[Interstitial pneumonia and venlafaxine use]. / Interstitiële pneumonie bij venlafaxine-gebruik.

We describe a 71-year-old woman who developed interstitial pneumonia within a complex somatic state. Diagnostic clearance suggested venlafaxine-induced interstitial pneumonia. In the literature, we found 13 cases of venlafaxine-induced interstitial pneumonia. Case reports were also described for other antidepressants. Based on these case reports, there is consensus in the literature that antidepressants may in rare cases give rise to (sub)acute or chronic interstitial pneumonia. Although a rare side effect, it seems important to be aware of this as a psychiatrist.

Physiological responses in female rescuers during 30 minutes sustained CPR with feedback: a comparison between medicine and physical education students.

OBJECTIVES: Since fatigue seems related to poorer physical fitness rather than to gender, we analyzed the physiological responses in female medicine and physical education students during a 30 minutes sustained cardiopulmonary resuscitation (CPR) sequence. METHODS: Handgrip strength and maximal aerobic power (V02 max) determined strength and endurance. Twenty-three medicine (M) and 27 physical education (PE) female students performed 30 minutes CPR. Compression quality and ECG were continuously monitored, heart rate and non-invasive blood pressure (NIBP) every 2 minutes. Capillary pH, PcCO2, lactate, potassium and sodium bicarbonate were analyzed every 10 minutes. RESULTS: Handgrip strength (PE 37 kg vs. M 35 kg; p<0.05) and V02 max (PE 50 ml/kg/min vs. M 44 ml/ kg/min; p<0.05) revealed a better strength and endurance in PE students. Six medicine and 1 PE student did not complete the entire 30 minutes of CPR. Percentage compressions >5 cm was comparable in both groups (PE 80%; M 79%; p=0.67). Mean heart rate during CPR was higher in the M group (148 bpm) compared to the PE group (132 bpm; p<0.05). No intergroup differences in NIBP, pH, PcCO2, potassium and sodium bicarbonate were observed. Mean lactate during CPR was higher in the M group: 3.5 mmol/l (SD 1.4) compared to the PE group: 2.5 mmol/I (SD 0.7) (p<0.05). CONCLUSION: A high quality sustained CPR effort was well tolerated by all female rescuers. Poorer physical condition (M group) resulted in more drop out after 10 and 20 minutes and in a higher heart rate and blood lactate over time. Improving physical condition may result in less physiological strain and lower perceived exertion.

Acute external ear lesions: clinical aspects, assessment and management.

Acute external ear lesions: clinical aspects, assessment and management. We reviewed the literature concerning the assessment and the management of the external ear traumas, which is not very rich. Nevertheless, we outlined the practical attitudes in the four major conditions met: the auricular haematoma, the auricular perichondritis, the auricular laceration and auricular bums. All these pathologies must be promptly treated because there is a risk of perichondritis, which can destroy the cartilage and will result in a severely deformed ear. Auricular haematomas must be drained as soon as possible, lacerations with exposed cartilage must be stitched urgently, and burnt ears should be washed, coated with alginates (Flaminal@) and covered with a loose dressing. Antibioprophyl- axy should always be prescribed after a complete microbiological sampling.

Cervical atypical glandular cells and false negative HPV testing: a dramatic reality of the wrong test at the right place.

BACKGROUND: Due to cervical cancer screening the number of squamous cancer have declined. The number of adenocarcinomas (ADCs) does appear to be rising. ADCs are often missed and human papillomavirus (HPV) testing could be helpful in detecting these abnormalities earlier. CASE: A 36-year-old woman, who had a normal smear three years earlier, had a pap smear with atypical glandular cells. The L1 HPV test showed that there was no HPV infection. Other HPV tests which looked at E6 and E7 showed an infection with HPV 16. Due to unknown reasons, no action was taken regarding the atypical glandular cells. Two years later the patient was diagnosed with a FIGO Stage IVb ADC of the cervix. The L1 HPV test was still negative and the E6/E7 HPV test was still positive. Despite several multiple treatment modalities she succumbed of her disease two years later leaving behind a young family. CONCLUSION: HPV test looking only at L1 can give false negative results if the virus is integrated in the human genome.

Clinical validation of a type-specific real-time quantitative human papillomavirus PCR against the performance of hybrid capture 2 for the purpose of cervical cancer screening.

To be acceptable for use in cervical cancer screening, a new assay that detects DNA of high-risk human papillomavirus (hrHPV) types must demonstrate high reproducibility and performance not inferior to that of a clinically validated HPV test. In the present study, a real-time quantitative PCR (qPCR) assay targeting the E6 and E7 genes of hrHPV was compared with Hybrid Capture 2 (hc2) in a Belgian cervical cancer screening setting. In women >30 years old, the sensitivity and specificity for intraepithelial neoplasias of grade 2 or worse (93 cases of cervical intraepithelial neoplasias of grade 2 or worse (CIN2+) and 1,207 cases of no CIN or CIN1) were 93.6% and 95.6%, respectively, and those of hc2 were 83.9% and 94.5%, respectively {relative sensitivity of qPCR/hc2 = 1.12 [95% confidence interval (CI), 1.01 to 1.23]; relative specificity = 1.01 [95% CI, 0.99 to 1.03]}. A score test showed that the sensitivity (P < 0.0001) and specificity (P < 0.0001) of the qPCR assay were not inferior to those of hc2 at the required thresholds of 90% and 98%, respectively. The overall agreement of hrHPV positivity between the two runs of the qPCR tests was 98.7% (95% CI, 97.5 to 99.4%), with a kappa value of 0.96 (95% CI, 0.83 to 1.00). The qPCR assay used in this study can be considered a reliable HPV assay that fulfills the clinical validation criteria defined for use in cervical cancer screening.

Late-onset Pompe disease (LOPD) in Belgium: clinical characteristics and outcome measures.

BACKGROUND: Late-onset Pompe disease (LOPD) is a rare, hereditary, progressive disorder that is usually characterized by limb-girdle muscle weakness and/or respiratory insufficiency. LOPD is caused by mutations in the acid alpha-glucosidase (GAA) gene and treated with enzyme replacement therapy (ERT). METHODS: We studied the clinical, brain imaging, and genetic features of the Belgian cohort of late-onset Pompe disease patients (N = 52), and explored the sensitivity of different outcome measures, during a longitudinal period of 7 years (2010-2017), including the activity limitations ActivLim score, 6 min walking distance (6MWD), 10 m walk test (10MWT), MRC sum score, and forced vital capacity (FVC) sitting/supine. RESULTS: In Belgium, we calculated an LOPD prevalence of 3.9 per million. Mean age at onset of 52 LOPD patients was 28.9 years (SD: 15.8 y), ranging from 7 months to 68 years. Seventy-five percent (N = 39) of the patients initially presented with limb-girdle weakness, whereas in 13% (N = 7) respiratory symptoms were the only initial symptom. Non-invasive ventilation (NIV) was started in 37% (N = 19), at a mean age of 49.5 years (SD: 11.9 y), with a mean duration of 15 years (SD: 10.2 y) after symptom onset. Brain imaging revealed abnormalities in 25% (N = 8) of the patients, with the presence of small cerebral aneurysm(s) in two patients and a vertebrobasilar dolichoectasia in another two. Mean diagnostic delay was 12.9 years. All patients were compound heterozygotes with the most prevalent mutation being c.-32-13 T > G in 96%. We identified two novel mutations in GAA: c.1610_1611delA and c.186dup11. For the 6MWD, MRC sum score, FVC sitting and FVC supine, we measured a significant decrease over time (p = 0.0002, p = 0.0001, p = 0.0077, p = 0.0151), which was not revealed with the ActivLim score and 10MWT (p > 0.05). CONCLUSIONS: Awareness on LOPD should even be further increased because of the long diagnostic delay. The 6MWD, but not the ActivLim score, is a sensitive outcome measure to follow up LOPD patients.

Time has come to include Human Papillomavirus (HPV) testing in sperm donor banks.

HPV is well known as a potential cause of cervical cancer. Less well known is its link to temporal subfertility that is caused by binding of infectious virions to the spermatozoa's head which induces sperm-DNA damage and causes a reduction in clinical pregnancy rates in women receiving HPV positive semen. This impact on the global fertility burden remains greatly underestimated and underexplored. This risk of reduced fertility due to infectious HPV in sperm is especially important when donor sperm insemination is considered, since testing for the presence of HPV virions before use seems warranted. We tested 514 donor sperm samples from 3 different sperm banks for 18 different HPV types. Overall 3.9% (20/514) of tested donor sperm was positive for HPV, with different prevalence among the 3 different sperm banks (3.6% bank A, 3.1% bank B and 16.7% bank C). Also the HPV virion per spermatozoon ratio in donor samples was similar across the different sperm banks (95% CI 0,01 to 1,07 HPV virions/spermatozoon). When HPV positive donor sperm was used, no clinical pregnancies resulted, whereas when HPV negative donor sperm was used the clinical pregnancy rate was 14.6%. From both a cost/benefit and a safety point of view we recommend that donor sperm should always be tested for HPV before using it for insemination.

Correlation between laminin-5 immunohistochemistry and human papillomavirus status in squamous cervical carcinoma.

BACKGROUND: Human papillomavirus (HPV) plays a critical role in the carcinogenesis of squamous cervical carcinoma. Integration of viral DNA into the host genome is a major contributing factor to malignant transformation. Viral load may influence integration. AIMS: To compare HPV status (type, viral load, integration status) between normal samples, carcinoma in situ and invasive carcinoma in order to elucidate the role of HPV in progression to invasive lesions. METHODS: The study population comprised 10 biopsy samples from each diagnostic group. Laminin-5 immunohistochemistry was performed to distinguish invasive carcinoma from non-invasive high-grade lesions. Real-time PCR was used to detect specific HPV types, viral load and integrated HPV, with quantification of viral E2 and E6 genes. RESULTS: Invasive carcinomas contained a higher number of laminin-5 immunoreactive cells as compared to non-invasive lesions. Almost all samples contained HPV, with a higher viral load and copy number of HPV16 integrated in E2 in cases of laminin-5 immunoreactivity and cases of invasive carcinoma. High HPV16 viral load was associated with more integrated copies in E2. CONCLUSIONS: HPV is important in progression from carcinoma in situ to invasive carcinoma. Viral load and HPV integration influence the development of cervical cancer towards invasiveness. Overall HPV status may be more predictive of patient outcome and may influence patient management.

Human Papillomavirus (HPV) virion induced cancer and subfertility, two sides of the same coin.

In the natural history of HPV infections, the HPV virions can induce two different pathways, namely the infec- tious virion producing pathway and the clonal transforming pathway. An overview is given of the burden that is associated with HPV infections that can both lead to cervical cancer and/or temporal subfertility. That HPV infections cause serious global health burden due to HPV-associated cancers is common knowledge, but that it is also responsible for a substantial part of idiopathic subfertility is greatly underestimated. The bulk of the detected HPV DNA whether in men or women is however infectious from origin. Because the dissociation between HPV viruses and HPV virions or infection and disease remains difficult for clinicians as well as for HPV detection, we propose a review of the different effects caused by the two different HPV virion induced pathways, and highlight the mechanisms that are responsible for causing transient subfertility and cancer.

Ki-67 immunocytochemistry in liquid based cervical cytology: useful as an adjunctive tool?

AIMS: To test the ability of Ki-67 to detect cytological lesions in a screening setting and its use as a surrogate marker of human papillomavirus (HPV) infection. METHODS: A study of liquid based cytology, HPV DNA testing by MY09/MY11 consensus polymerase chain reaction (PCR), type specific PCRs, and Ki-67 immunocytochemistry on a randomly selected series of 147 patients. RESULTS: Comparison of the number of Ki-67 immunoreactive cells/1000 cells in the different cytological groups showed that the HSIL group yielded a significantly higher mean count than did the other groups. The number of Ki-67 immunoreactive cells/1000 cells was significantly higher in HPV-16 positive samples than in samples containing infections with other high risk types. Receiver operating characteristic curves indicated a test accuracy (area under curve) of 0.68, 0.72, and 0.86 for atypical squamous cells of undetermined significance (ASCUS), low grade squamous intraepithelial lesions (LSIL), and high grade squamous intraepithelial lesions (HSIL), respectively. Thresholds for 95% sensitivity were 0.07, 0.08, and 0.15 Ki-67 immunopositive cells/1000 cells for ASCUS, LSIL and HSIL, respectively. The threshold for 95% specificity was 1.9 Ki-67 immunopositive cells/1000 cells. CONCLUSIONS: Ki-67 immunocytochemistry can be applied to liquid based cytology. The accuracy and diagnostic indices of the test are good when compared with those of other techniques. As part of a panel of screening procedures, it could be used as an adjunct to liquid based cytology to identify HSIL, and as a surrogate marker of HPV-16 infection.

The effects of combined conventional treatment, oral antioxidants and essential fatty acids on sperm biology in subfertile men.

We evaluated the effects of combined conventional treatment, oral antioxidants (N-acetyl-cysteine or vitamins A plus E) and essential fatty acids (FA) on sperm biology in an open prospective study including 27 infertile men. The evaluation included sperm characteristics, seminal reactive oxygen species (ROS), FA of sperm membrane phospholipids, sperm oxidized DNA (8-OH-dG), and induced acrosome reaction (AR). Treatment did not improve sperm motility and morphology, nor decrease the concentration of round cells and white blood cells in semen. Sperm concentration increased in oligozoospermic men (7.4+/-1.3 to 12.5+/-1.9 million/ml). Treatment significantly reduced ROS (mean+/-SEM) (775.3+/-372.2 to 150.3+/-105.2 x 10(3)counts/10 second) and 8-OH-dG (45.3+/-10.4 to 16. 8+/-3.3 fmol/microg DNA). Treatment increased the AR (55.1+/-2.2 to 71.6+/-2.2%), the proportion of polyunsaturated FA of the phospholipids, and sperm membrane fluidity. The overall pregnancy rate was 4.5% in 134 months. The per month pregnancy rate tended to be higher in partners of (ex)-smokers (7.15%, n=14,70 months) than in never-smokers (1.6%, n=13,64 months) (OR:4.57, 95% Cl:0.55-38.1).

Levels of hepatocyte growth factor/scatter factor (HGF/SF) in seminal plasma of patients with andrological diseases.

Hepatocyte growth factor/scatter factor (HGF/SF) has all the characteristics of a molecule suitable for functioning in regulatory networks of motility, such as the spermatogenic epithelium, where spermatogenic cells must migrate between the cells of Sertoli, and it exerts its effect through binding of its high-affinity receptor (c-met). Considering the findings that c-met receptor is expressed in the human testis and on spermatozoa, and that HGF/SF in seminal plasma consists of pro-HGF/SF, mature alphabeta-HGF/SF, and less active forms of HGF/SF, we investigated the concentration and biological activity of HGF/SF in seminal plasma and their correlation with parameters of spermatogenesis to obtain better insight into mechanisms that may be involved in the pathogenesis of male infertility. We also evaluated the potential value of assessment of hepatocyte growth factor concentration and its bioactivity for the diagnosis of certain pathological conditions of male reproduction. We studied the concentration and biological activity of HGF/SF in seminal plasma of normal men and of patients with a range of andrological diseases or conditions by measuring HGF/SF in seminal plasma by enzyme-linked immunosorbent assay and by scatter assay using Madin-Darby canine kidney epithelial cells. We identified three sources of HGF/SF in seminal plasma. In samples from vasectomized men (n = 30; 2.01 ng/ml) and in split ejaculate samples (n = 6; 1e fraction 2.75 ng/ml, 2e fraction 1.62 ng/ml), a prostatic origin can be certified. This HGF/SF has low biological activity (133.3 U/ml). In inflammation of the accessory sex glands (n = 40), a high amount of HGF/SF (3.04 ng/ml) can be generated by white blood cells and has moderate scatter activity (426.7 U/ml). In normozoospermic samples, there is a lower amount of HGF/SF (1.12 ng/ml), with strong scatter activity (1280.0 U/ml). Finally, the clear difference between the low amount of HGF/SF (1.06 ng/ml) with poor scatter activity (106.6 U/ml) in oligozoospermic samples (n = 28) and the high amount of HGF/SF (3.35 ng/ml) with strong scatter activity (853.3 U/ml) in samples from men with azoospermia of primary testicular failure (n = 18) suggests a mainly testicular origin, with different activity in different pathological conditions.

Hormonal regulation of inhibin B secretion by immature rat sertoli cells in vitro: possible use as a bioassay for estrogen detection.

The influences of follicle-stimulating hormone (FSH), gonadal steroids, and culture time were studied in relation to inhibin B production by Sertoli cells of immature rats cultured in vitro. Sertoli cell-enriched cultures were established from 18-day-old rats and were maintained in medium supplemented with insulin, transferrin, and epidermal growth factor at 34 degrees C. A recently developed ELISA for the measurement of inhibin B was used to assess the effects of recombinant human FSH (rh FSH), testosterone (T), and estradiol (E2) on inhibin B production and accumulation in the culture media of Sertoli cell-enriched cultures and to optimize the cell culture system to serve as a bioassay for the detection and quantification of estrogens and estrogenlike substances. Prolonging the incubation time (24, 48, or 72 hours) of Sertoli cells with control medium without rh FSH, T, or E2 resulted in a time-dependent increase of inhibin B production. Incubation with rh FSH (1, 2.5, 5, or 10 U/L) caused a dose- and time-dependent increase of inhibin B production by Sertoli cells (but not by cultured Leydig cells), reaching a plateau at 5 U/L rh FSH. Addition of T in concentrations of 2.88, 5, or 50 ng/ml to medium without rh FSH and E2 significantly lowered the daily production rate of inhibin B (P < 0.05). In contrast, addition of E2 (0.01 and 0.1 ng/ml) caused a dose-responsive increase in inhibin B production after 24 and 48 hours. The relative increment of inhibin B production induced by E2 was maximal after 24 hours in the presence of 2.5 U/L rh FSH (acting synergistically) and in the absence of T. When these conditions are implemented, the Sertoli cell culture system may serve as a bioassay for estrogenic substances, and it may reflect the possibly harmful effect they may have on spermatogenesis.

The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection.

The presence of various cytokines, namely hepatocyte growth factor (HGF), interleukin-1 receptor antagonist (IL-1 RA), and interleukins (IL-1 alpha, IL-6, and IL-8), as well as the production of reactive oxygen species (ROS) was investigated in seminal plasma of fertile and infertile patients in order to evaluate the possible value of measuring these substances for the diagnosis of male accessory gland infection, and to assess the possible relationship between oxidative stress and cytokines during leucocytospermia and male accessory gland infection (MAGI). Our findings indicate that all of the measured cytokines seem to be produced locally as well as by white blood cells (WBC) and that, due to the presence of higher numbers of WBC, accessory gland infection may exert a deleterious effect on sperm quality through the production of ROS and/or of particular cytokines such as IL-1 alpha, IL-1 RA, and IL-8. The most specific marker for a sensitivity of 95% in discriminating between cases with or without MAGI is the measurement of IL-6 in seminal plasma. In the absence of WBC several cytokines are constitutively produced and correlate with sperm concentration (HGF, IL-8), alpha-glucosidase (IL-6), and gamma-glutamyltransferase activity (HGF). The measurement of these cytokines in semen may provide clinically useful information for the diagnosis of male accessory gland infection, as well as in the absence of WBC where it can provide information about certain mechanisms of male reproductive function and dysfunction.

The clinical and biologic significance of serum inhibins in subfertile men.

Inhibin B is a marker of spermatogenesis and Sertoli cell function. The objective of this study was to evaluate the biologic significance of inhibins in subfertile men and the usefulness of inhibin B for the detection of male reproductive dysfunction. Forty-seven subfertile men were evaluated by semen analysis and clinical examination. In addition to semen analysis and hormone determinations, inhibins A and B (Serotec) in all 47 and inhibin A in 25 of these samples using another kit (Biosource) were measured. Higher inhibin B (median, range: 160.3, 81.8-328.5 pg/mL vs. 94.9, 15.6-389.7 pg/mL, P = 0.024) and lower FSH (P = 0.001) were detected in men with sperm concentrations > or =20 million/mL (n = 9), compared to oligozoospermia (sperm concentration <20 million/mL, n = 38). Inhibin B correlated significantly negatively with FSH, LH, and E2, and patient's age and positively with sperm concentration, testicular volume, and TSH. Multiple regression analysis indicated FSH, LH, E2, TSH, and age as the independent variables for inhibin B with a coefficient of determination (R) of 0.53. Simultaneous measurement of both FSH and inhibin B identified more cases with oligozoospermia than either hormone alone. Taking into account the body mass index, the age of the patient, and the indirect mixed antiglobin reaction (MAR) test result in addition to FSH and inhibin B led to the correct semen classification in 45 out of 47 cases. The simultaneous measurement of FSH and inhibin B, taking into account age, body mass index, and the indirect MAR test result appears accurate in identifying subfertility. Inhibin A is detectable in some subfertile men but its significance is not clear.

[A strategy for the prevention of male infertility]. / Een strategie voor de preventie van mannelijke infertiliteit.

Since 1990 there has been a simultaneous reduction of natality in Flanders (by approximately 12%) with increased demand for assisted reproduction, while sperm quality, mostly motility and morphology, have clearly deteriorated over recent decades. This evolution has been ascribed to the deleterious effects of hormone disrupting substances in the environment, synergistically enhancing unfavorable influences from life style and possible genito urinary diseases that can impair the function of the testes and accessory sex glands. It is probable that this synergistic effect is exerted through the intermediate of free oxygen radicals (also called reactive oxygen species) that damage both the sperm membrane and sperm DNA, which could allow certain minimal inborn genetic defects (such as point lesions) to come to expression. Both pseudo- or xeno-estrogens (such as certain organo chlorides, alkyl phenols, phthalates, etc.) and anti-androgens are held responsible for prenatal testicular damage and increased prevalence of testicular carcinoma and oligozoospermia, for anatomical malformations, as well as postnatal depression of testicular function and spermatogenesis. However, methods presently available to detect hormone disrupters are tedious and not fully adequate. A first strategic goal is to develop a simple method for the detection of these substances so that environmental pollution can be mapped. Fazing out the production and application of hormone disrupters, and removing them from the environment are the second strategic step. Also, a health food is being developed that will inhibit the absorption of these chemicals from the intestinal tract. In addition it is projected to detect and treat common genital diseases that can cause infertility, such as varicocele and infection of the urinary tract and accessory sex glands. The first could be organized to take place during medical examinations at school, whereas the second requires correct medical treatment of any cysto urethritis in adolescents. Non surgical treatment of varicocele by means of transcatheter embolization offers a cost effective approach, with minimal risk and complications, and high level of efficacy. Improving food quality and educational efforts aimed at a healthier life style should score high priority. The suggested strategy uses several entries in order to address the multifactorial mechanisms involved in the pathogenesis of male infertility. Preliminary epidemiological and biological data suggest that the proposed strategy can, indeed, be successful within a relatively short lapse of time.

MedCalc: a new computer program for medical statistics.

In recent years, the use and abuse of statistics in the medical literature has extensively been reviewed. Amongst others, the importance of the P-value has been challenged and the use of misleading graphics, including 3-dimensional displays, has been criticized. The ease of access to more complex statistical procedures, since the introduction of several statistical software packages for personal computers, has been identified as one of the factors involved in the misuse of statistics. Therefore, we have developed a new computer program that includes those statistical procedures commonly encountered in the medical literature and in statistical textbooks for medical researchers. More complex statistical analyses are not implemented in the software. If researchers with limited statistical training require more sophisticated statistical analyses, they should refer to a statistician, not to a more complete statistical software package.

Cervical cancer screening: which HPV test should be used--L1 or E6/E7?

Cervical cancer can and should be a historical disease. The reality, however, is that every year more than half a million women are diagnosed with cervical cancer and a quarter of a million die of this disease. The causal factor for cervical cancer is a persistent HPV infection and therefore a vaccine was developed: prophylactic HPV vaccination will reduce cervical cancer by 70%. Screening based on cytology will miss more than 40% of the abnormalities. The introduction of vaccination should lead to the reintroduction of cervical cancer screening based on HPV detection. Primary HPV screening followed by cytology will detect almost all abnormalities. Not all HPV tests, however, are the same! Clinicians are generally not aware that there is a huge difference among HPV tests. If a low grade lesion progresses to a high grade or invasive cancer, their HPV is likely to integrate. During integration L1 expression can be lost, but E6/E7 expression will always remain present. If the viral HPV is completely integrated then a L1 test looking for only L1 expression will miss this (pre)cancer, while the E6/E7 test will not miss it. HPV tests used in cervical cancer screening should be based on the early (E) and the late (L) genes in order not to miss the abnormality.