[Repurposing of chlorpromazine in COVID-19 treatment: the reCoVery study]. / Repositionnement de la chlorpromazine dans le traitement du COVID-19 : étude reCoVery.

OBJECTIVES: The ongoing COVID-19 pandemic comprises a total of more than 2,350,000 cases and 160,000 deaths. The interest in anti-coronavirus drug development has been limited so far and effective methods to prevent or treat coronavirus infections in humans are still lacking. Urgent action is needed to fight this fatal coronavirus infection by reducing the number of infected people along with the infection contagiousness and severity. Since the beginning of the COVID-19 outbreak several weeks ago, we observe in GHU PARIS Psychiatrie & Neurosciences (Sainte-Anne hospital, Paris, France) a lower prevalence of symptomatic and severe forms of COVID-19 infections in psychiatric patients (∼4%) compared to health care professionals (∼14%). Similar observations have been noted in other psychiatric units in France and abroad. Our hypothesis is that psychiatric patients could be protected from severe forms of COVID-19 by their psychotropic treatments. Chlorpromazine (CPZ) is a phenothiazine derivative widely used in clinical routine in the treatment of acute and chronic psychoses. This first antipsychotic medication has been discovered in 1952 by Jean Delay and Pierre Deniker at Sainte-Anne hospital. In addition, to its antipsychotic effects, several in vitro studies have also demonstrated a CPZ antiviral activity via the inhibition of clathrin-mediated endocytosis. Recently, independent studies revealed that CPZ is an anti-MERS-CoV and an anti-SARS-CoV-1 drug. In comparison to other antiviral drugs, the main advantages of CPZ lie in its biodistribution: (i) preclinical and clinical studies have reported a high CPZ concentration in the lungs (20-200 times higher than in plasma), which is critical because of the respiratory tropism of SARS-CoV-2; (ii) CPZ is highly concentrated in saliva (30-100 times higher than in plasma) and could therefore reduce the contagiousness of COVID-19; (iii) CPZ can cross the blood-brain barrier and could therefore prevent the neurological forms of COVID-19. METHODS: Our hypothesis is that CPZ could decrease the unfavorable evolution of COVID-19 infection in oxygen-requiring patients without the need for intensive care, but also reduce the contagiousness of SARS-CoV-2. At this end, we designed a pilot, phase III, multicenter, single blind, randomized controlled clinical trial. Efficacy of CPZ will be assessed according to clinical, biological and radiological criteria. The main objective is to demonstrate a shorter time to response (TTR) to treatment in the CPZ+standard-of-care (CPZ+SOC) group, compared to the SOC group. Response to treatment is defined by a reduction of at least one level of severity on the WHO-Ordinal Scale for Clinical Improvement (WHO-OSCI). The secondary objectives are to demonstrate in the CPZ+SOC group, compared to the SOC group: (A) superior clinical improvement; (B) a greater decrease in the biological markers of viral attack by SARS-CoV-2 (PCR, viral load); (C) a greater decrease in inflammatory markers (e.g. CRP and lymphopenia); (D) a greater decrease in parenchymal involvement (chest CT) on the seventh day post-randomization; (E) to define the optimal dosage of CPZ and its tolerance; (F) to evaluate the biological parameters of response to treatment, in particular the involvement of inflammatory cytokines. Patient recruitment along with the main and secondary objectives are in line with WHO 2020 COVID-19 guidelines. CONCLUSION: This repositioning of CPZ as an anti-SARS-CoV-2 drug offers an alternative and rapid strategy to alleviate the virus propagation and the infection severity and lethality. This CPZ repositioning strategy also avoids numerous developmental and experimental steps and can save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easy to manage side effects. Indeed, CPZ is an FDA-approved drug with an excellent tolerance profile, prescribed for around 70 years in psychiatry but also in clinical routine in nausea and vomiting of pregnancy, in advanced cancer and also to treat headaches in various neurological conditions. The broad spectrum of CPZ treatment - including antipsychotic, anxiolytic, antiemetic, antiviral, immunomodulatory effects along with inhibition of clathrin-mediated endocytosis and modulation of blood-brain barrier - is in line with the historical French commercial name for CPZ, i.e. LARGACTIL, chosen as a reference to its "LARGe ACTion" properties. The discovery of those CPZ properties, as for many other molecules in psychiatry, is both the result of serendipity and careful clinical observations. Using this approach, the field of mental illness could provide innovative therapeutic approaches to fight SARS-CoV-2.

Repurposing chlorpromazine to treat COVID-19: The reCoVery study.

OBJECTIVES: The ongoing COVID-19 pandemic has caused approximately 2,350,000 infections worldwide and killed more than 160,000 individuals. In Sainte-Anne Hospital (GHU PARIS Psychiatrie & Neuroscience, Paris, France) we have observed a lower incidence of symptomatic forms of COVID-19 among patients than among our clinical staff. This observation led us to hypothesize that psychotropic drugs could have a prophylactic action against SARS-CoV-2 and protect patients from the symptomatic and virulent forms of this infection, since several of these psychotropic drugs have documented antiviral properties. Chlorpromazine (CPZ), a phenothiazine derivative, is also known for its antiviral activity via the inhibition of clathrin-mediated endocytosis. Recentin vitro studies have reported that CPZ exhibits anti-MERS-CoV and anti-SARS-CoV-1 activity. METHODS: In this context, the ReCoVery study aims to repurpose CPZ, a molecule with an excellent tolerance profile and a very high biodistribution in the saliva, lungs and brain. We hypothesize that CPZ could reduce the unfavorable course of COVID-19 infection among patients requiring respiratory support without the need for ICU care, and that it could also reduce the contagiousness of SARS-CoV-2. For this purpose, we plan a pilot, multicenter, randomized, single blind, controlled, phase III therapeutic trial (standard treatment vs. CPZ+standard treatment). CONCLUSION: This repurposing of CPZ for its anti-SARS-CoV-2 activity could offer an alternative, rapid strategy to alleviate infection severity. This repurposing strategy also avoids numerous developmental and experimental steps, and could save precious time to rapidly establish an anti-COVID-19 therapy with well-known, limited and easily managed side effects.

Micro-fragmented fat injection reduces sepsis-induced acute inflammatory response in a mouse model.

BACKGROUND: Severe sepsis has a high mortality rate. There is increasing evidence that human mesenchymal stem cells possess immunomodulatory properties in sepsis, particularly those from adipose tissue. We hypothesised that micro-fragmented human fat, obtained with minimal alteration of the stromal vascular niche, attenuates the inflammatory response and improves outcome in a murine model of sepsis. METHODS: Micro-fragmented fat, lipoaspirate, or saline was administered intraperitoneally 2 h after caecal ligation and puncture (CLP) in C57Bl/6RJ ketamine-xylazine anaesthetised mice. The primary endpoint was the inflammatory score. Secondary endpoints included survival, physiological, histological, and biological parameters. RESULTS: In CLP mice, micro-fragmented fat administration significantly decreased the median (range) inflammatory score compared with saline [17 (14-20) vs 9 (8-12), P=0.006]. Secondary endpoints were also significantly improved in micro-fragmented fat-treated compared with saline-treated CLP mice. Improvement in inflammatory score and in survival was suppressed when micro-fragmented fat was co-administered with liposomes loaded with clodronate (macrophage toxin) or NS-398 (cyclo-oxygenase 2 inhibitor), but not with SC-560 (cyclo-oxygenase 1 inhibitor). CONCLUSIONS: In a murine model of severe sepsis, micro-fragmented fat improved early inflammatory status and outcome, at least in part, by a cyclo-oxygenase-2-mediated mechanism. The potential therapeutic value of micro-fragmented fat in severe sepsis warrants further investigation.

Mismatch negativity to predict subsequent awakening in deeply sedated critically ill patients.

BACKGROUND: Mismatch negativity (MMN) is the neurophysiological correlate of cognitive integration of novel stimuli. Although MMN is a well-established predictor of awakening in non-sedated comatose patients, its prognostic value in deeply sedated critically ill patients remains unknown. The aim of this prospective, observational pilot study was to investigate the prognostic value of MMN for subsequent awakening in deeply sedated critically ill patients. METHODS: MMN was recorded in 43 deeply sedated critically ill patients on Day 3 of ICU admission using a classical 'odd-ball' paradigm that delivers rare deviant sounds in a train of frequent standard sounds. Individual visual analyses and a group level analysis of recordings were performed. MMN amplitudes were then analysed according to the neurological status (awake vs not awake) at Day 28. RESULTS: Median (inter-quartile range) Richmond Assessment Sedation Scale (RASS) at the time of recording was -5 (range, from -5 to -4.5). Visual detection of MMN revealed a poor inter-rater agreement [kappa=0.17, 95% confidence interval (0.07-0.26)]. On Day 28, 30 (70%) patients had regained consciousness while 13 (30%) had not. Quantitative group level analysis revealed a significantly greater MMN amplitude for patients who awakened compared with those who had not [mean (standard deviation) = -0.65 (1.4) vs 0.08 (0.17) µV, respectively; P=0.003). CONCLUSIONS: MMN can be observed in deeply sedated critically ill patients and could help predict subsequent awakening. However, visual analysis alone is unreliable and should be systematically completed with individual level statistics.

Cryopreserved Stem Cells Incur Damages Due To Terrestrial Cosmic Rays Impairing Their Integrity Upon Long-Term Storage.

Stem cells have the capacity to ensure the renewal of tissues and organs. They could be used in the future for a wide range of therapeutic purposes and are preserved at liquid nitrogen temperature to prevent any chemical or biological activity up to several decades before their use. We show that the cryogenized cells accumulate damages coming from natural radiations, potentially inducing DNA double-strand breaks (DSBs). Such DNA damage in stem cells could lead to either mortality of the cells upon thawing or a mutation diminishing the therapeutic potential of the treatment. Many studies show how stem cells react to different levels of radiation; the effect of terrestrial cosmic rays being key, it is thus also important to investigate the effect of the natural radiation on the cryopreserved stem cell behavior over time. Our study showed that the cryostored stem cells totally shielded from cosmic rays had less DSBs upon long-term storage. This could have important implications on the long-term cryostorage strategy and quality control of different cell banks.

Jean Talairach (1911-2007). An untold story of the pioneer of stereotactic and functional neurosurgery.

CONTEXT: The Department of neurosurgery of the Sainte-Anne Hospital hosted Jean Talairach who created and developed stereotactic neurosurgery in France. Despite numerous neurosurgical and neuroscientific achievements, little is known about the life of Jean Talairach. METHODS: Systematic screening of Sainte-Anne Hospital Museum, Henry Ey Library, and Bibliothèque Inter-Universitaire de Santé funds, and medical databases using the term "Jean Talairach". RESULTS: Jean Talairach started his medical career at the Sainte-Anne Hospital in 1942 as a psychiatrist and became a neurosurgeon due to his interest in stereotactic neurosurgery. During World War II, Jean Talairach joined the French Resistance in Paris, then the French First Army. Jean Talairach created an original and specific stereotactic methodology with appropriate stereotactic frame and tools and performed one of the first human stereotactic surgeries in 1948. He described the reference lines passing by the anterior and posterior commissures in 1952 and developed a tridimensional co-planar stereotactic atlas of the human brain. With the collaboration of Jean Bancaud, he created stereo-electroencephalography to investigate patients suffering from drug-resistant epilepsy. The "Sainte-Anne school" trained French and foreign stereotactic and functional neurosurgeons ensuring the spread of Jean Talairach's innovative ideas. Jean Talairach retired in 1980. CONCLUSION: Jean Talairach's achievements encapsulate the evolution of neurosurgery in France during the 20th century. He developed an original stereotactic methodology including a tridimensional stereotactic atlas of the human brain and a stereotactic frame. He created stereo-electroencephalography, which remains the gold-standard to investigate patients suffering from drug-resistant epilepsy.

Symptomatic progestin-associated atypical grade II meningioma. A first case report.

BACKGROUND: Long-term use of high-dose progestin is known to promote the development of meningioma. Atypical meningioma in a patient under progestin has not previously been reported. CASE REPORT: A 53-year-old right-handed woman presented with focal onset seizures, without impaired consciousness. Medical history featured endometriosis, treated successively by cyproterone acetate 25mg/day for 2 months then 50mg/day for 101 months, and chlormadinone acetate 5mg/day for 68 months then 10mg/day for 83 months. Brain MRI revealed multiple extra-axial lesions suggestive of left central meningioma associated with anterior skull base meningiomatosis. Surgical resection of the left central meningioma was achieved and progestin was withdrawn. Neuropathology diagnosed grade II atypical meningioma. Close clinical and imaging monitoring was implemented without adjuvant oncological treatment. At 25 months, imaging follow-up showed no recurrence of the left central meningioma and a significant regression of all other lesions, except for the right frontal lesion. CONCLUSIONS: Neurosurgeons should be aware of the possible aggressiveness of meningioma in patients under progestin, and particularly those treated by different types of progestin over a long period of time without interruption. This may require systematic close monitoring, to adapt neurosurgical management.

Bone mass and microarchitecture of irradiated and bone marrow-transplanted mice: influences of the donor strain.

UNLABELLED: Total body irradiation and bone marrow transplantation induced dramatic trabecular bone loss and cortical thickening in mice. Transplanted cells were engrafted in bone marrow, along trabeculae, and in periosteal and endosteal envelopes. None of the osteocytes were of donor origin. Bone microarchitecture of transplanted mice changed to tend toward the donor phenotype. INTRODUCTION: Osteopenia and osteoporosis are complications of bone marrow transplants (BMT) attributed to related chemotherapy. However, the specific influence of total body irradiation (TBI) is unknown. METHODS: We investigated the effects of TBI and BMT on bone mass and microarchitecture by micro-CT. Eighteen C57Bl/6 (B6) mice receiving lethal TBI had a BMT with marrow cells from green fluorescent protein--transgenic-C57Bl/6 (GFP) mice. Transplanted (T(GFP)B6), B6, and GFP mice were euthanized 1, 3, and 6 months after BMT or at a related age. RESULTS: T(GFP)B6 presented a dramatic bone loss compared with B6 and did not restore their trabecular bone mass over time, despite a cortical thickening 6 months after BMT. Serum testosterone levels were not significantly reduced after BMT. During aging, GFP mice have less trabeculae, thicker cortices, but a narrower femoral shaft than B6 mice. From 3 months after BMT, cortical characteristics of T(GFP)B6 mice differed statistically from B6 mice and were identical to those of GFP mice. GFP(+) cells were located along trabecular surfaces and in periosteal and endosteal envelopes, but none of the osteocytes expressed GFP. CONCLUSION: Our findings suggest that engrafted cells did not restore the irradiation-induced trabecular bone loss, but reconstituted a marrow microenvironment and bone remodeling similar to those of the donor. The effects of irradiation and graft on bone remodeling differed between cortical and trabecular bone.

[Intracranial ependymomas in adult patients. Diagnosis and histological prognostic factors]. / Ependymomes intracrâniens de l'adulte. Diagnostic histologique et facteurs histopronostiques.

BACKGROUND: Intracranial ependymomas are rare in adults and histopathological prognostic factors are poorly determined. PURPOSE: A retrospective multicentric study was conducted in France in order to assess the prognostic value of histology. MATERIAL: Between 1990 and 2004, 216 adult patients with newly diagnosed ependymomas were treated in 19 French centers. Eligibility required institutional histopathological confirmation of an ependymoma and available clinical history and MRI features (see comparison paper). METHODS: Histological preparations and one paraffin embedded block from each patient were sent to Pr D. Figarella-Branger in Marseille. Central review by four neuropathologists (D. Figarella-Branger, A. Maues de Paula, C. Fernandez and A. Jouvet) was performed. Specimens for which all pathologists agreed with the histological diagnosis of ependymomas were included, whereas cases for which all disagree were excluded and reclassified. In the event of doubt and/or discrepancies between pathologists immunostaining was performed in order to reach a consensus diagnosis. Diagnostic of ependymomas was confirmed in 121 cases (56%). In theses cases, ependymomas were classified according to the WHO system (subtype and grade). The potential prognostic value (overall survival OS and disease free survival DFS) of the following histological parameters was examined: perivascular pseudorosettes, ependymal rosettes, hyalinized vessels, mitotic index, microvascular proliferation, necrosis, area of increased cellularity, nuclear atypia, brain invasion and Mib-1 labelling index. RESULTS: Among the 121 ependymomas, 88 were grade II (47 classic, 17 cellular, 2 papillar, 6 clear cells and 16 tanicytic) and 33 grade III. WHO grading, occurrence of microvascular proliferation, necrosis, nuclear atypia and high proliferative index were correlated with both OS and DFS. Moreover, quantification of certain parameters enabled a reproducible grading system correlated with both OS and DFS.

Sepsis induces long-term metabolic and mitochondrial muscle stem cell dysfunction amenable by mesenchymal stem cell therapy.

Sepsis, or systemic inflammatory response syndrome, is the major cause of critical illness resulting in admission to intensive care units. Sepsis is caused by severe infection and is associated with mortality in 60% of cases. Morbidity due to sepsis is complicated by neuromyopathy, and patients face long-term disability due to muscle weakness, energetic dysfunction, proteolysis and muscle wasting. These processes are triggered by pro-inflammatory cytokines and metabolic imbalances and are aggravated by malnutrition and drugs. Skeletal muscle regeneration depends on stem (satellite) cells. Herein we show that mitochondrial and metabolic alterations underlie the sepsis-induced long-term impairment of satellite cells and lead to inefficient muscle regeneration. Engrafting mesenchymal stem cells improves the septic status by decreasing cytokine levels, restoring mitochondrial and metabolic function in satellite cells, and improving muscle strength. These findings indicate that sepsis affects quiescent muscle stem cells and that mesenchymal stem cells might act as a preventive therapeutic approach for sepsis-related morbidity.

Neuronal apoptosis in Creutzfeldt-Jakob disease.

Neuronal loss is a salient feature of prion diseases; however, its causes and mechanisms are unclear The possibility that it could occur through an apoptotic process has been postulated and is consistent with the lack of inflammation in prion disorders as supported by experimental studies. In order to test this hypothesis in humans, we examined samples of frontal and temporal cerebral cortex, striatum, thalamus, and cerebellum from 16 patients who died from Creutzfeldt-Jakob disease. They included 5 sporadic cases, 5 familial, 3 iatrogenic, and 3 cases with the new variant. These were compared with age and sex matched controls. Using in situ end labelling, we identified apoptotic neurons in all the cases of Creutzfeldt-Jakob disease. A single labelled neuron was found in the eldest control. Apoptotic neurons were mostly found in damaged regions and their presence and abundance seemed to correlate closely with neuronal loss. This supports the view that apoptosis of neurons is a feature of prion diseases and may contribute to the neuronal loss which is one of the main characteristics of these conditions. Neuronal apoptosis also correlated well with microglial activation, as demonstrated by the expression of major histocompatibility complex class II antigens, and axonal damage, as identified by beta-amyloid protein precursor immunostaining. In contrast, we found no obvious relationship between the topography and severity of neuronal apoptosis and the type, topography, and abundance of prion protein deposits as demonstrated by immunocytochemistry.

Neuronal apoptosis in fatal familial insomnia.

The possibility that neuronal loss in prion diseases occurs through an apoptotic process has been postulated and is consistent with the lack of inflammation in these disorders. In order to test this hypothesis in FFI, in which neuronal loss is the predominant neuropathological feature, we examined samples of thalamus, basal ganglia, cerebral cortex, cerebellum and medulla from 10 subjects with FFI. All the patients had the characteristic 178 N mutation of the PrP gene. Eight subjects were homozygous methionine/methionine at codon 129 and 2 were heterozygous methionine/valine. Apoptotic neurons were identified by in situ end labelling in all the FFI cases and in none of the controls. They were mostly found in damaged regions and their presence and abundance seemed to correlate closely with the neuronal loss. They were particularly abundant in the thalamus and medullary olives. In heterozygous cases who had a longer disease duration and more widespread cerebral changes, apoptotic neurons were also found in the neocortex and striatum. The abundance of apoptotic neurons also correlated well with microglial activation as demonstrated by the expression of major histocompatibility complex class II antigens. PrPres immunostaining was almost invariably negative, consistent with previous data showing the lack of obvious correlation between neuronal loss and PrPres deposits in prion diseases.

Neuropathology of early HIV-1 infection.

Early HIV-1 invasion of the central nervous system has been demonstrated by many cerebrospinal fluid studies; however, most HIV-1 carriers remain neurologically unimpaired during the so called "asymptomatic" period lasting from seroconversion to symptomatic AIDS. Therefore, neuropathological studies in the early pre-AIDS stages are very few, and the natural history of central nervous system changes in HIV-1 infection remains poorly understood. Examination of brains of asymptomatic HIV-1 positive individuals who died accidentally and of rare cases with acute fatal encephalopathy revealing HIV infection, and comparison with experimental simian immunodeficiency virus and feline immunodeficiency virus infections suggest that, invasion of the CNS by HIV-1 occurs at the time of primary infection and induces an immunological process in the central nervous system. This includes an inflammatory T-cell reaction with vasculitis and leptomeningitis, and immune activation of brain parenchyma with increased number of microglial cells, upregulation of major histocompatibility complex class II antigens and local production of cytokines. Myelin pallor and gliosis of the white matter are usually found and are likely to be the consequence of opening of the blood brain barrier due to vasculitis; direct damage to oligodendrocytes by cytokines may also interfere. These white matter changes may explain, at least partly, the early cerebral atrophy observed, by magnetic resonance imaging, in asymptomatic HIV-1 carriers. In contrast, cortical damage seems to be a late event in the course of HIV-1 infection. There is no significant neuronal loss at the early stages of the disease, no accompanying increase in glial fibrillary acid protein staining in the cortex, and only exceptional neuronal apoptosis. Although HIV-1 proviral DNA may be demonstrated in a number of brains, viral replication remains very low during the asymptomatic stage of HIV-1 infection. This makes it likely that, although opening of the blood brain barrier may facilitate viral entry into the brain, specific immune responses including both neutralising antibodies and cytotoxic T-lymphocytes, continuously inhibits viral replication at that stage.

Neuropathy in diffuse infiltrative lymphocytosis syndrome: an HIV neuropathy, not a lymphoma.

OBJECTIVE: To determine whether CD8 lymphoid infiltrates in nerves of patients with HIV-associated diffuse infiltrative lymphocytosis syndrome (DILS) corresponds to a lymphomatous neoplastic process or to a proliferation of T cells reactional to HIV. BACKGROUND: DILS is characterized by persistent CD8 hyperlymphocytosis and multivisceral CD8 T-cell infiltration, which may affect peripheral nerves. METHODS: Presence of monoclonal T cells and HIV-1 proviral load were evaluated by polymerase chain reaction (PCR) techniques in frozen peripheral nerve samples from six patients with DILS neuropathy and 22 patients with other HIV-associated peripheral neuropathies, including mononeuritis multiplex (MM:6), inflammatory demyelinating polyneuropathies (IDP:6), distal sensory polyneuropathy (DSP:5), and toxic distal sensory polyneuropathy (TDSP:5). RESULTS: Five of six patients with DILS showed no detectable monoclonal T-cell clones in their nerves. Nerve proviral load in DILS (6.8 +/- 0.2 log/10(5) cells) was much higher than in MM (p < 0.008), IDP (p < 0.001), DSP (p < 0.001), and TDSP (p < 0.005). CONCLUSIONS: DILS neuropathy represents a separate entity among HIV-associated neuropathies. It is associated with massive HIV proviral load in nerve and must not be confused with a peripheral nerve T-cell lymphoma.

Effect of nomegestrol acetate on spinability, ferning and mesh dimension of midcycle cervical mucus.

A study was carried out in order to determine the impact of Nomegestrol acetate on the human cervix and to evaluate the ability of changes induced in cervical mucus to render the cervical canal hostile to spermatozoa at midcycle. Under the influence of Nom Ac, loss of spinability, absence of ferning pattern and drastic tightening of the glycoprotein meshwork rendered midcycle mucus very similar to that elaborated during physiological states under total progesterone dominance. The results obtained in this study gave clear evidence that Nomegestrol acetate may provide cervical blocking thereby preventing sperm transport to the uterine cavity.

PIP: The effect of the oral progestin nomegestrol acetate on spinnbarkeit, ferning and mesh size of midcycle cervical mucus was examined. This 19-norprogestin inhibits ovulation and LH surges, and binds to uterine cytosol progesterone receptors. It is 17-alpha-acetoxy-6-methyl-19-nor-4,6-pregnadiene-3,20-dione, or Lutenyl (Laboratories Theramex, Monaco). Nomegestrol was given to 16 normally cycling volunteers at 2.5 or 5 mg/day for 3 consecutive cycles. Spinnbarkeit was determined automatically with 10 mcl mucus with a spinability-meter (Filancemetre SEFAM), or manually between tweezers if too thick to measure. Cervical mucus was scant, to dry, and related to dose. Spinnbarkeit ranged from absent to 3 mm at 5 mg, and from 11-28 on the meter, compared to 90mm in controls at midcycle. Ferning by standard methods was nonexistent with amorphous structure at 2.5 and 5 mg doses, compared to the usual dendrites and arborization at midcycle in controls. When the mucus was observed by scanning electron microscopy, it resembled that seen at the end of pregnancy or menopause. Mesh size averaged 0.5 mcm at both doses, smaller than the diameter of sperm heads. Nomegestrol acetate is currently used to treat luteal deficiency.

Experimental study of cervical blockage induced by continuous low-dose oral progestogens.

An investigation correlating scanning electron microscopic observations with sperm penetration tests carried out on cervical mucus under the influence of low-dose continuous progestogen (Norgestrienone) is presented. The results demonstrate that such type of contraceptive is involved in drastic alterations of mid-cycle cervical mucus at the macromolecular level. The meshwork which constitutes the infrastructure of the cervical secretion appears to be greatly tightened as a result of the treatment, thus giving the woof a general appearance typical of cervical mucus in the late luteal phase. The immobilizing effect of such modified mucus on spermatozoa is demonstrated and the duration of effectiveness after the administration of a last pill on the morning of day 13 is determined.

PIP: The antifertility and obstructive effects toward spermatozoa of a continuous low-dose progestogen contraceptive are examined in this study. Scanning electron microscopy (SEM) observations were correlated with sperm penetration tests carried out on cervical mucus. 11 healthy women aged 19 to 36 who were using no oral contraceptives were studied for 2 consecutive cycles. During the 2nd cycle, the women took a single, daily low-dose progestogen pill (350 ug of Norgestrienone) from the 1st till the 13th day. Blood samples were collected for determination of plasma estrogen levels, which were found to be normal during the control cycle. The progestogen was found to dramatically alter midcycle cervical mucus at the macromolecular level. The meshwork constituting the infrastructure of cervical secretion appeared to be greatly tightened by the treatment, giving the woof a general appearance typical of cervical mucus in the late luteal phase. The mucus framework revealed a tangle of micelles, and sperms leaving the seminal pool in the vagina were faced with such a succession of exhausting physical obstacles that they were unable to penetrate the uterine cavity. The SEM data shows that rendering the midcycle cervical mucus hostile interferes with sperm transport and this probably accounts for the effectiveness of the continuous low-dose progestogen therapy.