. RESULTS: Subjects (3,506 or 28.6%) were found to have one or more CV risk factors (hypertension, obesity, smoking, hypercholesterolemia). During an average of 2 years, follow-up BP, weight reduction, and smoking cessation remained statistically significant. Total cholesterol was unchanged. Over this period, the standardized mortality ratio (SMR) in the area for acute MI fell from 100 to 76 (P < 0.01), for CV disease from 129 to 107 (P < 0.0001), and for hypertension from 121 to 87 (P < 0.1 NS). The project saved many life-years at no additional net cost to society, and cost effectiveness analysis showed positive results. CONCLUSIONS: A community approach with mainly nonpharmacological treatment is feasible and cost effective in reducing CV morbidity and mortality.

Risk factor profile and achievement of treatment goals among hypertensive patients from the Israeli Blood Pressure Control (IBPC) program--initial cost utility analysis.

AIMS: Blood pressure (BP) reduction is crucial in reducing cardiovascular morbidity and mortality. The IBPC (Israeli Blood Pressure Control) program was initiated in order to enhance the control of modifiable risk factors among high-risk hypertensive patients under follow-up by general practitioners in Israel. The cost effectiveness of an intervention program is an important factor in the decision-making process of its implementation and therefore was evaluated here. The objective of this evaluation is to estimate the costs, monetary savings and benefits in terms of QALYs (quality-adjusted life years) that would be expected if the program were to be expanded to 100 clinics nationwide, enabling around 14800 persons to be treated. METHODS: Hypertensive patients were screened in 30 general practice clinics, supervised by specialists in family medicine, each seeing 1000-5000 patients; 50-250 hypertensive patients were diagnosed at each participating clinic. BP levels, body mass index (BMI), lipid and glucose levels, as well as target organ damage and medications were recorded for all patients. RESULTS: A total of 4948 (2079, 42% males) were registered. Mean age was 64.8 +/- 12 years. After 1 year of follow-up versus baseline, the various parameters were as follows: BP control was achieved in 46.4% vs 29% of all hypertensive patients. LDL control (JNC VI criteria) was achieved in 41.7% vs 31.2% of all patients. Fasting plasma glucose control (glucose < 126 mg/dl) was achieved in 22% vs 19% of diabetic patients and 5.2% vs 3.1% of the diabetics had fasting plasma glucose levels > 200 mg/dl. Obesity (BMI > 30 kg/m2) was noted in 36.7% vs 43.8% at baseline. The cost utility analysis of the reduction in risk factors was calculated based on the international dicta applied to the reduction in risk factors as a result of treatment. For 100 clinics nationwide and 14800 persons to be treated the net saving to health services would be $977993 and the increase in QALYs would be 602 years. CONCLUSIONS: Better risk factor control in hypertensive patients by general practitioners could reduce morbidity and mortality as well as be cost effective.

Subtorsion of the ovary: sonographic features and clinical management.

OBJECTIVE: To define the sonographic imaging criteria of ovarian subtorsion. METHODS: Fourteen women 16 to 35 years of age with suspected unilateral twisted ovaries were sonographically evaluated in a tertiary care center before laparoscopy. Transvaginal sonography was performed to determine the longest ovarian dimension, diameter of the periovarian vessels, and degree of intraovarian blood flow and to evaluate ovarian morphology. Laparoscopy was performed to verify the sonographic findings and to perform detorsion. RESULTS: All ovaries with subtorsion were of normal size, although still significantly longer than the contralateral, normal ovaries (47.5 and 29.6 mm, respectively; P = .001). The mean diameter of the periovarian vessels was significantly greater for the ovaries with subtorsion than the normal ovaries (29.9 and 19.2 mm, respectively; P= .0001). At laparoscopy, the ovary was twisted less than 180 degrees in 9 patients and 180 degrees to 360 degrees in 5. The degree of twisting correlated significantly with the size of the ovary (P = .016) and diameter of the periovarian vessels (P = .046). The 3-month sonographic follow-up after detorsion revealed bilateral normal ovarian dimensions with proper follicular growth. CONCLUSIONS: Congestion of the periovarian vessels with normal ovarian morphology and persistent blood flow on sonography, combined with the presence of appropriate clinical signs, may be indicative of ovarian subtorsion.

Influence of hormone replacement therapy on postmenopausal pelvic organs.

OBJECTIVE: To assess the influence of hormone replacement therapy (HRT) on the pelvic organs of postmenopausal women by vaginal ultrasonography. DESIGN: The study (case-control) included 753 consecutive, postmenopausal women who were referred for routine transvaginal ultrasound examination. A total of 290 women who were using HRT at the time of examination (study group) were compared with 463 who were not treated (control group). RESULTS: The women using HRT were younger and had been menopausal for a shorter period, compared with those who had not been treated. Mean uterine volume, endometrial thickness and ovarian area were all increased in the HRT group, compared to the control group. A negative correlation was found between menopausal age and uterine volume, and ovarian area in both treated and untreated groups. However, endometrial thickness was negatively correlated with menopausal age in the untreated group only. After controlling for various parameters, a multivariate logistic analysis demonstrated that endometrial thickness was treatment status-dependent only. Uterine volume was also treatment status-dependent, but was also negatively correlated with menopausal age. As expected, the endometrium was thicker and the uterine volume was larger in the treated group. Ovarian area was not found to be treatment-dependent for all menopausal ages. CONCLUSIONS: Postmenopausal women treated with HRT have a larger uterus and thicker endometrium than those of non-treated matched controls. There is a negative correlation between menopausal age and uterine and ovarian size. Endometrial thickness was found to be negatively correlated with menopausal age in only the untreated group, and is almost entirely HRT-dependent. In contrast to the uterus and the endometrium, the ovaries are not influenced by HRT.

Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic signaling.

The Fas/tumor necrosis factor (TNF)/TRAIL receptors signal death through a cytoplasmic death domain (DD) containing six alpha-helices with positively charged helix 2 interacting with negatively charged helix 3 of another DD. DD mutation occurs in head/neck and lung cancer (TRAIL receptor KILLER/DR5) and in lpr mice (Fas). We examined the apoptotic potential of known KILLER/DR5 lung tumor-derived mutants (n = 6) and DD mutants (n = 18) generated based on conservation with DR4, Fas, Fas-associated death domain (FADD), and tumor necrosis factor receptor 1 (TNFR1). With the exception of Arg-330 required in Fas or FADD for aggregation or for TNFR1 cytotoxicity, surprisingly major loss-of-function KILLER/DR5 alleles (W325A, L334A (lpr-like), I339A, and W360A) contained hydrophobic residues. Loss-of-function of I339A (highly conserved) has not been reported in DDs. Charged residue mutagenesis revealed the following points. 1) E326A, conserved in DR4, is dispensable for death; the homologous residue is positively charged in Fas, TNFR1, and FADD and is critical for DD interactions. 2) K331A, D336A, E338A, K340A, K343A, and D351A have partial loss-of-function suggesting multiple charges stabilize receptor-adapter interactions. Analysis of the tumor-derived KILLER/DR5 mutants revealed the following. 1) L334F has partial loss-of-function versus L334A, whereas E338K has major loss-of-function versus E338A, examples where alanine and tumor-specific substitutions have divergent phenotypes. 2) Unexpectedly, S324F, E326K, K386N, and D407Y have no loss-of-function with tumor-specific or alanine substitutions. Loss-of-function KILLER/DR5 mutants were deficient in recruitment of FADD and caspase 8 to TRAIL death-inducing signaling complexes. The results reveal determinants within KILLER/DR5 for death signaling and drug design.

Enhanced TRAIL sensitivity by p53 overexpression in human cancer but not normal cell lines.

The cytotoxic ligand TRAIL is a promising anti-cancer agent that is entering into clinical trials. We previously identified a major subgroup of TRAIL resistant cancer cell lines with absent, or reduced DR4 expression containing a K441R polymorphism or harboring elevated levels of the caspase activation inhibitor FLIP. In the present study, we explored the use of a gene therapeutic approach utilizing p53, delivered by an adenovirus-p53 (Ad-p53) vector, which directly controls expression of the TRAIL receptor KILLER/DR5 in a panel of 8 cell lines including normal and TRAIL sensitive or resistant cancers. The functional status of the delivered p53 was monitored by detection of induced p21WAF1 expression by immunocytochemistry. In normal cells, which are TRAIL resistant, TRAIL did not reduce cell viability over and above the effect of Ad-p53 alone. All cancer cell lines were sensitive to Ad-p53 and up-regulated expression of the TRAIL receptor KILLER/DR5. TRAIL-resistant cancer cells became more sensitive to TRAIL at low Ad-p53 multiplicities of infection but TRAIL resistance was not completely overcome in one TRAIL-resistant cell line probably because of a high level of expression of FLIP. The results reveal that Ad-p53 induces the TRAIL receptor KILLER/DR5 and, like radiation or chemotherapy may effectively reverse TRAIL resistance.

Treatment of the twisted cystic ovary with normal blood flow by simple aspiration.

Simple aspiration was performed in eight patients to correct torsion of cystic ovaries with normal blood flow, imaged by the colour Doppler technique. Abdominal pain resolved spontaneously following aspiration. Symptoms recurred in three patients, necessitating detorsion by laparoscopy. Normal follicular growth was assessed within 3 months in the non-pregnant patients.

Spectrum of normal intrauterine cavity sonographic findings after first-trimester abortion.

OBJECTIVE: To characterize the sonographic appearance of the uterine cavity after uncomplicated first-trimester abortion. METHODS: Women who underwent uterine evacuation for first-trimester abortion were referred for endovaginal sonographic examination within the week after the procedure. Special attention was directed to characterizing the intrauterine cavity. Demographic and clinical parameters were collected. A repeated postmenstrual examination was carried out in selected cases. RESULTS: In all, 57, 10, and 7 sonographic examinations were performed after termination of pregnancy, incomplete (spontaneous) abortion, and missed abortion, respectively. Fifty-seven (77%) of the 74 examinations showed considerable amounts of intrauterine content with various echogenicities (anteroposterior thickness range, 7-61 mm). No association could be documented between the pattern of appearance and gravidity, parity, gestational age, or type of abortion procedure. All postmenstrual reevaluations of patients with excessive amounts of intrauterine material at the initial examination (n = 7) showed empty intrauterine cavities. CONCLUSION: Within the week after first-trimester abortion, the uterine cavity is seldom empty. Thick heterogeneous material is an expected finding after examination. By being familiar with this normal range of appearances, clinicians can avoid unnecessary repeated invasive evacuation procedures. A follow-up sonographic evaluation during the follicular phase of the next menstrual cycle is recommended to confirm the absence of retained products of pregnancy.

The caspase 9 inhibitor Z-LEHD-FMK protects human liver cells while permitting death of cancer cells exposed to tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis of transformed and cancer cells but not of most normal cells. Recent studies have revealed an unforeseen toxicity of TRAIL toward normal human hepatocytes, thereby bringing into question the safety of systemic administration of TRAIL in humans with cancer. We found that SW480 colon adenocarcinoma, or H460 non-small cell lung cancer cell lines, which are sensitive to TRAIL, were not protected by the caspase 9 inhibitor Z-LEHD-FMK from TRAIL-induced apoptosis. However, a human colon cancer cell line HCT116 and a human embryonic kidney cell line 293, which are sensitive to TRAIL, were protected by Z-LEHD-FMK from TRAIL-mediated death. Both HCT116 and SW480 cells were protected from TRAIL by the caspase 8 inhibitor Z-IETD-FMK, dominant-negative FADD and cellular FLIP-s and interestingly both cell lines displayed caspase 9 cleavage to a similar extent after TRAIL exposure. We confirmed that normal human liver cells are sensitive to TRAIL. Moreover, we found that normal human liver cells could be protected from TRAIL-induced apoptosis by simultaneous exposure to Z-LEHD-FMK. A similar brief exposure to TRAIL plus Z-LEHD-FMK inhibited colony growth of SW480 but not HCT116 cells. Because some cancer cell lines are not protected from TRAIL-mediated killing by Z-LEHD-FMK, we believe that a brief period of caspase 9 inhibition during TRAIL administration may widen the therapeutic window and allow cancer cell killing while protecting normal liver cells. This strategy could be further developed in the effort to advance TRAIL into clinical trials.

Bax is a transcriptional target and mediator of c-myc-induced apoptosis.

The c-Myc oncoprotein is a transcription factor involved in cellular transformation as well as apoptotic cell death. We show here that over-expression of c-Myc delivered by an adenovirus vector up-regulates endogenous proapoptotic bax mRNA and protein expression in human cells. In contrast, the cytotoxic tumor necrosis factor-related apoptosis-inducing ligand induces cell death without up-regulating bax expression. c-Myc/Max heterodimers bind to canonical E-box elements located in the bax promoter region as demonstrated by electrophoretic mobility shift analysis and DNaseI foot-printing assays. Analysis of bax regulatory region mutants suggests a model involving myc-dependent activation as well as relief of repression through distinct E-box elements. c-Myc-null cells are deficient in bax-promoter activation as compared with wild-type c-Myc-expressing cells. Overexpression of c-Myc in serum-starved human or mouse embryonic cells leads to apoptosis which is significantly reduced in the presence of growth factor-containing serum. c-Myc-induced apoptosis appears to be deficient in bax-null as compared with bax-wild-type mouse embryonic fibroblasts. The results suggest that the cell death-promoting gene bax is directly downstream of c-Myc in a pathway leading to apoptosis.

Natural-cycle in vitro fertilization in women aged over 44 years.

Women who are 44 years of age or more are usually denied infertility treatment because of their low response to ovarian stimulation and the extremely low pregnancy rate that can be achieved. The object of this study was to assess the place of natural-cycle in vitro fertilization (IVF) in this population. From January 1996 to September 1997, all consecutive women aged 44-47 years who approached our unit seeking infertility treatment with their own oocytes were enrolled in the study. After a counselling session in which the advantage of egg donation was discussed, women who still wished to try to conceive by utilizing their own oocytes were treated according to the following protocol. Ultrasound and hormonal surveillance was carried out starting 5 days prior to the presumed ovulation day, based on previous menstrual history. Ovum pick-up was timed either by detection of the luteinizing hormone surge or by human chorionic gonadotropin administration. In total, 48 treatment cycles were conducted in 20 women. Oocyte retrieval was successful in 22 cycles. Fertilization and cleavage rates of 48% and 100%, respectively, were detected. Nine of the 12 embryos transferred were defined as grade A. One chemical and one ongoing pregnancy were achieved. We conclude that, despite the fact that high-quality embryos can be obtained in this population, the likelihood of pregnancy is low.